What are the mechanisms of disabling extrinsic control of heart?

What are the mechanisms of disabling extrinsic control of heart?

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I started this thread by thinking this question but I developed it further below

What is the mechanism maintaining refractory period of pacemakers?

My conjecture is that the mechanism is the simultaneous depolarisation of at least SA node and AV node. I am not convinced yet about the Purkinje fibers' participation.

Bigger question from this is:

How do pacemakers work under threshold without action potential? There are continually leaking Funny channels (Na+) in pacemakers. There has to be chemical changes intrinsic changes

  • change in the permeability of Funny channels or
  • active pumping of Na+ out OR pumping something negative inside the cell (probably Cl-, not sure) and

extrinsic changes

  • reflex arch blocking the action potential of pacemakers when enough preceeding sensitisation of AV node
    • I have no evidence for that this kind of sensitisation would happen in SA node or in Purkinje fibers.

which all seem to be working together in firing recovery mechanism through AV node without specific SA node stimulation. Example logic tree for a myocardial infarction patient of 68 years old:

  • R wave of atrial fibrillation and flutter
  • extrinsic stimulus to start sensitisation of AV node
  • intrinsic sensitisation of AV node
  • extrinsic stimulus through reflex arch
  • systole and upper-systole of AV node starting
  • lower-systole of AV node
    • intersection of upper- and lower-systoles
  • unstable end of lower-systole
  • unstable systole
  • extrinsic firing simultaneous SA and AV node (similar extrinsic regulation as in the beginning of this logic tree)
  • prolonged and stable refractory period and long compensatory pause

It is debated whether the pathophysiology of IST and POTS results from abnormal autonomic regulation or abnormal sinus node function.

My conjectures based on my logic tree

  • Pathophysiology of IST results from normal extrinsic (recovery) mechanism of autonomic regulation which body uses to recover from abnormal stimuli (etc atrial fibrillation and flutter)
  • Pathophysiology of POTS results from abnormal extrinsic mechanism of autonomic regulation when there is no stimuli after abnormal stimuli

What is causing the abnormal autonomic mechanism in POTS? I would say that IST precedes POTS. Prolonged IST seems to be going to POTS. Physical explanation is that the body cannot last regular IST so it goes to POTS, since losing its normal extrinsic regulation. What is this (apparently cumulative, not necessarily long-term) trigger of disabling the extrinsic autonomic regulation of the heart?


Vasoconstriction is the narrowing or even closing of the lumen of a vein, artery, or arteriole as a result of smooth muscle cell constriction in the blood vessel wall. By reducing the diameter of a blood vessel, circulating blood must move through a smaller area under higher pressures. Vasoconstriction is regulated by the autonomic nervous system.

What is Intrinsic Pathway

Intrinsic pathway refers to multiple cascades of protein interactions activated by a trauma inside the blood vessels. It is also activated by platelets, exposed endothelium, or collagen. Generally, intrinsic pathway takes time to form a blood clot. The proteins involved in the formation of the blood clot are known as clotting factors. They are designated by I-XIII. The activation mechanism of these factors is known as the clotting cascade. The clotting factors involved in the intrinsic pathway are factors VIII, IX, XI, and XII. The clotting factors involved in both intrinsic and extrinsic pathways are shown in figure 1.

Figure 1: Clotting Factors

The intrinsic pathway is activated by the binding of factor XII to a negatively-charged foreign surface that is exposed to blood. This sequentially activates factors IX, X, and XI, further activating the factor II that converts prothrombin to thrombin. Thrombin converts fibrinogen to fibrin. Platelets are trapped inside a fibrin mesh, forming a blood clot.

The accelerans, or sympathetic nerves, carry nerve impulses from the medulla oblongata in the brain to the heart. The heart responds by increasing both the rate of contraction and the strength of the contractions. Exercise is one way that this pathway is activated, and can increase your heart rate to up to 180 beats per minute. This will increase the amount of blood pumped by the heart and sent out to exercising muscles.

When you exercise, your cells use up more oxygen and more carbon dioxide is produced. The increased concentration of carbon dioxide is recorded by special receptors in the aorta and carotid arteries, and this information is passed to the medulla oblongata. Another effect of exercise is that the muscle pump works harder. The muscle pump is the contraction of muscles surrounding your veins, which pushes blood back to the heart. The harder the muscle pump works, the more blood gets sent to the right atrium of the heart. As the atrium stretches to accommodate the extra blood, the stretch receptors in the heart muscle relay the information to the medulla oblongata. These two sources of information will cause the activation of the pathway that will increase your heart rate, thus relieving the full atrium and moving excess carbon dioxide to the lungs for expulsion from the body.

Reflex and Central Mechanisms involved in the Control of the Heart and Circulation

Macrophage polarization refers to how macrophages have been activated at a given point in space and time. Polarization is not fixed, as macrophages are sufficiently plastic to integrate multiple signals, such as those from microbes, damaged tissues, and . Read More

Figure 1: Developmental regulation of macrophages from monocytes. (a) Three outcomes can follow the seeding of tissues or inflammatory sites by monocytes: death, stable residency, and intermingling wi.

Figure 2: Timeline of research on macrophage polarization. Not all primary papers are cited herein due to space constraints. The selection of key findings and advances represents the author's interpre.

Figure 3: Extrinsic and intrinsic factors control macrophage polarization. (a) M2 macrophages and (b) M1 macrophages are shown with some of the factors linked to their development. It should be noted .

Figure 4: TNF is a major anti-M2 factor. Exposure of macrophages to TNF blocks M2 polarization on two levels: (a) through its direct effects on macrophages and (b) through the indirect effects of TNF .


The major cardiac syndromes, myocardial infarction and heart failure, are responsible for a large portion of deaths worldwide. Genetic and pharmacological manipulations indicate that cell death is an important component in the pathogenesis of both diseases. Cells die primarily by apoptosis or necrosis, and autophagy has been associated with cell death. Apoptosis has long been recognized as a highly regulated process. Recent data indicate that a significant subset of necrotic deaths is also programmed. In the review, we discuss the molecular mechanisms that underlie these forms of cell death and their interconnections. The possibility is raised that small molecules aimed at inhibiting cell death may provide novel therapies for these common and lethal heart syndromes.


Cells die primarily by apoptosis or necrosis. Apoptosis is a highly regulated mode of cell suicide. 1 Although necrosis has traditionally been regarded as passive and unregulated, data accumulated over the past decade indicate that a substantial proportion of necrotic deaths is actively executed by the cell in a highly regulated manner. This form of necrosis is sometimes referred to as regulated or programmed. Both apoptosis and necrosis play critical roles in normal biology including prenatal development and postnatal homeostasis. 2 Accordingly, when increased, decreased, or mislocalized, cell death plays major roles in human diseases, including cardiovascular disease, cancer, 3,4 diabetes mellitus, 5,6 sepsis, 7 and some neurological disorders. 8,9

This article accompanies the ATVB in Focus: Cell Death in Cardiovascular Disease series that was published in the December 2011 issue.

Apoptosis is characterized by cell shrinkage, 10 fragmentation into membrane-enclosed apoptotic bodies, and phagocytosis of these corpses by macrophages, or occasionally, neighboring cells. 11 When this clean-up operation is efficient, inflammation is avoided. ATP levels in apoptotic cells are reasonably well maintained both because of continued production and decreased expenditures. 12,13 The net result of apoptosis is the stealth deletion of individual cells within a tissue. In contrast, necrosis is characterized by loss of plasma membrane integrity, cellular and organellar swelling, and marked inflammation. ATP levels are dramatically reduced in necrotic cells, both because of severe mitochondrial damage that cripples ATP generation as well as unrestrained energy expenditures. 14 The chicken-and-egg relationships between ATP deficits and loss of plasma membrane integrity remain unclear. Similarly, although it is tempting to speculate that the decision of a doomed cell to undergo apoptosis versus necrosis is determined by energetics, this possibility has not yet been definitively established.

Mechanisms of Cell Death

Apoptosis and necrosis are mediated by distinct, but highly overlapping central pathways (Figure). The extrinsic pathway involves cell surface death receptors (DRs) and the intrinsic pathway uses the mitochondria and endoplasmic reticulum (ER). These pathways, which mediate both apoptosis and necrosis, are linked by multiple biochemical and functional connections. Extrapolating this degree of connectivity, the possibility is raised that these cell death mechanisms comprise single unified death machinery. However, given the morphological differences among types of cell death and the presumption that each arose at a specific time in evolution for a specific purpose, the notion of a unified model remains to be established.

Figure. Cell death pathways. Apoptosis and necrosis are mediated by death receptor (extrinsic) and mitochondrial (intrinsic) pathways. In the death receptor pathway, a death ligand (eg, tumor necrosis factor-α [TNF-α]) binds its cognate death receptor to trigger assembly of either the death-inducing signaling complex (DISC, not shown) or complex I. When receptor interacting protein 1 (RIP1) is K63-polyubiquinated by cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2), complex I signals survival through nuclear factor-kappaB (NF-kB) activation (not shown). If death receptor dissociates from complex I, the complex is endocytosed, RIP1 undergoes deubiquitiniation, and a Fas-associated via death domain (FADD)-RIP3 complex is recruited, complex II is formed. This complex signals apoptosis or necrosis depending on procaspase-8 activity. Activation of procaspases-8 leads to cleavage and activation of downstream procaspases that proteolyze cellular proteins to bring about apoptosis. Procaspase-8 also cleaves RIP1 and RIP3, to preclude necrosis. In contrast, with caspase-8 inhibition, RIP1 and RIP3 undergo a series of cross-phosphorylation events that trigger necrosis by a variety of mechanisms (see text). In the mitochondrial pathway, the critical event in apoptosis is permeabilization of the outer mitochondrial membrane (OMM), which results in release of mitochondrial apoptogens (eg, cytochrome c) to the cytoplasm. Complex interactions among B-cell lymphoma 2 (Bcl-2) family members (eg, Bax and Bak) mediate OMM permeabilization (see text). Once in the cytoplasm, cytochrome c stimulates assembly of the apoptosome, a multiprotein complex in which procaspase-9 is activated. Procaspase-9 goes on to activate downstream procaspases. In contrast, the defining event in necrosis is opening of the mitochondrial permeability transition pore (mPTP) in the inner membrane, which collapses the electrical gradient across the inner mitochondrial membrane (IMM) leading to cessation of ATP synthesis and promotes the influx of water into the mitochondrial matrix resulting in severe mitochondrial swelling. Multiple connections exist between these pathways. Apaf-1 indicates apoptotic protease activating factor 1 Bak, Bcl-2 homologous antagonist/killer Bax, Bcl-2 associated X protein Cyt c, cytochrome c TNFR1, tumor necrosis factor receptor 1 TRADD, TNF receptor-associated death domain and TRAF2, TNFR-associated factor 2.

Extrinsic (DR) Pathway: Apoptosis and Necrosis

In the DR pathway, a variety of death ligands bind their cognate receptors to trigger cell death. Some of these ligands are soluble (eg, tumor necrosis factor [TNF]-α), and some are bound to the surface of other cells (eg, Fas ligand). The efficiency with these ligands to induce death varies with cell type. Recent work has shown that the same death ligands may induce apoptosis or necrosis, the choice mediated by downstream events.

