Coronary arterial vasculature in the pathophysiology of hypertrophic cardiomyopathy

Abstract

Alterations in the coronary vascular system are likely associated with a mismatch between energy demand and energy supply and critical in triggering the cascade of events that leads to symptomatic hypertrophic cardiomyopathy. Targeting the early events, particularly vascular remodeling, may be a key approach to developing effective treatments. Improvement in our understanding of hypertrophic cardiomyopathy began with the results of early biophysical studies, proceeded to genetic analyses pinpointing the mutational origin, and now pertains to imaging of the metabolic and flow-related consequences of such mutations. Microvascular dysfunction has been an ongoing hot topic in the imaging of genetic cardiomyopathies marked by its histologically significant remodeling and has proven to be a powerful asset in determining prognosis for these patients as well as enlightening scientists on a potential pathophysiological cascade that may begin early during the developmental process. Here, we discuss questions that continue to remain on the mechanistic processes leading to microvascular dysfunction, its correlation to the morphological changes in the vessels, and its contribution to disease progression.

Keywords: Energetics; Hypertrophic cardiomyopathy; Ischemia; Microvascular; Pathogenesis.

Fig. 1

Gross and microscopic features of hypertrophic cardiomyopathy: HCM is characterized by focal lesions of replacement fibrosis within regions of gross hypertrophy as well as subendocardial fibrosis. Extensive small arterial remodeling is observed in these regions but not exclusively. The inset portrays mid-myocardial features associated with affected myocardial tissue: myofiber disarray, perivascular fibrosis (increased collagen deposition is indicated by blue as would be with Masson Trichrome staining), microvascular rarefaction, ischemic cardiac remodeling, interstitial fibrosis. Bottom right portrays a cross-section through an intra-mural artery undergoing typical changes observed during vascular injury (fibromuscular dysplasia), which include myofibroblast trans-differentiation and activation, medial hypertrophy, smooth muscle cell intimal infiltration and elaboration of extracellular matrix, and breakdown of the internal elastic membrane

Fig. 2

Cascade of events leading to the cyclical remodeling pattern in HCM: The initial HCM-causing mutation leads to an alteration in the contractile dynamics of the myofilaments that either directly is the cause of diastolic abnormalities or through inefficient energy consumption leads to diastolic dysfunction. Inefficient energy consumption causes arterial remodeling (fibromuscular dysplasia) likely through shear stress–related vascular injury. When remodeling is severe enough, perfusion is impaired leading to ischemic cardiac remodeling that can act to lower energy costs but when severe enough may replace cells with fibrous tissue. Loss of viable myocardium eventually leads to a compensatory hypertrophy that not only increases energy requirements but also the transmural distance required for coronary flow to traverse (not drawn). Comorbidities such as hypertension, valvular disease, or aging can increase metabolic demands of the myocardium. Possible direct targets of some current and prospective therapeutic treatments are noted. RAAS, renin-angiotensin-aldosterone-system; S1P, sphingosine-1-phosphate; non-DHP CCB, non-dihydropyridine calcium channel blockers