Medical Therapies to Improve Left Ventricular Outflow Obstruction and Diastolic Function in Hypertrophic Cardiomyopathy

Figures

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  Central Illustration. Mechanisms and Available Evidence of Current Pharmacologic Treatment Options to Reduce Left Ventricular Outflow Tract Gradient in Obstructive Hypertrophic Cardiomyopathy Beta-blockers and calcium-channel blockers reduce left ventricular contractile force while increasing left ventricular filling time and volume via beta 1 receptor and L-type calcium channel modulation, respectively. Disopyramide exerts a negative inotropic effect by modulating sodium channels and intracellular calcium. Cardiac myosin inhibitors directly decrease myosin-actin interactions with a negative inotropic and lusitropic effect. ATP = adenosine triphosphate; BB = beta-blockers; CA = calcium; cAMP = cyclic adenosine monophosphate; CCB = calcium-channel blocker; CMI = cardiac myosin inhibitors; LTCC = L-type calcium channel; LV = left ventricular; NCX = Na(+)/Ca(2+) exchanger; PKA = protein kinase; RYR2 = cardiac ryanodine receptor 2.

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  Figure 1. Pharmacologic Effects of Nonvasodilating Beta-Adrenergic Blockers on the Pathomechanisms of Obstructive Hypertrophic Cardiomyopathy This drug class modulates the sympathetic tone leading to the following effects: 1) decrease in heart rate that causes prolongation of the diastolic phase, ultimately mitigating the obstructive effects on the LVOT; and 2) decrease in inotropy causing a decrease in myocardial oxygen demand and LVOT obstruction, both ultimately leading to the decrease of patient-felt symptoms. LVOT = left ventricular outflow tract.

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  Figure 2. Pharmacologic Effects of Nondihydropyridine Calcium-Channel Blockers on the Pathomechanisms of Obstructive Hypertrophic Cardiomyopathy This drug class blocks the calcium influx into the SA and AV nodes resulting to negative effects on: 1) chronotropy leading a decrease in heart rate that causes prolongation of the diastolic phase, ultimately mitigating the obstructive effects on the LVOT; and 2) inotropy causing a decrease in myocardial oxygen demand and LVOT obstruction, both ultimately leading to the decrease of patient-felt symptoms. However, diltiazem is known to have a systemic vasodilating effect that may lead to a paradoxical increase in LVOT obstruction. AV = atrioventricular; LVOT = left ventricular outflow tract; SA = sinoatrial.

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  Figure 3. Pharmacologic Effects of Disopyramide on the Pathomechanism of Obstructive Hypertrophic Cardiomyopathy This drug decreases LVOT obstruction by mitigating the effects of energy-wasting hypercontractility in HCM by blocking the sodium channels on cardiomyocytes, leading to a decrease in sodium-calcium exchanger activity, causing a fall in intracardiomyocyte calcium levels. HCM = hypertrophic cardiomyopathy; LVOT = left ventricular outflow tract.

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  Figure 4. Pharmacologic Effects of Cardiac Myosin Inhibitors on the Pathomechanism of Obstructive Hypertrophic Cardiomyopathy This novel drug class selectively and reversibly binds the allosteric binding site of the cardiac myosin ATPase, leading to a decrease in excessive myosin ATPase activity, which causes pathologic hypercontractility in HCM. Hence, in a downstream of events, causes a decrease in LVOT obstruction as well as diastolic dysfunction by mitigating the impaired LV relaxation in HCM. HCM = hypertrophic cardiomyopathy; LV = left ventricle; LVOT = left ventricular outflow tract.