Binding of ligand to receptor induces the formation of either of 2 multiprotein complexes: the death-inducing signaling complex (DISC) and complex I. 15,16 The DISC signals apoptosis whereas complex I can signal either apoptosis, necrosis, or cell survival. The DISC has been studied most intensively in the context of Fas ligand/Fas signaling and complex I in the setting of TNF/TNF receptor 1 signaling. However, which ligand/receptor combinations use the DISC versus complex I, or both, is incompletely understood.

In DISC formation, the binding of death ligand induces a conformational change in the cytosolic domain of the DR, which recruits an adaptor protein (eg, Fas-associated via death domain, TNF receptor-associated death domain). 17 This adaptor protein, in turn, binds upstream procaspases-8 or -10 to form the DISC. 15,17 Procaspases are the zymogen form of caspases, cystenyl proteases that cut after aspartic acid residues. 18 Within the DISC, procaspases-8 and -10 are activated through a forced proximity mechanism. 19,20 Once activated, these caspases cleave, and activate downstream procaspases-3 and -7. Caspases-3 and -7 then cut multiple cellular proteins to bring about apoptotic death through mechanisms that are incompletely understood. In most cells, activation of the extrinsic pathway alone is insufficient to kill, and requires amplification through the intrinsic pathway. One means by which amplification is achieved is through the cleavage of the B-cell lymphoma 2 (Bcl-2) family protein BH3-interacting domain death agonist (Bid) by caspase-8, after which truncated Bid translocates to the mitochondria and contributes to outer mitochondrial membrane (OMM) apoptotic events described below. 21

In the assembly of complex I, the binding of death ligand to receptor recruits TNF receptor-associated death domain, which recruits receptor interacting protein 1 (RIP1, a serine/threonine kinase), cellular inhibitor of apoptosis proteins (IAP) 1 and 2, and TNF receptor-associated factor 2 and 5. 16 RIP1 undergoes K63-polyubiquitination by cellular IAP 1 and 2. 22,23 This provides a platform for the recruitment of additional kinases that activate nuclear factor-kappaB, resulting in the transcription of survival proteins. 24 However, after dissociation of DR, endocytosis, deubiquitination of RIP1, and recruitment of a Fas-associated via death domain-RIP3 complex, complex I morphs into complex II. 25,26 Complex II signals apoptosis when Fas-associated via death domain recruits procaspase-8 leading to its activation by forced proximity. 16,19 Caspase-8 not only activates downstream caspases to bring about apoptosis, it also cleaves RIP1 and RIP3 abrogating their ability to signal necrosis (see below). 27 If caspase-8 activity is inhibited experimentally or by certain viral or cancer proteins, apoptosis is blocked, obligating the cell to undergo necrosis in this pathway. 28,29 Necrosis is triggered by the interaction of RIP1 with RIP3, a second serine/threonine kinase, resulting in a complex series of cross-phosphorylation events. Necrostatin-1, a small molecule inhibitor of the kinase activity of RIP1, ablates necrosis in the DR pathway. 30

Events in this pathway downstream of RIP1 and RIP3 are incompletely understood, but include phosphorylation by RIP3 of mixed lineage kinase domain-like protein, 31 phosphoglycerate mutase 5 (a mitochondrial phosphatase), 32 and certain catabolic enzymes (glutamate dehydrogenase 1, glutamate ammonia ligase, and glycogen phosphorylase), the latter potentially eliciting necrosis through the generation of reactive oxygen species (ROS). 33 The effects of ROS on the mitochondria are discussed below. In addition, ROS-mediated DNA damage leads to overactivation of poly(ADP-ribose) polymerase 1, a nuclear enzyme that consumes nicotinamide adenine dinucleotide leading to significant ATP consumption, a key feature of necrosis. 34 Other downstream events that have been implicated in DR necrosis signaling include activation of calpains, phospholipases, lipoxygenases, and sphingomyelinases and permeabilization of lysosomes. For further details, the reader is referred to a recent review. 35

Intrinsic (Mitochondrial/ER) Pathway: Apoptosis and Necrosis

Mitochondria and ER are central to both apoptotic and necrotic signaling, and the intrinsic pathway mediates a more diverse array of death stimuli than does the DR pathway. These include deprivation of nutrients, oxygen, and survival factors, oxidative stress, DNA damage, proteotoxic stress, and chemical and physical toxins. Present understanding suggests that the pathways and events that mediate apoptosis and necrosis at the mitochondria are spatially and mechanistically distinct. The primary event in apoptosis is permeabilization of the OMM resulting in the release of apoptogens. 1 In contrast, the defining event in primary necrosis is the early opening of a channel in the inner mitochondrial membrane termed the mitochondrial permeability transition pore (mPTP). 36

Mitochondrial Signaling: Apoptosis

The main regulators of the mitochondrial apoptosis pathway are the Bcl-2 family proteins. 37 In addition, as discussed below, recent data also implicate these proteins in the regulation of necrosis. The Bcl-2 family is composed of both antiapoptotic (eg, Bcl-2, Bcl-extra large, Mcl-1) and proapoptotic members, and the proapoptotics are further divided into multidomain (eg, Bcl-2 associated X protein [Bax], Bcl-2 homologous antagonist/killer [Bak]) and BH3-only proteins (multiple members). 37 In healthy cells, Bax resides primarily in the cytosol. In response to death stimuli, Bax undergoes conformational activation, and translocates to the mitochondria, where it inserts into the OMM. 38 Apoptotic signals also stimulate the conformational activation of Bak, which is constitutively localized to the OMM. 39 Within the OMM, Bax and Bak homo- and hetero-oligomerize to bring about OMM permeabilization through poorly understood mechanisms. 40 The noxious stimuli that activate Bax and Bak are transduced from various locations in the cell via specific BH3-only proteins. For example, loss of the survival signals, insulin and insulin-like growth factor 1 leads to activation of the BH3-only protein Bcl-2-associated death promoter by decreasing Bcl-2-associated death promoter phosphorylation and permitting its release from the 14-3-3 protein. 41 The means by which BH3-only proteins activate Bax and Bak is complex. Certain BH3-only proteins called activators (eg, Bcl-2-interacting mediator, Bid) bind directly to Bax (and possibly Bak) to conformationally activate these proteins. Other BH3-only proteins called sensitizors displace the activator BH3-only proteins from antiapoptotics such as Bcl-2 and Bcl-extra large. Conversely, antiapoptotic Bcl-2 proteins inhibit Bax and Bak by sequestering the BH3-only activators, and possibly also through direct interactions with Bax and Bak. 38

Permeabilization of the OMM leads to the release of apoptogens, including cytochrome c, second mitochondria-derived activator of caspases/direct IAP binding protein with low isoelectric point, Omi/high temperature requirement protein A2, apoptosis-inducing factor, and endonuclease G from the mitochondria to the cytosol. Cytosolic cytochrome c and dATP bind to the adaptor protein apoptotic protease activating factor 1 resulting in a presumed conformational change that stimulates apoptotic protease activating factor 1 oligomerization and its recruitment of upstream procaspase-9 into a complex termed the apoptosome. 42,43 Procaspase-9 is activated by forced proximity within this complex, and goes on to cleave and activate procaspases-3 and -7. Apoptosis is opposed by IAP family members, the same proteins that act in the DR necrosis pathway to signal survival through their K63-polyubiquination of RIP1. In the mitochondrial apoptosis pathway, these IAPs inhibit already activated downstream caspases by occluding access of substrates to the active sites of these caspases. 44–46 The apoptogens second mitochondria-derived activator of caspases/direct IAP binding protein with low isoelectric point and Omi/high temperature requirement protein A2 reverse caspase inhibition by IAPs through binding to IAPs and displacing the caspases. 47–50 In addition, Omi/high temperature requirement protein A2 possesses serine protease activity that cleaves X-linked IAP. 51 Apoptosis-inducing factor, which in combination with perhaps endonuclease G causes fragmentation of DNA from ≈200 to 50 kb fragments, has been hypothesized to mediate a form of caspase-independent cell death. 52,53 However, it is possible that the primary role of apoptosis-inducing factor–induced DNA damage is to further augment activation of poly(ADP-ribose) polymerase 1 leading to ATP depletion during necrosis.

A host of inhibitors oppose these apoptosis pathways. They include Fas-associated via death domain-like interleukin-1β–converting enzyme inhibitory protein which inhibits DISC assembly and function, 54 antiapoptotic Bcl-2 proteins that block release of mitochondrial apoptogens, and IAP family members that inhibit already activated downstream caspases as described. Although these inhibitors act on either the DR or mitochondrial apoptosis pathways, apoptosis repressor with caspase recruitment domain inhibits both pathways by disrupting DISC assembly and inhibiting Bax activation. 55 Apoptosis repressor with caspase recruitment domain expression was initially believed to be limited to cardiac and skeletal myocytes and neurons, but recent data show that it is also induced at high levels in cancer cells 56–58 and hypoxic pulmonary artery smooth muscle cells in vivo. 59

Mitochondrial Signaling: Necrosis

In contrast to OMM permeabilization in apoptosis, the defining event of necrosis at the mitochondria is opening of the mPTP, a pore in the inner mitochondrial membrane. In healthy mitochondria, the inner mitochondrial membrane is impermeable to water, ions, and even single protons. Because substrates are metabolized in the mitochondrial matrix resulting in the transport of electrons along the respiratory chain, protons are pumped from the matrix to the intermembrane space. This creates an electrochemical gradient (mitochondrial membrane potential) between the intermembrane space and matrix, which provides the potential energy necessary to drive ATP synthesis. Necrotic stimuli, such as Ca 2+ , trigger opening of the mPTP. 60 Ca 2+ -induced mPTP opening can be potentiated by ROS, alkalosis, and depletion of ATP or ADP. 61,62 Opening of the mPTP causes abrupt loss of mitochondrial membrane potential leading to cessation of mitochondrial ATP synthesis. In addition, mPTP opening allows water to rush down its osmotic gradient into the matrix, leading to mitochondrial swelling, and sometimes frank rupture of the OMM. Although rupture of the OMM can cause release of cytochrome c and activate caspases, 63 it is unclear how much engagement of downstream apoptosis signaling contributes to cell death in the mitochondrial necrosis pathway given the other cataclysmic events precipitated by mPTP opening. However, as discussed below, potential caspase activation during necrosis complicates interpretation of assays such as terminal deoxynucleotidyl transferase dUTP nick-end labeling, which are traditionally assumed to be specific to apoptosis.

Despite extensive research in the field, the components of the mPTP remain unknown. The adenine nucleotide translocase and phosphate carrier in the inner mitochondrial membrane, voltage-dependent anion channel, and peripheral benzodiazepine receptor in the OMM, hexokinase which is loosely attached to the cytosolic face of the OMM, and cyclophilin D (a peptidyl-prolyl cis-trans isomerase) in the matrix have been proposed to be components of the pore. 36 However, genetic studies have excluded adenine nucleotide translocase, 64 voltage-dependent anion channel, 65 and cyclophilin D 63,66 as core pore components, although adenine nucleotide translocase and cyclophilin D are important positive regulators of pore opening. 63,64,66

Necrosis can occur as a primary event or secondary to apoptosis, the latter when the disposal of apoptotic bodies is delayed. Delayed clean-up occasionally occurs in vivo, and is almost always observed at late time points in cell culture. 11 In primary necrosis, mPTP opening occurs early, before cytochrome c release. If mPTP opening takes place during apoptosis, it occurs coincident with or after cytochrome c release. In this case, mPTP opening may result from caspase-dependent events. 67 Although the kinetics differ markedly, these observations explain why loss of mitochondrial membrane potential may provide a marker for both necrosis and apoptosis.

