Systolic Dysfunction in Heart Failure

Cellular and Molecular Determinants: A View From 30,000 Feet

The greatest advances in understanding of HF over the past decade have come from the elucidation of its molecular-cellular determinants and their impact at the organ level. Most of this work comes from studies in mice with genetic manipulations, and is discussed in some detail in Chapter 1 .

Systolic force generation starts at the level of the actin-myosin cross-bridge, which, in turn, is coupled via structural proteins to the surface membrane to transduce into net chamber contraction. Sarcomere proteins play a central role in systolic dysfunction revealed by HF causing mutations that depress molecular motors and the myriad of posttranslational modifications that alter their function. Mouse models recapitulating sarcomere defects that induce dilated cardiomyopathy (DCM) exhibit reduced power generation and loss of function of the actin–myosin cross-bridge. Mutations in titin are common, perhaps reflecting its enormous size, and are associated with DCM. The most frequent mutations inducing hypertrophic cardiomyopathy are in myosin-binding protein C (MyBP-C), though they can also induce dilated HF. The phosphorylation of troponin I (TnI), tropomyosin, myosin light chain, MyBP-C, and titin also impacts contractility (see Chapter 2 ). Troponin I and -T phosphorylation modulates myofilament calcium sensitivity, whereas MyBP-C phosphorylation is required for β-adrenergic stimulated contractility. Both TnI and MyBP-C can also undergo proteolytic cleavage in the setting of ischemic injury, with the former resulting in a loss-of-function peptide, and the latter in a poison peptide fragment —both inducing DCM.

HF also entails disruption of intermediate filament proteins that structurally couple the sarcomere to the cell membrane. Loss of function mutations in muscle limb protein, plasma membrane sarcoglycan-dystrophin complex, focal adhesion complexes, including vinculin and metavinculin, and nuclear or mitochondrial membrane linking filaments, such as laminin, lamin, and desmin, are associated with DCM.

Another major cause of systolic impairment are abnormalities of calcium homeostasis (see Chapter 1, Chapter 2 ). This involves ion channels at the plasma membrane and intracellular proteins and calcium storage systems such as the sacroplasmic reticulum (SR). Cycling of calcium via the SR is regulated by phospholamban (PLN) through its control of the SR calcium ATPase (SERCA), but other proteins are involved, including histidine-rich calcium-binding protein, HS-associated protein X-1 (HAX-1), and heat shock protein 20. Posttranslational regulation PLN by phosphatase PP1c is controlled by inhibitor I-1, and reduced I-1 levels observed in failing hearts results in dephosphorylation of PLN and systolic depression. Abnormal activation of protein kinase C α that inhibits I-1 has been proposed as a mechanism. Hyperactive calcium release from the SR is common in failing hearts and particularly linked to excessive calcium-calmodulin activated kinase II phosphorylation of the ryanodine receptor. Other modifications of calcium-handling proteins including oxidation, nitrosylation, and SUMOylation also impair excitation-contraction coupling in the failing heart. Another set of nonvoltage gated nonselective cation channels known as transient receptor potential channels can cause abnormal mechanosensing and prohypertrophic/fibrotic signaling. Relevant species in the heart include TRPV2, TRPC1, TRPC3, and TRPC6.

Molecular signaling abnormalities are vast in the failing heart, and as an increasing number have been manipulated by genetic gain- and loss-of-function studies, their role in contractile failure has been revealed. Beyond specific genes and proteins, broad epigenetic transcriptional regulators such as BET-bromodomains (gene readers), nonprotein coding messenger RNAs (mRNAs) including microRNA (miRNA), long-non-coding RNA, and circular RNAs are also important. Lastly, the global biochemical milieu that the failing heart operates within has itself become a focus of attention. The presence of obesity, with diabetes and proinflammatory conditions, is changing the metabolic and signaling conditions in which even an otherwise “healthy” heart operates. Changes in high-energy phosphate metabolism and fuel substrate utilization have a major impact on systolic function and reserve (see Chapter 17 ).

