Contractile Patterns in Physiologic and Pathologic Hypertrophy

 Effects of Mechanical Load on Contraction and Relaxation

Wall Stress and Compensated Left Ventricular Hypertrophy

Meerson, in 1962, studied the cardiac hypertrophic response to experimental constriction of the aorta. He described the prolonged protective state of “compensatory hyperfunction” of the heart. Thereafter, if the pressure load were continued, the left ventricle developed fibrosis with a transition to the “decompensated” state with failure and dilation. To explain the mechanism of the LV hypertrophy, Grossman, in 1975, proposed that the hypertrophic response was evoked by increased wall stretch, the result of an increased intraventricular LV pressure . According to his systolic stress correction hypothesis, pressure overload caused myocytes to grow in width and to thicken. Then, according to the Laplace law, the increased wall thickness would decrease and even normalize the increased wall stress (for review, see Opie). This hypothesis is currently under challenge from studies on transgenic mice, yet the compensated hypertrophic state remains an oft-cited clinical entity. An examination of the signaling paths involved in LV hypertrophy can explain such apparent contradictions.

Left Ventricular Response to Mechanical Stress

There are two basic patterns of response to a sustained LV pressure load hypothetically associated with adaptive and maladaptive signals. According to the signaling stimulus invoked by the load, the myocyte can either survive, leading to “beneficial hypertrophy,” or undergo adverse patterns of signaling that lead to hypertrophy-associated apoptosis (programmed cell death) and related degenerative patterns. Thus, in adverse signaling, LV hypertrophy is associated with varying degrees of LV failure and dilation.

The “beneficial” survival paths include the prosurvival extracellular signal–regulated kinase (ERK), which, when genetically activated, yields an adaptive hypertrophy with normalized wall stress and fully compensated for an increased load. Likewise, exercise-induced heart hypertrophy (see later) involves the closely related enzyme Akt, also known as protein kinase B. The Akt path can also be activated by IGF-1. Two groups have recently emphasized the protective role of low-dose TNF-α. The current hypothesis is that TNF-α–induced cytoprotection is mediated by the subtype 2 receptor, which activates the survivor activating factor enhancement (SAFE) pathway.

Preload Versus Afterload: Differential Effects on Ventricular Function

Chronic elevation of the preload by aorto-caval shunt was compared with afterload elevation by transverse aortic constriction in mice. There were comparable increases of wall stress and LV hypertrophy, as measured by the ratio of LV weight to tibial length. The hypertrophic phenotypes were completely different. Aortic constriction caused maladaptive fibrotic hypertrophy with disturbed calcium cycling and apoptosis, rapid failure, and increased mortality. Knockout or inhibition of CaMKinase II  normalized calcium cycling and reduced apoptosis. In contrast, increased preload was associated with Akt activation without fibrosis, little apoptosis, better function, and lower mortality. This indicates that different patterns of load result in distinct phenotype differences that may require different therapeutic interventions.

Impaired Left Ventricular Function Related to Adverse Signaling

In response to an abrupt mechanical load or to increased systolic wall stress, angiotensin II is released from myocardium. After angiotensin II binds to its receptor, it activates the G protein G_q to initiate a signaling sequence that leads to the enzyme complex MAP kinase. Some of the MAP kinase components, such as ERK, promote prosurvival signaling; others, such as JNK, stimulate apoptosis and decrease myocyte survival. Other maladaptive paths include those that act through calcium-calmodulin, calcineurin and the nuclear factor NFAT, or CaMKII. Yet others promote fibrosis in response to angiotensin II, aldosterone, and transforming growth factor-β.

If pressure-induced angiotensin II stimulation leads to more maladaptive than adaptive growth and more apoptosis, genetic interruption of the angiotensin II path would lessen hypertrophy yet protect the myocardium. In a mouse model in which part of the angiotensin II receptor–related signaling system was transgenically inactivated by elimination of the G protein G_q, pressure loading gave less than predicted hypertrophy with decreased correction of wall stress, yet contractile function was better than in the wild type that had more LV hypertrophy. This finding shows that the wall stress model is not infallible, rather depending on which is the signaling path that promotes the hypertrophy.

Left Ventricular Hypertrophy and Diastolic Dysfunction 

In hearts with concentric hypertrophy, as in chronic hypertension or severe aortic stenosis, abnormalities of diastole are common and may precede systolic failure. Regarding the signaling paths involved in aortic stenosis with LV hypertrophy, there is strong evidence for growth signals such as angiotensin II and transforming growth factor-β being associated not only with myocyte growth but also with maladaptive fibrosis, myocyte degeneration, and eventual myocyte loss. Overall, taking both experimental and limited patient data into account, a sustained pressure load, as in aortic stenosis, is a mixed stimulus that produces both beneficial adaptive and adverse maladaptive remodeling. The latter could explain why the wall stress correction hypothesis does not always apply and why, in patients with aortic stenosis, increased LV mass predicts systolic dysfunction and heart failure.

Left Ventricular Dysfunction in Insulin Resistance

In conditions such as diabetes type 2, an accumulation of myocardial triglyceride (cardiac steatosis) is related to diastolic dysfunction rather than to systolic failure. The proposed mechanism is related to excess circulating free fatty acids and impaired glucose tolerance associated with insulin resistance.

Left Ventricular Volume Loading and the Signals Involved

Volume differs from pressure loading in several important ways. From the signaling point of view, volume-induced mechanical stress with progressively greater LV volumes releases increasing amounts of TNF from the normal myocardium. Passive stretch of ventricular muscle promotes TNF mRNA synthesis. Low-level TNF stimulation interlinks with other cytokines, such as cardiotrophin 1 acting on the glycoprotein 130 receptor, to promote prosurvival pathways so that the sarcomere units form in series to result in eccentric hypertrophy. Remodeling in early volume overload may be related to stretch-induced signaling via adaptive signals such as cardiotrophin 1, low-level TNF-α, cGMP, and IGF-1. In one of the few direct comparisons with pressure-loading mechanisms, pressure but not volume overload increased the potentially adverse signal JNK, compatible with the scheme in.

Does the Stress Correction Hypothesis Hold for a Volume Load?

Experimentally, after 3 months of severe mitral regurgitation in dogs, LV mass increased with cardiomyocyte lengthening, whereas end-diastolic volume and wall stress (both diastolic and systolic) increased substantially. Overall, the data are compatible with the Grossman concept of increased diastolic wall stress as the initiator of longitudinal myocyte growth in response to a chronic volume load. However, in severe experimental mitral regurgitation, end-diastolic wall stress is much higher (by about fourfold) so that stress correction has not occurred. This problem could be predicted because as myocyte length increases, so does the radius, thus increasing rather than decreasing wall stress. Furthermore, volume-induced ventricular enlargement may be self-perpetuating by promotion of increasing mitral regurgitation and increasing ventricular sphericity. At this late stage, it is likely that the growth paths that are stimulated would be chiefly those with the maladaptive patterns, for example, in response to excess TNF-α. Conversely, athletic training may induce pathways of volume and pressure loading in a manner that produces an enlarged but “balanced” heart.