How cell death stimuli connect with the mitochondrial necrosis machinery is incompletely understood. Some classic activators of this pathway, such as ischemia and ischemia-reperfusion (I/R), induce mPTP opening through Ca 2+ and ROS. In addition, activators of the DR necrosis pathway may ultimately engage the mitochondrial necrosis pathway through links that were previously discussed. It is likely, however, that additional connections/pathways exist.

ER-Mediated Apoptosis and Necrosis

The ER mediates the synthesis and proper folding of multiple proteins, some posttranslational modifications, trafficking of newly synthesized proteins to the Golgi apparatus, lipid biosynthesis, and Ca 2+ homeostasis. These effects are critical for normal cellular functioning. Under certain conditions, however, the ER can also mediate cell death, both apoptosis and necrosis. Considerable controversy exists as to the precise mechanisms by which the ER contributes to cell death, and the mechanisms that mediate the switch from adaptation to death. Although adaptive and death responses could be mediated by parallel pathways, the involvement of shared signaling components implicates the same pathways in both outcomes. For example, misfolded proteins in the ER lumen elicit a response mediated by ER transmembrane sensors protein kinase R-like ER kinase, inositol-requiring protein 1α, and activating transcription factor 6. These proteins activate complex transcriptional and posttranscriptional cascades to reestablish ER homeostasis. However, it is thought that, when various ER stresses (eg, misfolded proteins, oxidative stress, certain lipids) fail to be resolved in a timely manner, death may result. 68

Although the precise ER-specific machinery by which cell death is promoted remains incompletely understood, the transcription factor C/EBP homologous protein has been clearly implicated. C/EBP homologous protein, which is activated downstream of the ER transmembrane sensors, induces the expression of proapoptotic proteins Bcl-2-interacting mediator, 69 tetracycline response element-binding protein 3, 70 and DR5, 71 and represses that of Bcl-2. 72 Another important death mediator is Ca 2+ , which transits from the ER lumen to the mitochondria, to trigger apoptosis or necrosis through mechanisms that are discussed in the section on cross talk between mitochondrial apoptosis and necrosis pathways. Less clear are potential roles for various caspases, 73,74 c-Jun N-terminal kinases, 75 other ER membrane proteins, 76 and cleavage of multiple mRNAs by inositol-requiring protein 1α, 77 which also possesses endonuclease activity.

Autophagy-Associated Cell Death

Autophagy is a process in which the cell breaks down its own proteins and lipids. This provides energy during periods of starvation and stress, a means for the disposal of long-lived proteins, and a mechanism for protein quality control. 78 Accordingly, in organisms ranging from yeast to mammals, autophagy is a survival mechanism. That said, too much autophagy has been hypothesized to cause cell death, a process referred to as autophagic cell death or, more accurately, as autophagy-associated cell death. It is plausible that self-cannibalization could result in cell death. However, at this point in time, a direct causal link between autophagy and cell death has not been definitively demonstrated. One impediment in establishing this connection is the absence of markers for autophagy-associated death in distinction to the existence of abundant markers for autophagy itself. In most experiments, an intervention is used to alter rates of autophagy, the success of which is confirmed with autophagy markers, and this manipulation is then correlated with histological markers of cell death (eg, terminal deoxynucleotidyl transferase dUTP nick-end labeling). Although it is possible that autophagy kills cells indirectly through another form of cell death (see below), an autophagy-specific mode of killing has not been identified. Questions remain even regarding the interpretation of electron micrographs showing presumably dead or dying cells that contain autophagic vacuoles because it is unclear whether autophagy in this situation represents a pathogenic mechanism, a compensatory process, or is unrelated to the presumed cell death. 79 There are, however, some convincing data supporting a role for autophagy in cell death, eg, during regression of the salivary gland in Drosophila development. 80 In addition, we highlight studies linking autophagy to cell death during myocardial infarction and heart failure in the section on heart disease below.

Although a dedicated machinery for autophagy-associated cell death has not been identified, physical and functional connections between key autophagy and cell death proteins have been recognized, and might provide insights into interrelationships between these processes. 81 In the discussion to follow, the reader is referred to several comprehensive reviews dealing with autophagy. 78,82,83 Beclin-1, a protein involved in autophagosome formation, contains a BH3 domain analogous to those in BH3-only proteins, which as discussed above promote apoptosis. The Bcl-2-Beclin-1 interaction inhibits the proautophagic function of Beclin-1 in response to starvation without interfering with antiapoptotic function of Bcl-2. Moreover, multiple BH3-only proteins can displace Beclin-1 from Bcl-2 to promote autophagy. 81

Connections Between Cell Death Pathways

We have previously discussed connections that link (1) DR apoptosis with mitochondrial apoptosis pathways (eg, Bid) and (2) DR apoptosis with DR necrosis pathways (caspase-8 activity as a decision point in apoptosis versus necrosis in this pathway). In this section, we consider molecules/pathways connecting (1) necrosis signaling at DRs with that at the mitochondria and (2) mitochondrial apoptosis and necrosis pathways.

Cross Talk Between DR and Mitochondrial Necrosis Pathways

As previously discussed, activation of the DR pathway signals necrosis when caspase-8 is inhibited. 28,29 First, induction of necrosis in this paradigm is abrogated by the absence of Bax/Bak or cyclophilin D, genetically linking DR and mitochondrial necrosis events. 84,85 Second, RIP1 translocates to the mitochondria when activated in the DR necrosis pathway, although its mitochondrial actions are not yet understood. 86 Third, activation of RIP1 and RIP3 in the DR pathway stimulates ROS production through nicotinamide adenine dinucleotide phosphate oxidase 1 and glutamate dehydrogenase 1/glutamate ammonia ligase/glycogen phosphorylase 1 activation respectively, 33,87 and as discussed, ROS is a strong potentiator of Ca 2+ -induced mPTP opening. Fourth, as discussed previously, RIP3 activation in the DR pathway also triggers cell death through phosphorylation of the mitochondrial phosphatase phosphoglycerate mutase 5. 32 Other connections are likely to become evident as these pathways are understood in more detail.

Cross Talk Between Mitochondrial Apoptosis and Necrosis Pathways

We have previously discussed some connections between these pathways including how OMM rupture (not permeabilization) in necrosis may result in cytochrome c release, and how caspase activation in apoptosis may trigger late mPTP opening. Another important connection involves Bcl-2 proteins, which unite apoptosis and necrosis signaling at the mitochondria through their effects on Ca 2+ handling at the ER. 88 Bax, which induces OMM permeabilization during apoptosis, also increases the concentration of Ca 2+ in the ER lumen, such that a larger Ca 2+ bolus is released when the ER is presented with a death stimulus. ER Ca 2+ transits to the mitochondria either through the cytoplasm or via direct connections between mitochondria and ER. 89,90 Increases in mitochondrial Ca 2+ can trigger mPTP opening and necrosis or apoptosis through mechanisms that have not yet been defined. Bcl-2 opposes these Bax-induced effects on both the mitochondria and ER.

Cell Death in Heart Disease

Myocardial Infarction

Surgical occlusion of the left coronary artery is used as a surrogate for acute thrombosis in animal models of ST-segment elevation myocardial infarction. This process is usually studied in the context of reperfusion (I/R) because of the clear benefit of restoring blood flow in human myocardial infarction. It should be noted, however, that despite the net effect of reperfusion to reduce infarct size, the introduction of blood into an ischemic zone generates ROS, Ca 2+ , and alkalosis, all inducers of mPTP opening. 36 For this reason, significant research is directed toward reducing reperfusion injury. 91 Another point relevant to interpreting data from rodent models of I/R is that, despite rare reports to the contrary, it is unusual for genetic or pharmacological manipulations to reduce infarct size in the setting of prolonged ischemia without reperfusion (permanent occlusion), another reason why most studies use I/R.

Cell Death in Myocardial Infarction

In both permanent occlusion and I/R models of myocardial infarction, a large burst of cell death takes place within the area rendered ischemic over the first 6 to 24 hours. 92 Lesser amounts of cell death takes place in the periinfarct zone, initially the result of residual ischemia, but persisting due to cardiac remodeling driven by the loss of contractile units in the infarct. A yet lower magnitude of cell death continues for months in the remote myocardium as remodeling progresses. 93 In this section, we focus on cardiac myocyte death in the ischemic zone.

During myocardial infarction, cardiac myocytes in the ischemic zone die by both apoptosis and necrosis. Surprisingly, the magnitudes of each form of cell death remain unclear. The impediment has been limitations of current assays to definitively distinguish between apoptosis and necrosis in tissue from animals subjected to myocardial infarction. For example, although the primary consequence of mPTP opening during necrosis is cessation of ATP synthesis, the accompanying mitochondrial swelling can result in OMM rupture and cytochrome c release. It is unclear how often OMM rupture occurs in this situation, but the potential release of cytochrome c confounds the interpretation of assays based on caspase activation and DNA fragmentation (eg, terminal deoxynucleotidyl transferase dUTP nick-end labeling). Solutions include the direct evaluation of plasma membrane integrity in vivo using a variety of approaches and electron microscopy, although the latter is limited by differential sensitivities for the detection of necrotic versus apoptotic cells. Although these techniques have been used to some extent, a rigorous quantification of apoptosis and necrosis during myocardial infarction is needed.

Apoptosis in Myocardial Infarction

Multiple studies have demonstrated a causal connection between cardiac myocyte apoptosis and myocardial infarction. Both the DR and mitochondrial pathways have been shown to be critical. Hearts of mice lacking Fas (lymphoproliferative mice) exhibit smaller infarcts in response to I/R, when studied as isolated preparations or in vivo. 94,95 Given that death signals related to I/R potently activate the mitochondrial pathway, the reasons underlying the importance of the DR pathway in this process are not obvious. One explanation may be that death ligands themselves are important mediators of I/R, and in support of this, Fas ligand appears in the coronary effluent of isolated hearts during the reperfusion phase. Another possibility may be that activation of the DR pathway provides another input into activation of the mitochondrial apoptosis pathway through truncated Bid.

Cardiac-specific overexpression of Bcl-2 decreases infarct size and cardiac dysfunction after I/R in vivo. 96,97 In addition, deletion of Bax reduces infarct size in isolated hearts subjected to I/R. 98 Bax deletion has also been reported to cause mild reductions in infarct size after permanent occlusion in vivo. 99 Absence of p53 upregulated modulator of apoptosis, a p53 responsive BH3-only protein, reduces infarct size in isolated, perfused hearts subjected to I/R. 100 Thus, Bcl-2 family members modulate infarct size.

Cardiac overexpression of cellular IAP 2 results also in smaller infarcts in isolated perfused hearts subjected to I/R. 101 This effect may result from the inhibition of already activated downstream caspases by IAPs by cellular IAP 2 and its K63-polyubiquitination of RIP1 which activates the DR survival pathway. UCF-101, a small molecule inhibitor of the serine protease activity of Omi/high temperature requirement protein A2, decreases infarct size after I/R. 102,103 Pan-caspase inhibitors provide varying degrees of reduction in the size of infarcts elicited by I/R. 104–107 Overexpression of apoptosis repressor with caspase recruitment domain, which inhibits both DR and mitochondrial apoptosis pathways, also decreases infarct size after I/R. 108 The fact that multiple manipulations of apoptosis pathways affect infarct size provides confidence that this form of cell death is involved in myocardial infarction.