Lastly, it is important to note that systolic dysfunction extends well beyond the myocyte, engaging the extracellular matrix, and the organ systems to which the heart is coupled. Studies suggest inadequate vasculogenesis to match demands of a hypertrophied ventricle contributes to dysfunction. MiRNAs expressed only in fibroblasts can impair heart function, while inversely, molecular signaling in the myocyte can potently impact interstitial fibrosis and inflammatory responses. Inflammatory modulation and matrix remodeling—often associated with metalloproteinase stimulation—can also impact myocyte performance (see Chapter 4 ). Signaling from peripheral organs, such as the kidney, lung, and liver, are known to impact heart function. Thus therapy to improve systolic function should be viewed broadly and include factors extrinsic to the myocyte itself.

Measuring Systolic Function: A Primer on Pressure-Volume Relations

EF is the most common index of contractile function though it lacks specificity and sensitivity. In fact, EF mostly reflects chamber dilation (end-diastolic volume) rather than contractility, since it is a ratio of stroke volume to end-diastolic volume, and the former is generally maintained until late-stage HF. Second, EF is sensitive to loading changes, notably afterload, but in dilated or hyperdynamic hearts, also to preload. From the 1960s to the 1990s, cardiovascular physiologists focused on developing more specific contractility measures based on various combinations of pressure, volume, or flow. By plotting simultaneous chamber pressure versus volume, Suga, Sagawa, and colleagues revealed how ventricular pressure-volume (PV) loops and relations provided a very powerful framework to dissect intrinsic cardiac contractile and diastolic properties from the loading systems to which the heart was coupled. This framework has since become the primary method used to identify more precise properties of the intact heart and separate them from those mediated by loading.

The fundamental concept underlying PV depictions of heart contraction is that heart muscle acts like a spring with a time-varying stiffness constant. The spring constant at the level of a chamber is called elastance, and the time-varying elastance (elastance is the inverse of compliance), which is easily derived from simultaneous pressure and volume measurements of a ventricular chamber, shows stiffness transitioning from diastole to systole and back again ( Fig 10.1A ). This time-varying elastance waveform shape is remarkably conserved among mammals (see Fig. 10.1B ), among patients with various forms of heart disease or acute modifications. It is also conserved among many gene-mutation models in mice. An exception is in heart muscle lacking MyBP-C. This sarcomere protein imposes a restraint on cross-bridge cycling kinetics, and is required for systolic elastance to be sustained once ejection starts. A newly therapy for HF in clinical trials, omecamtiv mecarbil, invokes a mechanism to prolong the time to peak elastance (discussed more below), and so also changes this underlying shape. Fig. 10.1C shows how this approach differs from a β-adrenergic receptor agonist (dobutamine).

Fig 10.2A displays typical human left ventricular (LV) PV data obtained at rest and during transient reduction of chamber preload volume. The loop furthest to the right shows the rest condition, and the labeling depicts end-diastole (point A), isovolumic contraction (point A-B), opening of the aortic valve (point B), ejection (point B-C), isovolumic relaxation (point C-D), opening of the mitral valve and initiation of diastolic filling (point D), and diastolic filling (point D-A). The loop width is stroke volume, the ratio of width to end-diastolic volume is EF, and the loop area is external (or stroke) work. When ventricular preload is rapidly reduced, both stroke volume and systolic pressure decline with each ensuing beat. This is the Frank–Starling relationship. Indeed, the same data can be used to generate typical Frank–Starling curves by plotting end-diastolic pressure for each beat versus the respective stroke volume (or cardiac output). The loops also reveal the ventricular end-systolic elastance (Ees), the slope of the end-systolic PV relationship formed by the upper-left corners of each loop. This corner point (end-systole) is determined as the time of peak elastance (Pressure/[Volume-V _o ]); where V _o is the chamber end-systolic volume at zero pressure. The collection of points from multiple cardiac cycles at varying loads forms the end-systolic PV relationship (ESPVR). The position and slope of this relation define systolic function. An important feature of the ESPVR is its relative insensitivity to changes in vascular loading. As shown, it is generated over a range of preload, and its linearity (often but not always the case) indicates that the slope (Ees) is preload insensitive. The ESPVR is also fairly afterload insensitive, although this is not absolute. The behavior observed in the heart is also found in single cardiac myocytes, in this case plotting sarcomere length versus tension Fig. 10.2B . As in the whole heart, myocyte end-systolic stiffness is fairly insensitive to the load applied to the cell.

