Containing hypertrophy with a PICOT fence.

Why Is a Big Heart a Bad Thing? From the perspective of cardiac mechanics, it seems surprising that cardiac hypertrophy is a killer. The physics of reactive hypertrophy date to the 19th century1 and predict that hypertrophy will compensate for increased hemodynamic loading through normalization of ventricular wall stress, the phylogenetically conserved set point for cardiac load.2 The Laplace relationship (stress 1⁄2 pr/h), describes wall stress increasing in direct proportion with intraluminal pressure (p) and chamber radius (r), but decreasing as wall thickness (h) grows. Accordingly, whether the ventricle dilates or is subjected to increased pressure, hypertrophic thickening of its walls should compensate.3 And it does. However, long-term functional compensation relies on the quality of hypertrophied myocardium being invariant as quantity increases, which is not the case. Multiple studies have defined molecular, cellular, and functional characteristics of reactive hypertrophy that differentiate it from normal myocardium and from cardiac enlargement caused by physiological conditioning.4–6 Such findings gave rise to the notions of pathological and physiological hypertrophies7 and provide a mechanistic framework for why reactive hypertrophy ultimately fails,8 whereas physiological conditioning of the heart does not. Cardiac hypertrophy also has effects unrelated to contractility and ventricular ejection performance. To quote Joseph Stalin out of context, “Quantity has a quality all its own”, meaning that a steady quantitative change can create a sudden qualitative shift. The heart aptly demonstrates this principle because reactive hypertrophy and wall thickening increase ventricular stiffness, which leads to diastolic dysfunction and heart failure with preserved ejection fraction.9 Moreover, a number of studies have suggested that cardiac hypertrophy is not essential to functional compensation after pressure overload. When genetic techniques were employed to inhibit critical hypertrophy signaling pathways after pressure overloading of mice, the absence of reactive hypertrophy was not associated with functional deterioration.10–12 Although the long-term efficacy of hypertrophy inhibition and its chronic consequences on ventricular function have not been completely defined, these results demonstrate that it is possible to suppress reactive hypertrophy without catastrophic functional decompensation. Thus, cardiac hypertrophy appears to be both undesirable and dispensable.