Necrosis in Myocardial Infarction

Regulated necrosis has also been demonstrated to play a role in the development of myocardial infarction. Necrostatin, the inhibitor of the kinase activity of RIP1, reduces infarct size in response to I/R in vivo. Interestingly, its cardioprotective effect is dependent on the presence of cyclophilin D, suggesting connections between RIP1 and mitochondrial necrosis events. 109

Bax and Bak have recently been shown to regulate necrosis. In addition to reducing infarct size, deletion of Bax and Bak markedly reduces the degree of necrotic injury in the hearts of mice subjected to I/R. These effects occur through a pathway distinct from the regulation of apoptosis by Bax and Bak, as evidenced by the ability of oligomerization-deficient Bax mutants, which cannot support apoptosis, but retain the ability to mediate necrosis. 110

Mice lacking cyclophilin D, a positive regulator of mPTP opening, demonstrate decreased infarct size after I/R. 63,66 Pharmacological inhibition of cyclophilin D, using cyclosporine A or sangliferin A, also reduces infarct size. 111–114 A pilot study has translated this work to a small number of patients with ST-segment elevation myocardial infarction. When superimposed on angioplasty and stenting, cyclosporine A resulted in statistically significant reduction in infarct size as measured by serum levels of creatine kinase, but not troponin I, and by magnetic resonance imaging. 115 Although significant reductions in infarct size persisted in 6 months postmyocardial infarction, only a nonstatistically significant trend toward preserved cardiac function was observed. 116 Thus, further work is needed to assess the efficacy of this cardioprotective strategy in humans.

Taken together, these studies demonstrate that both apoptosis and necrosis contribute to the pathogenesis of myocardial infarction.

Autophagy-Associated Death in Myocardial Infarction

Autophagy is induced during both I/R and permanent occlusion. However, the mechanisms and the consequences of this induction appear to be different. 117 During permanent occlusion, 5' AMP-activated protein kinase is activated, and inhibits mammalian target of rapamycin, a potent inhibitor of autophagy. Consequently, autophagy is induced. Inhibition of autophagy by transgenic overexpression of dominant negative 5' AMP-activated protein kinase resulted in worsening of infarct size in response to permanent occlusion. 117 Similar results were obtained when autophagy was inhibited by overexpression of Rheb, 118 overexpression of a dominant negative form of glycogen synthase kinase 3β, or deletion of 1 allele of glycogen synthase kinase 3β. 119 Thus, consistent with the survival role of autophagy during starvation, these data suggest that autophagy protects the myocardium during prolonged ischemia. During I/R, however, Beclin-1 levels increase to activate autophagy. Mice, in which 1 allele of Beclin-1 has been inactivated, exhibit smaller infarcts in this situation. 117 Similar results were found when autophagy was decreased by loss-of-function manipulations of glycogen synthase kinase 3β as described above. 119 These and other studies 120,121 suggest that autophagy is associated with a protective role during ischemia and a pathogenic role during I/R. Further investigation is needed, however, to determine the extent to which alterations in autophagy explain these changes in infarct size.

Cell Death and Heart Failure

Apoptosis in Heart Failure

In contrast to myocardial infarction in which there is an explosive and short-lived burst of cell death, the absolute percentage of apoptotic cardiac myocytes in failing human hearts is low (0.08%–0.25% as assessed by terminal deoxynucleotidyl transferase dUTP nick-end labeling). However, this percentage of cardiac myocyte apoptosis is ≈10- to 100-fold higher than that observed in control hearts (0.001%–0.01%). 122–124 These data suggest the hypothesis that low, but elevated levels of cardiac myocyte apoptosis, result over time in cumulative loss of cardiac myocytes and heart failure. This possibility was first tested in transgenic mice with a conditionally activatable procaspase-8 allele, which showed that rates of cardiac myocyte apoptosis as low as 0.023% elicit a lethal dilated cardiomyopathy. Control mice overexpressing an enzymatically dead procaspase-8 remained normal. 125 These data establish the sufficiency of clinically relevant levels of apoptosis to induce heart failure.

Conversely, the necessity of cardiac myocyte apoptosis for heart failure was tested using pan-caspase inhibition in a model of peripartum cardiomyopathy. 126 This was induced by cardiac-specific overexpression of Gαq, a surrogate for humoral stimuli relevant to heart failure. Pregnancy precipitated lethal heart failure in 30% of Gαq transgenic mice. Pretreatment with a pan-caspase inhibitor reduced cardiac myocyte apoptosis, preserved heart function, and completely rescued mortality. These data demonstrate the necessity of cardiac myocyte apoptosis for heart failure in this model. These concepts have also been extended to other models. For example, after myocardial infarction, deletion of Bcl-2/adenovirus E1B 19kD-interacting protein 3, a BH3-like protein, reduced pathological remodeling in the periinfarct zone and resultant heart failure. 127

Necrosis in Heart Failure

Cardiac myocyte necrosis may also play a role in heart failure. Cardiac myocyte-specific transgenic overexpression of the β2-α subunit of the L-type Ca 2+ channel resulted in Ca 2+ overload, mPTP opening, necrosis, and cardiac dysfunction. 128 This phenotype was rescued by deletion of peptidylprolyl isomerase F encoding cyclophilin D, but not overexpression of Bcl-2, suggesting that heart failure in this model is attributable to cardiac myocyte necrosis. Similarly, doxorubicin-induced cardiomyopathy was ameliorated by knockout peptidylprolyl isomerase F. In contrast to myocardial infarction, involvement of necrosis in heart failure is somewhat unexpected. Although this interpretation may be correct, it is important to also consider recently discovered effects of cyclophilin D on cardiac metabolism. 129 Future work is needed to determine the magnitude of cardiac myocyte necrosis in failing hearts and the general applicability to pathogenesis of this syndrome.

Autophagy-Associated Death in Heart Failure

A previous study of failing human hearts has suggested that autophagy-associated cell death is the most common form of cellular demise during heart failure. 130 However, the markers used to diagnose various forms of cell death in the present study were not specific. Stronger data concerning the relationship of autophagy and heart failure have been provided by genetic loss- and gain-of-function studies. Autophagy protein 5 deletion in the heart precipitates ventricular enlargement and cardiac dysfunction after hemodynamic overload implying that autophagy is a compensatory mechanism during heart failure. 131 In contrast, Beclin-1 +/− mice subjected to pressure overload exhibited decreased pathological remodeling and cardiac dysfunction whereas Beclin-1 overexpression resulted in the opposite. 132 The explanation for the conflicting results in the autophagy protein 5 and Beclin-1 studies is not known, but may be related to differences in the genetic manipulations or apparent severity of pressure overload. Therefore, the role of autophagy in the pathogenesis of pressure overload-induced heart failure is not clear. On the other hand, deletion of 1 allele of Beclin-1 worsens cardiac remodeling and function and mortality in response to proteotoxic stress induced by transgenic overexpression of the R120G mutant of αβ-crystallin, a model of desmin-related cardiomyopathy. 133 Thus, in keeping with its role in disposing of defective proteins, autophagy plays a protective role in heart failure initiated by proteotoxicity. Taken together, these data highlight that autophagy may be protective in response to some cardiomyopathic stimuli and pathogenic in response to others.

Concluding Remarks

The present review discusses the role of cell death in the major syndromes that affect the heart: myocardial infarction and heart failure. Although myocardial infarction and heart failure are complex and involve multiple cellular processes, the data indicate that cell death plays a critical role in the pathogenesis of both syndromes. The regulated nature of much of the cell death in these diseases opens up the possibility of manipulating death pathways to therapeutic advantage. Given its acute nature, myocardial infarction is the most attractive target. An important issue in this setting is how the drug will access tissue in which the blood supply is compromised. One possibility is drug delivery at the time of reperfusion. However, administration even before reperfusion may have beneficial effects on the periinfarct region as well as potentially extending the window for effective reperfusion. Heart failure may also be a viable target, but potential oncogenic effects of chronic cell death inhibition are a concern. To circumvent this obstacle requires the development of approaches to target drug to the myocardium. The hope is that, in combination with therapies directed at atherosclerosis and plaque rupture, small molecules approaches to decrease the susceptibility of the myocardium to cell death will limit tissue damage and ultimately reduce mortality.


We thank Gloria Kung and Wendy M. McKimpson for their critical comments on the article.

The Scientist's Guide to Cardiac Metabolism

The Scientists Guide to Cardiac Metabolism combines the basic concepts of substrate metabolism, regulation, and interaction within the cell and the organism to provide a comprehensive introduction into the basics of cardiac metabolism.

This important reference is the perfect tool for newcomers in cardiac metabolism, providing a basic understanding of the metabolic processes and enabling the newcomer to immediately communicate with the expert as substrate/energy metabolism becomes part of projects.

The book is written by established experts in the field, bringing together all the concepts of cardiac metabolism, its regulation, and the impact of disease.

The Scientists Guide to Cardiac Metabolism combines the basic concepts of substrate metabolism, regulation, and interaction within the cell and the organism to provide a comprehensive introduction into the basics of cardiac metabolism.

This important reference is the perfect tool for newcomers in cardiac metabolism, providing a basic understanding of the metabolic processes and enabling the newcomer to immediately communicate with the expert as substrate/energy metabolism becomes part of projects.

The book is written by established experts in the field, bringing together all the concepts of cardiac metabolism, its regulation, and the impact of disease.

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Intrinsic and Extrinsic Heart Regulation

Intrinsic and Extrinsic Heart Regulation The rate and force of myocardia contraction (heart rate and force) are dependant on two primary factors: intrinsic factors and extrinsic factors.

Cardiac Regulation Pathway Medicine

  • The pumping action of the heart must be finely regulated to meet physiological demands and is controlled by both intrinsic and extrinsic processes
  • The Frank-Starling Relationship describes an intrinsic regulatory mechanism of the heart which guarantees that the organ pumps out any blood that enters its chambers.

Extrinsic Regulation of Blood Flow

  • The term extrinsic regulation refers to control by the autonomic nervous system and endocrine system
  • Angiotensin II, for example, directly stimulates vascular smooth muscle to produce generalized vasoconstriction
  • Antidiuretic hormone (ADH) also has a vasoconstrictor effect at high concentrations this is why it is also called vasopressin.

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  • Extrinsic controls of the cardiovascular system include neuronal, humoral, reflex, and chemical regulatory mechanisms
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  • Extrinsic regulation of heart rate is exerted by both branches of the autonomic nervous system (ANS)
  • Their influence on pacemaker cells of the heart can be described by which of the following? A.) the parasympathetic system accelerates the rate of Kt channel closing and the sympathetic system accelerates the rate of K+ channel opening B.) the

Heart Rate and its Regulation (With Diagram)

  • Heart Rate and its Regulation (With Diagram) Normal heart rate is about 60-90 beats per minute
  • On an average, the rate at which the heart beats is about 75 per minute
  • It depends on the balanced activity between the sympathetic and parasympa­thetic nerve influence that are acting on it
  • Heart rate can be increased because of either an

Innervation of the heart: Sympathetic and parasympathetic DA: 14 PA: 44 MOZ Rank: 64

  • The innervation of the heart refers to the network of nerves that are responsible for the functioning of the heart.The heart is innervated by sympathetic and parasympathetic fibres from the autonomic branch of the peripheral nervous system.
  • The network of nerves supplying the heart is called the cardiac plexus.It receives contributions from the right and left vagus nerves, as well as

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  • Thus, increasing the heart rate by 25 beats per minute
  • Regulation of Heart Rate: Autonomic Nervous System Chapter 18, Cardiovascular System * Atrial (Bainbridge) Reflex Atrial (Bainbridge) reflex – a sympathetic reflex initiated by increased blood in the atria Causes stimulation of the SA node Stimulates baroreceptors in the atria, causing

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  • extrinsic regulation of heart rate purpose
  • Modifies the heart rate and maintain the stroke volume when blood volume is less or when heart is not very strong
  • Extrinsic regulators of heart rate
  • Nervous system regulation Chemical regulation Other physical factors.