PV analysis facilitates the assessment of acute changes in contractility. This is shown by clinical example in Fig. 10.2C in a patient before and after receiving the calcium channel blocker verapamil by intravenous injection. The decline in contractility is depicted by the reduced Ees. As verapamil is also a vasodilator, EF did not decline, and indeed for a long time the impact of this commonly used clinical drug on contractility was underappreciated because of this. In acute settings, changes in Ees can be unambiguously interpreted as altered contractility. However, contractility changes may manifest by shifting the entire relationship upward and leftward with or without a slope change, and this also should be interpreted as a rise in contractile performance. It is the position and not solely the slope of the relation with such acute changes that is important. Ees is also impacted by ventricular geometric changes independent of underlying muscle properties, so alterations with chronic disease are not as directly equitable with contractility change. For example, with dilated HF, PV relations shift to rightward and Ees often declines. The right shift reflects chronic chamber dilation, while the slope, can decline due to dilation per se, but also due to depressed contractility. An example of this behavior is shown in Fig. 10.2D from a mouse model. There are geometric formulas that estimate myofibrillar stress and strain from pressure-dimension data, and these can provide a more chamber-geometry independent index of muscle stiffness.

Fig. 10.2A displays another key feature of PV loops, their simultaneous depiction of total vascular afterload. The diagonal line connecting the lower right to upper left is known as the effective arterial elastance (Ea), and it incorporates both mean resistance and pulsatile vascular loading imposed on the heart during systole. Ea is calculated from the ratio of end-systolic pressure/stroke volume. It is not synonymous with vascular stiffness; its value is actually most influenced by mean arterial resistance and heart rate (Ea = ESP/SV ≈ R × HR). We do not typically think of HR as an “afterload” but, for any given arterial resistance, a pure rise in HR increases the systemic blood pressure as cardiac output increases. The net effective systolic afterload imposed on the heart is thus greater. However, unlike arterial blood pressure, Ea is minimally altered if only cardiac preload is changed (note how in Fig. 10.2A , diagonal lines from beats with different preloads remain parallel; e.g., Ea is the same). Clinical use of Ea and Ees to assess heart-vascular interaction have shown changes with aging, disease, and drugs, and as a marker of cardiovascular risk. Such analysis also has been extended to the right ventricle (RV) in patients with pulmonary hypertension.

There are some caveats to the ESPVR and its mathematical analysis. First, while the relation is often linear over a constrained range of physiological loading, its overall shape is more often nonlinear, and concaves downward. This is a particularly common observation in small mammals, such as mice, and it should be considered when linear fits are used. There are methods to parameterize the relation independent of a model-fit that can circumvent this problem. Ees is also impacted by noncontractile properties such as chamber geometry, hypertrophy, and interstitial fibrosis, inflammation, and edema. Ees rises with aging in conjunction with arterial stiffening, though this more likely reflects changes in passive than systolic-developed stiffness. Cardiac hypertrophy also manifests by a rise in ventricular Ees. This can reflect hypercontractility, but similar behavior is found in hearts with gene mutations inducing hypertrophy with depressed sarcomere function, as the hypertrophy can still stiffen muscle in the absence of abnormally enhanced contraction.

Beat-to-Beat Regulation of Systolic Function

There are three primary mechanisms that regulate beat-to-beat systolic performance of cardiac muscle. They involve the dependence of systolic force on (a) sarcomere length at the onset of contraction, (b) tension imposed during contraction, and (c) beat frequency. In the intact heart, these components translate to the impact of chamber end-diastolic volume (preload), systemic vascular impedance or wall stress (afterload), and heart rate on cardiac systolic function.