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  • Extrinsic, as the name suggests, is something outside the heart itself
  • There are nerves between the brain and heart that can influence rate and contractility as well as hormones released into the blood that do the same thing.

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  • Sunday, June 28, 2015 2.2.4 Describe the intrinsic and extrinsic regulation of heart rate and the sequence of excitation of the heart muscle
  • The electrical impulse is generated by the sinoatrial node (SA node), with is called the “pacemaker”.

Physiologic framework of extrinsic controls

  • Extrinsic controls of the cardiovascular system include neuronal, humoral, reflex, and chemical regulatory mechanisms
  • These extrinsic controls regulate heart rate, myocardial contractility, and vascular smooth muscle to maintain cardiac output, blood flow distribution, and arterial blood pressure.

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Autonomic and endocrine control of cardiovascular function

  • To achieve this goal, a normal human heart must beat regularly and continuously for one’s entire life
  • Heartbeats originate from the rhythmic pacing discharge from the sinoatrial (SA) node within the heart itself
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CV Physiology Control of Heart Rate

  • Heart rate is normally determined by the pacemaker activity of the sinoatrial node (SA node) located in the posterior wall of the right atrium
  • The SA node exhibits automaticity that is determined by spontaneous changes in Ca ++, Na +, and K + conductances.This intrinsic automaticity, if left unmodified by neurohumoral factors, exhibits a spontaneous firing rate of 100-115 beats/min.

Autonomic Cardiac Regulation Pathway Medicine

  • Any person who has experienced fear or elation knows the capacity of emotions to modulate the rate and intensity of cardiac activity
  • Beyond these higher neurological processes a large variety of other stimuli, extrinsic to the heart, can regulate the beating of the organ and are largely coordinated by

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  • During heart surgery, the body temperature is sometimes intentionally lowered to slow the heart rate and metabolism
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Mechanisms and Models in Heart Failure

From the Winters Center for Heart Failure Research, Department of Medicine, Baylor College of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Tex (D.L.M.), and Division of Cardiology and Cardiovascular Institute, University of Colorado Health Science Center, Denver (M.R.B.).

From the Winters Center for Heart Failure Research, Department of Medicine, Baylor College of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Tex (D.L.M.), and Division of Cardiology and Cardiovascular Institute, University of Colorado Health Science Center, Denver (M.R.B.).

Despite repeated attempts to develop a unifying hypothesis that explains the clinical syndrome of heart failure, no single conceptual paradigm for heart failure has withstood the test of time. Whereas clinicians initially viewed heart failure as a problem of excessive salt and water retention that was caused by abnormalities of renal blood flow (the “cardiorenal model” 1 ), as physicians began to perform careful hemodynamic measurements, it also became apparent that heart failure was associated with a reduced cardiac output and excessive peripheral vasoconstriction. This latter realization led to the development of the “cardiocirculatory” or “hemodynamic” model for heart failure, 1 wherein heart failure was thought to arise largely as a result of abnormalities of the pumping capacity of the heart and excessive peripheral vasoconstriction. However, although both the cardiorenal and cardiocirculatory models for heart failure explained the excessive salt and water retention that heart failure patients experience, neither of these models explained the relentless “disease progression” that occurs in this syndrome. Thus, although the cardiorenal models provided the rational basis for the use of diuretics to control the volume status of patients with heart failure, and the cardiocirculatory model provided the rational basis for the use of inotropes and intravenous vasodilators to augment cardiac output, these therapeutic strategies have not prevented heart failure from progressing, nor have they led to prolonged life for patients with moderate to severe heart failure. 1,2

In the present review we will summarize recent advances in the field of heart failure, with a focus on the new therapeutic strategies that have been developed for treating systolic heart failure. For a complete discussion on recent advances in the diagnosis and treatment of diastolic heart failure, the interested reader is referred to several recent reviews on this topic. 3–5 To provide the proper framework for this discussion, we will review current and emerging therapies within the context of the extant conceptual biological models that clinician scientists have used for envisioning the syndrome of systolic heart failure. However, as discussed at the conclusion of this review, our current working models for heart failure are insufficient for explaining several of the new and emerging therapies for treating systolic heart failure. To this end, we suggest a simplified conceptual model for heart failure that both unites and extends several of the existing working models for heart failure.

Heart Failure as a Progressive Model

Figure 1 provides a general conceptual framework for discussing the development and progression of heart failure. As shown, heart failure may be viewed as a progressive disorder that is initiated after an “index event” either damages the heart muscle, with a resultant loss of functioning cardiac myocytes, or alternatively disrupts the ability of the myocardium to generate force, thereby preventing the heart from contracting normally. This index event may have an abrupt onset, as in the case of a myocardial infarction, it may have a gradual or insidious onset, as in the case hemodynamic pressure or volume overloading, or it may be hereditary, as in the case of genetic cardiomyopathies. Regardless of the nature of the inciting event, the common feature in each of these index events is that they all, in some manner, produce a decline in pump function of the heart. In most instances patients will remain asymptomatic or minimally symptomatic after the initial decline in pumping capacity of the heart or will develop symptoms only after the dysfunction has been present for some time. Thus, when viewed within this conceptual framework, left ventricular (LV) dysfunction is necessary but not sufficient for the development of the syndrome of heart failure.

Figure 1. Pathogenesis of heart failure. Heart failure begins after an index event produces an initial decline in pumping capacity of the heart. After this initial decline in pumping capacity of the heart, a variety of compensatory mechanisms are activated, including the adrenergic nervous system, the renin-angiotensin system, and the cytokine system. In the short term these systems are able to restore cardiovascular function to a normal homeostatic range, with the result that the patient remains asymptomatic. However, with time the sustained activation of these systems can lead to secondary end-organ damage within the ventricle, with worsening LV remodeling and subsequent cardiac decompensation. As a result of resultant worsening LV remodeling and cardiac decompensation, patients undergo the transition from asymptomatic to symptomatic heart failure.

As shown in Figure 1, the compensatory mechanisms that are activated after the initial decline in the pumping capacity of the heart are able to modulate LV function within a physiological/homeostatic range, such that the functional capacity of the patient is preserved or is depressed only minimally. The portfolio of compensatory mechanisms that have been described include early activation of the adrenergic nervous system and salt- and water-retaining systems in order to preserve cardiac output, 6–8 as well as activation of a family of vasodilatory molecules, including natriuretic peptides, prostaglandins (PGE2 and PGEI2), and nitric oxide, to counteract the excessive vasoconstriction resulting from excessive activation of the adrenergic and renin-angiotensin systems. 9,10 However, our understanding of the family of molecules that may be involved in this process is far from complete. Although patients with depressed systolic function may remain asymptomatic or minimally symptomatic for years, at some point patients will become overtly symptomatic, with a resultant striking increase in morbidity and mortality. The transition to symptomatic heart failure is accompanied by further activation of neurohormonal and cytokine systems, as well as a series of adaptive changes within the myocardium, collectively referred to as “LV remodeling.” Although there are further modest declines in the overall pumping capacity of the heart during the transition to symptomatic heart failure, the weight of experimental and clinical evidence suggests that heart failure progression occurs independently of the hemodynamic status of the patient.

Neurohormonal Mechanisms for the Progression of Heart Failure

In the latter part of the 1980s and early 1990s, evidence began to appear that certain other types of medical therapy might have a beneficial effect on the natural history of LV dysfunction or myocardial failure, despite initial hemodynamic effects that were either unimpressive 11–13 or even adverse. 11,12,14,15 These 2 types of therapies, namely, ACE inhibitors and β-adrenergic blocking agents, have dramatically changed the way in which we conceptualize heart failure. As will be discussed below, data generated from both experimental model systems and clinical trials suggest that both types of therapy may prevent the progression of pump dysfunction that characterizes the natural history of heart failure and may halt or even reverse the progressive cardiac dilatation that occurs as heart failure progresses. It is important to emphasize that the beneficial effects of these treatments are not pharmacological but rather are due to favorable effects on the biology of the failing heart. The aforementioned observations led to a point of view that heart failure should be viewed as a “neurohormonal model,” in which heart failure progresses as a result of the overexpression of biologically active molecules that are capable of exerting deleterious effects on the heart and circulation. 16 “Neurohormone” is largely a historical term, reflecting the original observation that many of the molecules that were elaborated in heart failure were produced by the neuroendocrine system and thus acted on the heart in an endocrine manner. However, it has since become apparent that a great many of the so-called classic neurohormones such as norepinephrine and angiotensin II are synthesized directly within the myocardium and thus act in an autocrine and paracrine manner. Furthermore, molecules such as angiotensin II, endothelin, natriuretic peptides, and tumor necrosis factor (TNF) are peptide growth factors and/or cytokines that are produced by a variety of cell types within the heart, including cardiac myocytes, and thus do not necessarily have a neuroendocrine origin. Nonetheless, the important unifying concept that arises from the neurohormonal model is that the overexpression of portfolios of biologically active molecules can contribute to disease progression independently of the hemodynamic status of the patient, by virtue of the deleterious effects that these molecules exert on the heart and circulation.

The evidence in support of the foregoing point of view is derived from 2 lines of investigation. First, a number of experimental models have shown that pathophysiologically relevant concentrations of neurohormones 17–19 or overexpression of single components of their signal transduction cascade 20–22 is sufficient to mimic some aspects of the heart failure phenotype. Second, clinical studies have shown that antagonizing neurohormones leads to clinical improvement in patients with heart failure. 23–30 Thus, a logical explanation for the progression of heart failure is that long-term activation of a variety of neurohormonal mechanisms produces direct end-organ damage within the heart and circulation. Accordingly, progressive activation of neurohormonal mechanisms may explain why heart failure may develop insidiously many years after an acute myocardial infarction, despite the absence of ongoing ischemia. The neurohormonal model also explains why the so-called heart failure phenotype appears remarkably consistent in patients with different etiologies for their heart failure, insofar as disease progression is ultimately driven by very similar portfolios of biologically active molecules, regardless of the inciting cause.

Thus far, a variety of proteins, including norepinephrine, angiotensin II, endothelin, aldosterone, and TNF, have been implicated as some of the potentially biologically active molecules whose biochemical properties are sufficient to contribute to disease progression in the failing heart. Disease progression may also be engendered by the loss of the beneficial effects of endogenous vasodilators such as nitric oxide, natriuretic peptides, prostaglandins, and kinins, which are insufficient to counteract the peripheral vasoconstriction that results for endothelial cell dysfunction and the vasoconstrictor properties of angiotensin II and norepinephrine. The most powerful compensatory mechanism activated to support the failing heart is perhaps an increase in cardiac adrenergic drive. 31 Unlike other compensatory mechanisms, adrenergic activation accesses all the known means by which myocardial performance can be stabilized or increased. 7 These include an increase in contractile function, increase in heart rate, cardiac myocyte hypertrophy, and volume expansion/increased end-diastolic volume (via β-adrenergic signaling of nonosmotic vasopressin release). 7 However, in addition to the positive effects on stabilizing myocardial performance, increased myocardial adrenergic signaling, particularly through β1-adrenergic receptor pathways, 32 is also highly cardiomyopathic. 18,22,33 A summary of some of these helpful and harmful adrenergic receptor pathways is given in Table 1, although this table is somewhat oversimplified.

TABLE 1. Biological/Physiological Responses Mediated by Postjunctional Adrenergic Receptors in the Human Heart

As implied by a greater number of harmful than helpful effects of activation of the adrenergic receptor pathways listed in Table 1, the net effect of a sustained increase in cardiac adrenergic activity in the failing heart is to promote myocardial disease progression and to accelerate the natural history of heart failure. Indeed, repeated observations of the salutary effects of β-blocking agents in clinical trials have shown that chronically elevated β-adrenergic signaling has adverse effects on contractile function, remodeling, and heart failure morbidity and mortality. As shown in Table 2, 134–136 these effects appear to be primarily delivered through β1-receptor signaling, inasmuch as both β1-receptor selective (metoprolol CR/XL and bisoprolol) or nonselective agents (carvedilol, bucindolol) have similar salutary effects in terms of molecular responses and clinical outcomes. The reasons for this are 2-fold: the increased myopathic potential of β1- versus β2- or α1-receptor signaling that is summarized in Table 1 32,34 and the binding affinity selectivity of norepinephrine for β1 versus β2 or α1 receptors. 32 Thus, the beneficial effects of β-blocking agents appear to be due to the class effects of β1-receptor blockade, at least in terms of molecular responses 35 and clinical outcomes. 28,36

TABLE 2. Class Effects of β-Adrenergic Blockade in Chronic Heart Failure

The adverse effects of β-adrenergic signaling on heart failure natural history would seem to dictate that any type of antiadrenergic therapy would be equally effective, as long as it inhibited the β1-adrenergic signaling. However, recent clinical trial data indicate that the type of antiadrenergic therapy, particularly receptor blockade versus reducing norepinephrine release, is critically important. 37–39 The likely explanation for the polar difference in the response of these 2 general classes of antiadrenergic agents is that, during the crucial early period of adrenergic inhibition, sympatholytic agents produce an irreversible removal of adrenergic support, with inability to recruit adrenergic drive when needed to support cardiac function. In contrast, β-blockers are mass-action agents whose inhibition can be easily reversed by norepinephrine competition, which allows for retention and recruitment of the powerful adrenergic support mechanism on an as-needed basis. Extensions of these observations include the potentially favorable effects of therapeutic approaches that allow the beneficial aspects of adrenergic inotropic support to be maintained in the presence of β-blockade 40 or the addition to β-blockade to positive inotropic device therapy. 41 On the basis of experience with the β-sympatholytic agent bucindolol in the Beta-Blocker Evaluation of Survival Trial (BEST), 42 it is apparent that β-blocking agents can interact with certain characteristics of heart failure subpopulations to produce differences in clinical response. This is in contrast to the rather unvarying pharmacological properties and clinical responses to ACE inhibitors. These observations highlight the complexities encountered in therapeutic development in heart failure, wherein surprises predominate, and the only way to directly test hypotheses is in phase III clinical trials.

Of major relevance to antiadrenergic strategies in heart failure is the impact of adrenergic receptor polymorphisms on myocardial disease progression and on therapeutic response. For example, a double adrenergic receptor polymorphism, an α2C deletion/loss of function genotype (α2C Del322-325), combined with a high-functioning β1-receptor genotype (β1 Arg389), confers a 10-fold risk for the development of heart failure. 43 The α2C polymorphism likely leads to a reduction in the natural brake on norepinephrine release provided by α2 receptors, and the increased adrenergic drive in these individuals then presumably damages the heart to a greater extent in individuals with the high-functioning β1 receptor polymorphism. Transgenic mice with genetic ablation of the α2C receptor have elevated norepinephrine levels and develop evidence of cardiomyopathy. 44 Importantly, the α2C polymorphism is enriched in black persons, 43 and it provides a potential explanation for certain characteristics of heart failure in this population, including worse cardiac function and prognosis per a given degree of functional incapacity. When transgenically overexpressed in mouse hearts, 45 the high-functioning β1Arg389 receptor variant, which by prevalence is the wild-type form of the β1-adrenergic receptor, is much more cardiomyopathic than the lower-functioning β1Gly389 polymorphic counterpart. There is evidence from the BEST study (S. Liggett, MD, P. Lavori, MD, M.R. Bristow, MD, unpublished data, 2005) that the clinical response to bucindolol was affected in a predictable manner by these genetic variants. On the basis of these and other observations, we may be close to the time when genotyping will be a necessary prerequisite to selecting the proper treatment for chronic heart failure patients, at least in terms of antiadrenergic therapy.

Is the Neurohormonal Model Adequate to Explain the Progression of Heart Failure?

Despite the many strengths of the neurohormonal model in terms of explaining disease progression and the many insights that neurohormonal models have provided in terms of drug development for heart failure, there is increasing clinical evidence to suggest that our current neurohormonal models fail to completely explain disease progression in heart failure. Our current medical therapies for heart failure will stabilize heart failure and in some cases reverse certain aspects of the disease process. However, in the overwhelming majority of patients, heart failure will progress, albeit at a slower rate. Moreover, as heart failure progresses, many patients will be refractory and/or intolerant to conventional medical therapy and often require withdrawal of conventional medical therapies. 46 In addition, many types of neurohormonal inhibition have been shown to be ineffective or even harmful in heart failure patients (reviewed in Mann et al 47 ). Although the precise mechanism(s) for this attenuation, loss, or lack of effectiveness of neurohormonal antagonism is not known, there are at least 5 potential explanations that warrant a brief discussion. One obvious explanation is that it may not be possible to achieve complete inhibition of the renin-angiotensin system or the adrenergic system in heart failure because of dose-limiting side effects of ACE inhibitors and β-blockers. A second explanation is that there may be alternative metabolic signaling for neurohormones that are not antagonized by conventional treatment strategies (eg, the conversion of angiotensin I to angiotensin II within the myocardium by tissue chymase). 48,49 Indeed, the results of recent clinical trials in which angiotensin receptor antagonists and aldosterone antagonists have been shown to have benefit when added to conventional therapy with ACE inhibitors and β-blockers clearly support this point of view. 30,50,51 Third, the currently available portfolio of neurohormonal antagonists, namely, ACE inhibitors and β-blockers, may not antagonize all of the alterations in biologically active systems that become activated in the setting of heart failure (Table 3). Indeed, given the inherent biological redundancy of all mammalian systems, it is perhaps predictable that there will be a number of biologically active molecules that are sufficient to contribute to disease progression by virtue of their toxic effects on the heart and the circulation. Thus, it is likely that with the current technologies for gene expression monitoring, as well as the innovative cloning strategies that are being used, it is only a matter of time before investigators identify new families/classes of biologically active molecules that are capable of contributing to disease progression. A fourth factor is that some heart failure–activated neurohormonal/cytokine signaling pathways capable of producing harmful effects in cardiac myocytes is isolated systems (eg, endothelin, TNF) may have also have favorable effects when functioning in the complex heart failure milieu. A fifth explanation for the loss of effectiveness of neurohormonal antagonism is that, at some point, heart failure may progress independently of the neurohormonal status of the patient. Thus, analogous to the limitations described for hemodynamic models for heart failure, neurohormonal models may be necessary but not sufficient to explain all aspects of disease progression in the failing heart.

TABLE 3. Overview of LV Remodeling

LV Remodeling as a Cause of Disease Progression in Heart Failure

Natural history studies have shown that progressive LV remodeling is directly related to future deterioration in LV performance and a less favorable clinical course in patients with heart failure. 52–54 Although some investigators currently view LV remodeling simply as the end-organ response that occurs after years of exposure to the deleterious effects of long-term neurohormonal stimulation, others have suggested that LV remodeling may contribute independently to the progression of heart failure. 52,55 Although a complete discussion of the complex changes that occur in the heart during LV remodeling is well beyond the intended scope of this brief review, it is worth emphasizing that the process of LV remodeling extends to and affects importantly the biology of the cardiac myocyte, the volume of myocyte and nonmyocyte components of the myocardium, and the geometry and architecture of the LV chamber (Table 3). Although each of these various components of the remodeling process may contribute importantly to the overall development and progression of heart failure, the reversibility of heart failure is determined by whether the changes that occur at the level of the myocyte, the myocardium, or the LV chamber are reversible. In this regard, the changes that occur at the level of the myocyte and the LV chamber appear to be at least partially reversible in some experimental and/or clinical models. 14,56–58

A number of changes that occur during the process of LV remodeling may contribute to worsening heart failure. Principal among these changes is the increase in LV wall stress that occurs during LV remodeling. Indeed, one of the first observations with respect to the abnormal geometry of remodeled ventricle was the consistent finding that the remodeled heart was not only larger but was also more spherical in shape. 59 As depicted in Table 4, the increase in LV size and resultant change in LV geometry from the normal prolate ellipse to a more spherical shape creates a number of de novo mechanical burdens for the failing heart, most notably an increase in LV end-diastolic wall stress. Insofar as the load on the ventricle at end-diastole contributes importantly to the afterload that the ventricle faces at the onset of systole, it follows that LV dilation itself will increase the work of the ventricle and hence the oxygen utilization as well. In addition to the increase in LV end-diastolic volume, LV wall thinning also occurs as the ventricle begins to remodel. The increase in wall thinning along with the increase in afterload created by LV dilation leads to a functional “afterload mismatch” that may further contribute to a decrease in forward cardiac output. 60–63 Moreover, the high end-diastolic wall stress might be expected to lead to episodic hypoperfusion of the subendocardium, with resultant worsening of LV function, 64–66 as well as increased oxidative stress, with the resultant activation of families of genes that are sensitive to free radical generation (eg, TNF and interleukin-1β).

TABLE 4. Mechanical Disadvantages Created by LV Remodeling

Given the potential central importance of LV remodeling in the progression of heart failure, the following section will focus on the basic cellular and molecular mechanisms that are responsible for this process. Although the complex changes that occur in the heart during LV remodeling have canonically been described in anatomic terms, the process of LV remodeling also has an important impact on the biology of the cardiac myocyte, changes in the volume of myocyte and nonmyocyte components of the myocardium, and the geometry and architecture of the LV chamber (Table 3). Although each of these various components of the remodeling process may contribute importantly to the overall development and progression of heart failure, it is extremely unlikely that any single aspect of the remodeling process itself will satisfactorily explain the progressive cardiac decompensation that occurs as heart failure advances. Accordingly, the remaining discussion will focus on the collective changes that occur in the cardiac myocyte, the myocardium, and the LV chamber, with an emphasis on those aspects of the remodeling process that might potentially contribute to disease progression.

Alterations in the Biology of the Cardiac Myocyte

In both animal models and in the human heart, it is generally held that cardiac myocyte 67 or global pump is the primary initiating event that leads to cardiac remodeling, although remodeling can occur in the absence of myocyte dysfunction in some experimental models. 68,69 Numerous studies have suggested that failing human cardiac myocytes undergo a number of important changes that might be expected to lead to a progressive loss of contractile function, including decreased expression of α-myosin heavy chain gene with increased expression of β-myosin heavy chain, 70,71 progressive loss of myofilaments in cardiac myocytes, 72 alterations in cytoskeletal proteins, 72 alterations in excitation contraction coupling, 73 and desensitization of β-adrenergic signaling. 74 Although many of the aforementioned changes may be thought of as beneficial in terms of protecting myocytes against the potential deleterious consequences of excessive neurohormonal activation, collectively these changes would be expected to lead to a defect in myocyte contractile function, as well as decreased loss of responsiveness to normal adrenergic control mechanisms, both of which are hallmarks of failing human myocardium. Indeed, when the contractile performance of isolated failing human myocytes has been examined under very simple experimental conditions, investigators have found that there is ≈50% decrease in cell shortening in failing human cardiac myocytes compared with nonfailing human myocytes. 75 Moreover, as noted in the foregoing discussion, this defect in cell shortening has a number of important components that may act combinatorially to produce the observed phenotype of cellular contractile dysfunction. Thus, the contractile dysfunction that develops within myocytes during the process of LV remodeling is likely to involve ensembles of genes, including those that regulate calcium handling, sarcomerogenesis, β-adrenergic signaling, and the cytoskeleton, all of which may interact in an exceedingly complex manner within the cardiac myocyte to produce contractile dysfunction.

Are the Defects in Myocyte Function Reversible?

The experimental literature suggests that alterations in the biology and contractility of the failing cardiac myocyte are reversible after β-adrenergic blockade. 35,56 Although the mechanism for the improved contractile performance in isolated myocytes is not known, the improvement in myocyte contractility has been linked to an increase in the density of myofilaments within the failing myocytes. Thus, in this experimental model β-adrenergic blockade appeared to be able to reverse some of the deleterious alterations in the biology of the myocyte. More recent studies in patients who have been treated with β-blockers showed that patients who had an increase in their ejection fraction also had an increase in sarcoplasmic reticulum calcium ATPase mRNA and α-myosin heavy chain mRNA and a decrease in β-myosin heavy chain mRNA, thus demonstrating that the functional improvement in ventricular function after treatment with β-blockers is associated with favorable changes in myocardial gene expression. Another example of the potential reversibility of myocyte contractile defects is suggested by the studies in which isolated failing myocytes obtained from hearts that had been supported with a LV assist device manifested improved shortening and relaxation compared with myocytes isolated from hearts that had not been supported with a LV assist device. 76 Although this interesting study did not directly address the mechanism for this finding, 2 recent studies may provide a partial explanation. In the first study, support with a LV assist device was shown to improve the force-frequency relationship of isolated strips of ventricular tissue, along with improvements in genes encoding for proteins involved in Ca 2+ handling (sarcoplasmic reticulum calcium ATPase, the ryanodine receptor, and the sarcolemmal sodium-calcium exchanger). 77 In the second study, LV assist device support led to a restoration of the integrity of the dystrophin cytoskeleton, which had been shown to be disrupted in myocytes from failing hearts. 78 Together, these latter 2 studies illustrate the plasticity of the molecular phenotype in failing myocytes and suggest that alterations in calcium handling and the myocyte cytoskeleton contribute to contractile dysfunction in the failing heart.

Additional Maladaptive Changes in Remodeled, Failing Myocardial Tissue

The unfavorable alterations that occur in failing myocardium may be categorized broadly into those that occur in the volume of cardiac myocytes and changes that occur in the volume and composition of the extracellular matrix. With respect to the changes that occur in the cardiac myocyte component of the myocardium, there is increasing evidence to suggest that progressive myocyte loss, through both necrotic and apoptotic cell death, may contribute to progressive cardiac dysfunction and LV remodeling. For example, it has long been postulated that excessive adrenergic drive might be overtly deleterious by triggering myocyte necrosis. 79 Indeed, concentrations of norepinephrine that are available within myocardial tissue, as well as in circulating levels in patients with advanced heart failure, are sufficient to provoke myocyte necrosis in experimental model systems. 18 Moreover, excessive stimulation with either angiotensin II or endothelin has been shown to provoke myocyte necrosis in experimental models. 17 Until recently, the clinical evidence that suggested that myonecrosis occurred in heart failure was confined to histological specimens of myocardium obtained during implantation of LV assist devices, which revealed the presence of contraction band necrosis. However, additional evidence for the existence of ongoing myonecrosis in patients with heart failure is suggested by a recent study showing that levels of circulating troponin I were increased 3- to 4-fold in patients with advanced heart failure. 80 Taken together, these clinical studies suggest that myocyte necrosis may contribute to the progressive myocardial remodeling and LV dysfunction that occurs as heart failure progresses.

The relatively recent recognition that mammalian cells are capable of undergoing apoptosis, or programmed cell death, has prompted the intriguing thought that heart failure might also progress by virtue of progressive apoptotic cell death. Support for this point of view has increased with the recognition that DNA damage characteristic of apoptotic cell death occurs in myocytes from failing hearts. 81,82 Moreover, many of the factors that have been implicated in the pathogenesis of heart failure, including myocardial stretch, norepinephrine, TNF, oxidative stress, and angiotensin II, have been shown to trigger apoptosis in a variety of simple in vitro and in vivo experimental model systems. 83–85 Nonetheless, despite the undeniable intrinsic appeal of programmed cell death as a potentially important mechanism for disease progression in the failing heart, there are several caveats that warrant discussion. First, all of the currently available assessments of myocyte apoptosis in failing hearts have been performed in explanted hearts obtained from patients awaiting cardiac transplantation, many of whom were receiving intravenous inotropic support before cardiac transplantation. Given that catecholamines can provoke apoptosis in experimental models, 86 the existing clinical studies may overestimate the true frequency of apoptosis in the failing heart. 81,82 Second, at present, there are no data with respect to whether myocyte apoptosis occurs in patients with mild to moderate heart failure. Thus, it is not clear whether apoptosis contributes to disease progression in heart failure or whether instead it is a phenomenon observed only in end-stage heart failure. Third, the current estimates of myocyte apoptosis in failing myocardium range from clinically insignificant levels of 0.003%/y (estimated myocyte cell loss 0.1%/y) to clinically unrealistic estimates of 5%/y to 35%/y (estimated myocyte loss >100%/y). 87 These striking disparities make it difficult to know exactly what role apoptosis plays in progressive cardiac dysfunction. Thus, although the general concept that myocyte cell loss may contribute to progressive myocardial dysfunction and myocardial remodeling is likely to have validity, further clinical studies will be necessary to determine the frequency of necrosis and apoptosis in patients with mild to moderate heart failure to obtain a clearer understanding of whether cell death occurs early and continually in heart failure or whether instead cell death occurs only in end-stage hearts.

In addition to alterations in the volume and composition of the cardiac myocytes, a number of important changes occur within the extracellular matrix component of the myocardium. 88–91 Perhaps the most widely recognized alteration that occurs in the extracellular matrix is the development of perivascular fibrosis around intramyocardial blood vessels, as well as “replacement fibrosis.” This term has been used to describe the excessive deposition of fibrillar collagen that occurs after the death of myocytes. Enthusiasm for the point of view that progressive fibrosis plays an important role in the progression of heart failure has been engendered by experimental studies showing that angiotensin II, endothelin, and aldosterone 92–94 are sufficient to trigger excessive fibrosis in myocardial tissue, thus providing a potential biochemical explanation for the development of the excessive fibrosis in heart failure.

Although excessive collagen deposition has been invoked as a logical explanation to explain the progressive contractile dysfunction that occurs in the failing heart, until recently it has been difficult to explain precisely how excessive fibrosis (which would be expected to lead to stiffer and less compliant ventricle) could explain the progressive LV dilation that occurs during the process of LV remodeling. Recently, it has been suggested that a family of collagenolytic enzymes becomes activated within the failing myocardium. 88,89,91 Collectively, these collagenolytic enzymes have been referred to as matrix metalloproteinases (MMPs). Conceptually, progressive activation of MMPs might be expected to lead to progressive degradation of the extracellular matrix, which would in turn lead to mural realignment (“slippage”) of myocyte bundles and/or individual myocytes within the LV wall and thus account for the LV wall thinning and dilation that occurs in heart failure. Although the precise biochemical triggers that are responsible for activation of MMPs are not known, it is important to note that TNF, as well as other cytokines and peptide growth factors that are expressed within the failing myocardium, is capable of activating MMPs. However, the biology of matrix remodeling in heart failure is likely to be much more complex than the simple presence or absence of MMP activation, insofar as degradation of the matrix is also controlled by the glycoproteins tissue inhibitors of matrix metalloproteinases (TIMPs), which are capable of regulating the activation of MMPs by binding to and preventing these enzymes from degrading the collagen matrix of the heart. However, the exact role of TIMPs in the failing heart is far from clear in that it appears that under certain conditions TIMPs may actually stabilize and/or localize MMPs, which in turn may facilitate the activation of MMPs. When viewed together, the aforementioned observations suggest that the alterations in the extracellular matrix that occur during LV remodeling are likely to be far more complex than those proposed originally and that there may be periods of ongoing fibrin degradation and deposition throughout the process of LV remodeling.

Are the Defects in the Failing Myocardium Reversible?

In contrast to the defects that occur in the failing myocyte, many of the defects that occur within the myocardium, most notably those affecting myocyte survival, are not reversible and may therefore directly contribute to disease progression. Furthermore, although changes in the extracellular matrix may be partially reversible in some situations, 95–98 there is no current clinical evidence to suggest that the fibrotic changes that occur in the myocardium are completely reversible. Recent studies in which bone marrow cells or enriched hematopoietic stem cells have been delivered to adult hearts, either through intracoronary injection or direct myocardial injections 99–102 or mobilized from the periphery by administration of granulocyte colony-stimulating factor, 103 have suggested that these cells might transdifferentiate into cardiac myocytes, thereby allowing myocardial regeneration to occur. These initial findings have provoked extensive excitement in the field, which in turn has led to a number of ongoing clinical trials. Despite this initial enthusiasm, more recent studies have questioned the ability of hematopoietic stem cells to transdifferentiate into cardiac myocytes. 104–106 Indeed, Nygren and colleagues 106 have shown that the bone marrow–derived hematopoietic stem cells that engraft with cardiac myocytes are CD45 positive and α-actinin negative, suggesting that they are of hematopoietic rather than cardiac lineage. Moreover, this latter study suggested that the durability of the engrafted cells was very low after 28 days. 106 Although these and other recent studies 107,108 have raised important questions about the utility of hematopoietic stem cell transplantation in heart failure, these studies do not preclude the potential utility of nonhematopoietic-derived stem cells (eg, myocardial progenitor cells 109 ) in myocardial regeneration, nor do they preclude the possibility that hematopoietic stems cells may exert beneficial effects in the heart that are distinct from their ability to regenerate the myocardium (eg, angiogenesis). Nonetheless, at the time of this writing many of the myocardial defects that occur in heart failure appear to be largely irreversible and likely represent an important contributor to disease progression in heart failure.

Alterations in Ventricular Chamber Geometry

On the basis of the foregoing discussion, it is clear that the changes that occur in the biology of the failing myocyte and in the biology of failing myocardium contribute to the development of the LV dilation and LV dysfunction that occur during the process of LV remodeling. Several lines of evidence suggest that the deleterious changes that occur in the geometry of the remodeled left ventricle may promote worsening heart failure. One of the first observations with respect to the abnormal geometry of remodeled ventricle was the consistent finding that the remodeled heart was not only larger but also more spherical in shape. 59 As shown in Table 4, the increase in LV size and resultant change in LV geometry from the normal prolate ellipse to a more spherical shape creates a number of de novo mechanical burdens for the failing heart, as discussed above.

A second important problem that results from increased sphericity of the ventricle is that the papillary muscles are pulled apart, resulting in incompetence of the mitral valve and the development of “functional mitral regurgitation.” 110 Although the amount of functional mitral regurgitation was once thought to be mild, the advent of noninvasive imaging modalities has shown that functional mitral regurgitation is clinically significant. Apart from the more obvious problem of loss of forward blood flow, mitral regurgitation presents yet a second problem to the heart insofar as the mitral regurgitation results in further hemodynamic overloading of the ventricle. Taken together, the mechanical burdens that are engendered by LV remodeling might be expected to lead to decreased forward cardiac output, increased LV dilation (stretch), and increased hemodynamic overloading, any or all of which are sufficient to contribute to disease progression independently of the neurohormonal status of the patient. Moreover, the aforementioned changes in LV structure and function might be expected to make the cardiovascular system less responsive to normal homeostatic control mechanisms, such as increased adrenergic drive. Thus, alterations in the remodeled ventricle may foster a self-amplifying situation, in which worsening neurohormonal activation occurs in response to the inability of the remodeled left ventricle to respond appropriately to these compensatory mechanisms. Moreover, at some point it is predictable that the aggregate end-organ changes that occur within the cardiomyopathic ventricle may progress to the point that no amount of neurohormonal stimulation can maintain cardiovascular homeostasis, at which point heart failure may progress independently of the neurohormonal status of the patient.

Are the Defects in the Geometry of the Remodeled Left Ventricle Reversible?

The extant clinical experience suggests that it is possible to retard and possibly regress LV remodeling in some patients. The most obvious clinical example of “reverse” LV remodeling is the striking change that occurs in the dilated cardiomyopathic ventricle after implantation of a LV assist device. The salutary changes that have been reported include increased LV wall thickness, 111 decreased LV volume, 112 and a favorable leftward shift in the LV pressure-volume curve. 112 Medical therapy has also been shown to halt and/or reverse LV remodeling in some patients. For example, therapy with ACE inhibitors appears to prevent worsening LV dilation and further increases in LV mass 113,114 however, these agents will not regress or reverse LV remodeling. 113,114 Recently, β-blockers have been shown to favorably influence LV remodeling, including improvements in LV function and a decrease in LV end-diastolic volume. 14,57,56 Moreover, recent studies employing resynchronization therapy have been shown to lead to significant decreases in mitral regurgitation and LV end-diastolic volumes. 115,116 Thus, the preponderance of experimental and clinical evidence suggests that the defects in the remodeled LV chamber are at least partially reversible in some patients.

LV Remodeling as a Therapeutic Target in Heart Failure

The suggestion that LV remodeling contributes to the progression of heart failure raises the interesting possibility that therapeutic strategies specifically designed to prevent and/or antagonize LV remodeling may also be beneficial in heart failure. In addition to the beneficial effects of LV assist devices on LV remodeling, a number of different surgical approaches have been tried to prevent and/or retard LV remodeling, including surgical myoplasty, which has largely been abandoned, 117 mitral valve surgery, 118 volume reduction surgery (partial left ventriculectomy [so-called Batista procedure]), 119 endoventricular circular patch plasty/surgical anterior ventricular restoration (so-called Dor procedure), 120 and cardiac assist support devices. 58,121,122

Summary, Clinical Implications, and Future Developments

In the present review we have described the clinical syndrome of heart failure in terms of several different clinical model systems, including a cardiorenal model, a hemodynamic model, and a neurohormonal model. As noted, each of the models has strengths and weaknesses in terms of understanding the mechanisms responsible for heart failure and developing effective new therapies for heart failure. We also discussed the importance of the interaction between myocardial systolic dysfunction and cardiac remodeling in the development and progression of heart failure. As illustrated in Figure 2, these 2 fundamental components of the heart failure phenotype are closely interrelated, such that the development of one of them in isolation will usually contribute to the development of the other. Viewed together, these observations suggest that heart failure can be viewed as a biomechanical model, in which heart failure develops and progresses as a result of the deleterious changes in cardiac function and cardiac remodeling that occur as the result of sustained neurohormonal activation. Although this point of view does not obviate the importance of neurohormonal activation in the setting of heart failure, it extends the insights provided by this paradigm by focusing the treatment of heart failure on the downstream biological consequences of neurohormonal activation rather than on neurohormonal activation per se. Thus, clinicians should not only tailor therapeutic strategies to treat their patients’ symptoms (eg, diuretics and digitalis) but should also provide therapies that affect the adverse biological consequences of sustained neurohormonal activation (eg, ACE inhibitors, β-blockers, and aldosterone antagonists). One important departure of the biomechanical model from the neurohormonal model is that the biomechanical predicts that at some point heart failure will progress independently of the neurohormonal status of the patients. Thus, when the deleterious changes in cardiac function and cardiac remodeling are sufficiently advanced, they become self-sustaining and hence are capable of driving disease progression independently of the neurohormonal status of the patient. This may help to explain, at least in part, why conventional neurohormonal strategies lose effectiveness in end-stage heart failure, 46 as well as why many device-based therapies that concurrently affect LV pump performance and LV remodeling (eg, cardiac resynchronization) are beneficial.

Figure 2. Interrelationship between contractile dysfunction and cardiac remodeling. The close relationship between the development of contractile dysfunction and cardiac remodeling is responsible for disease progression in primary or secondary dilated cardiomyopathy (DCM). RAAS indicates renin-angiotensin-aldosterone system ANS, adrenergic nervous system and AR, adrenergic receptor. Reproduced with permission from Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia, Pa: WB Saunders 2004. 133

The biomechanical model predicts that therapeutic strategies that are designed to interrupt the viscous cycle of myocardial dysfunction and/or cardiac remodeling will favorably affect the heart failure phenotype and the natural history of heart failure progression. In designing such therapies, it makes sense to target molecular mechanisms that are operative within the pathological contexts of myocardial dysfunction and/or cardiac remodeling, such that their correction involves normalization of mechanisms that have become maladaptively upregulated or downregulated in direct relation to the development of the heart failure phenotype. Moreover, it makes sense to target molecular mechanisms that will affect both cardiac function and cardiac remodeling rather than treating either of these 2 components in isolation. In this context, it is useful to review how existing therapeutic interventions in heart failure affect myocardial systolic function and cardiac remodeling. As illustrated in Figure 3, ACE inhibitors prevent cardiac remodeling but have very modest overall effects on cardiac performance. 123 On the other hand, β-adrenergic blocking agents lead to improvements in pump performance as well as reverse cardiac remodeling, as discussed in detail above. Moreover, considerable additional potential exists for improved targeting of the renin-angiotensin system, as demonstrated by the Randomized Aldactone Evaluation Study (RALES), 29 Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), 51 and Candesartan in Heart Failure Morbidity and Mortality Assessment–Added 124 (CHARM-Added) trials. The development of cardiac resynchronization therapy, a treatment that instantaneously improves systolic pump function 40,125,126 by eliminating chamber contractile dyssynchrony caused by delayed intraventricular conduction, ultimately reverses remodeling 116,127 and improves the natural history of heart failure (reviewed by Abraham and Hayes 128 ). Indeed, in the recently reported Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial, the reduction in mortality by cardiac resynchronization therapy alone was statistically marginal (P=0.059) but numerically substantial (by 24%) and was due entirely to a reduction in pump function deaths. 40

Figure 3. Effect of medical therapies that affect the natural history of heart failure based on the primary site of action. CRT-(D) indicates cardiac resynchronization therapy plus defibrillator ACEIs, angiotensin-converting enzyme inhibitors and Aldo, aldosterone.

Where Will Future Advances in the Field of Heart Failure Lead Over the Next 5 to 10 Years?

In the context of the foregoing discussion, it will be interesting to see whether new therapies that affect both myocardial function and cardiac remodeling will improve the natural history of heart failure. For example, therapies that directly affect cardiac remodeling, such as passive cardiac support devices, 58,129 surgical restoration of LV shape (eg, the Dor procedure), 130 and stem cells are currently undergoing clinical trials and may find their way into routine clinical use within the next 5 years. Alternatively, newer agents that increase inotropic support of the heart without unwanted proarrhythmic effects, including low-dose type III phosphodiesterase inhibitors combined with β-blockers (eg, enoximone), 41 type III phosphodiesterase inhibitors that sensitize the myofilaments to Ca 2+ (eg, levosimendan), 131 or phospholamban inhibitors 132 are undergoing evaluation and, if proven to be safe, may be used earlier in the disease process to prevent and/or retard the development of cardiac deterioration. Additional benefits may also be derived from more optimal inhibition of the adrenergic nervous system, such as by targeting hyperresponder genetic variants in adrenergic receptors, as well as by more optimal correction of dyssynchronous ventricular chamber contraction by targeting ventricles with directly demonstrated dyssynchrony regardless of QRS length. In addition, it is obvious from even a superficial inspection of the elements of Figure 2 that there are multiple opportunities for developing new successful heart failure therapies. These would include pharmacological inhibitors that block final common signal transduction pathways that have been linked to pathological hypertrophy, which would be used to prevent LV remodeling and hence retard disease progression. Such drugs include agents that inhibit calcineurin signaling or protein kinase C signaling or drugs that inhibit the transcriptional activation of fetal contractile protein genes (eg, MEF2 inhibitors, class I histone deacetylase inhibitors). Many of these approaches are actually undergoing systematic development, and it is likely that at least some of them will be successful.

This research was supported by research funds from the Veterans Administration and the National Institutes of Health (P50 HL-O6H, RO1 HL58081-01, RO1 HL61543-01, HL-42250-10/10). We thank Mary Helen Soliz for secretarial assistance.

Negative Feedback

Negative feedback mechanisms reduce output or activity to return an organ or system to its normal range of functioning. Regulation of blood pressure is an example of negative feedback. Blood vessels have sensors called baroreceptors that detect if blood pressure is too high or too low and send a signal to the hypothalamus. The hypothalamus then sends a message to the heart, blood vessels, and kidneys, which act as effectors in blood pressure regulation. If blood pressure is too high, the heart rate decreases as the blood vessels increase in diameter ( vasodilation ), while the kidneys retain less water. These changes would cause the blood pressure to return to its normal range. The process reverses when blood pressure decreases, causing blood vessels to constrict and the kidney to increase water retention.

Negative Feedback Loop: The hypothalamus secretes corticotropin-releasing hormone (CRH), which directs the anterior pituitary gland to secrete adrenocorticotropic hormone (ACTH). In turn, ACTH directs the adrenal cortex to secrete glucocorticoids, such as cortisol. Glucocorticoids not only perform their respective functions throughout the body but also prevent further stimulating secretions of both the hypothalamus and the pituitary gland

Temperature control is another negative feedback mechanism. Nerve cells relay information about body temperature to the hypothalamus. The hypothalamus then signals several effectors to return the body temperature to 37 degrees Celsius (the set point). The effectors may signal the sweat glands to cool the skin and stimulate vasodilation so the body can give off more heat.

If body temperature is below the set point, muscles shiver to generate heat and the constriction of the blood vessels helps the body retain heat. This example is very complex because the hypothalamus can change the body&rsquos temperature set point, such as raising it during a fever to help fight an infection. Both internal and external events can induce negative feedback mechanisms.

Homeostatic Control: This image illustrates the feedback mechanisms of homeostatic controls.

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