Ohtani, Tomohito

Abstract Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant (HTx) rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumours. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples have significantly improved diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (i) an overview of the practical approach to EMB, (ii) an update on indications for EMB, (iii) a revised plan for HTx rejection surveillance, (iv) the impact of multimodality imaging on EMB, and (v) the current clinical practice in the worldwide use of EMB.

Background In adult Fontan patients, ventricular or arterial dysfunction may impact homeostasis of the Fontan circulation and predispose to heart failure. We sought to characterize ventricular‐arterial ( VA ) properties in adult Fontan patients. Methods and Results Adult Fontan patients (n=170), including those with right ( SRV , n=57) and left ( SLV , n=113) dominant ventricular morphology, were compared to age, sex, and body size matched controls (n=170). Arterial function, load‐insensitive measures of contractility, VA coupling, diastolic function, and ventricular efficiency were assessed. Compared to controls, Fontan patients had similar arterial (Ea), but lower end‐systolic ventricular (Ees), elastance, preload recruitable stroke work and peak power index, impaired VA coupling, eccentric remodeling, reduced ventricular efficiency and increased diastolic stiffness ( P <0.05 for all). Ventricular efficiency declined steeply with higher heart rate in Fontan, but not control, patients. Among Fontan patients (n=123) and controls (n=162) with preserved cardiac index ( CI ; ≥2.5 L/min per m 2 ), Fontan patients had worse contractility than controls, but CI was preserved owing to relative tachycardia, lower afterload, and eccentric remodeling. However, 25% of Fontan patients had reduced CI and were distinguished from those with preserved CI by less‐eccentric remodeling and worse diastolic function, rather than more‐impaired contractility. Conclusions Adult Fontan patients have contractile and diastolic dysfunction with normal afterload, impaired VA coupling, and reduced ventricular efficiency with heightened sensitivity to heart rate. Maintenance of CI is dependent on lower afterload, eccentric remodeling, and relative preservation of diastolic function. These data contribute to our understanding of circulatory physiology in adult Fontan patients.

Background— In vitro studies suggest that phosphorylation of titin reduces myocyte/myofiber stiffness. Titin can be phosphorylated by cGMP-activated protein kinase. Intracellular cGMP production is stimulated by B-type natriuretic peptide (BNP) and degraded by phosphodiesterases, including phosphodiesterase-5A. We hypothesized that a phosphodiesterase-5A inhibitor (sildenafil) alone or in combination with BNP would increase left ventricular diastolic distensibility by phosphorylating titin. Methods and Results— Eight elderly dogs with experimental hypertension and 4 young normal dogs underwent measurement of the end-diastolic pressure-volume relationship during caval occlusion at baseline, after sildenafil, and BNP infusion. To assess diastolic distensibility independently of load/extrinsic forces, the end-diastolic volume at a common end-diastolic pressure on the sequential end-diastolic pressure-volume relationships was measured (left ventricular capacitance). In a separate group of dogs (n=7 old hypertensive and 7 young normal), serial full-thickness left ventricular biopsies were harvested from the beating heart during identical infusions to measure myofilament protein phosphorylation. Plasma cGMP increased with sildenafil and further with BNP (7.31±2.37 to 26.9±10.3 to 70.3±8.1 pmol/mL; P <0.001). Left ventricular diastolic capacitance increased with sildenafil and further with BNP (51.4±16.9 to 53.7±16.8 to 60.0±19.4 mL; P <0.001). Changes were similar in old hypertensive and young normal dogs. There were no effects on phosphorylation of troponin I, troponin T, phospholamban, or myosin light chain-1 or -2. Titin phosphorylation increased with sildenafil and BNP, whereas titin-based cardiomyocyte stiffness decreased. Conclusion— Short-term cGMP-enhancing treatment with sildenafil and BNP improves left ventricular diastolic distensibility in vivo, in part by phosphorylating titin.

Background— Mechanisms promoting the transition from hypertensive heart disease to heart failure with preserved ejection fraction are poorly understood. When inappropriate for salt status, mineralocorticoid (deoxycorticosterone acetate) excess causes hypertrophy, fibrosis, and diastolic dysfunction. Because cardiac mineralocorticoid receptors are protected from mineralocorticoid binding by the absence of 11-β hydroxysteroid dehydrogenase, salt-mineralocorticoid–induced inflammation is postulated to cause oxidative stress and to mediate cardiac effects. Although previous studies have focused on salt/nephrectomy in accelerating mineralocorticoid-induced cardiac effects, we hypothesized that hypertensive heart disease is associated with oxidative stress and sensitizes the heart to mineralocorticoid, accelerating hypertrophy, fibrosis, and diastolic dysfunction. Methods and Results— Cardiac structure and function, oxidative stress, and mineralocorticoid receptor–dependent gene transcription were measured in sham-operated and transverse aortic constriction (studied 2 weeks later) mice without and with deoxycorticosterone acetate administration, all in the setting of normal-salt diet. Compared with sham mice, sham plus deoxycorticosterone acetate mice had mild hypertrophy without fibrosis or diastolic dysfunction. Transverse aortic constriction mice displayed compensated hypertensive heart disease with hypertrophy, increased oxidative stress (osteopontin and NOX4 gene expression), and normal systolic function, filling pressures, and diastolic stiffness. Compared with transverse aortic constriction mice, transverse aortic constriction plus deoxycorticosterone acetate mice had similar left ventricular systolic pressure and fractional shortening but more hypertrophy, fibrosis, and diastolic dysfunction with increased lung weights, consistent with heart failure with preserved ejection fraction. There was progressive activation of markers of oxidative stress across the groups but no evidence of classic mineralocorticoid receptor–dependent gene transcription. Conclusions— Pressure-overload hypertrophy sensitizes the heart to mineralocorticoid excess, which promotes the transition to heart failure with preserved ejection fraction independently of classic mineralocorticoid receptor–dependent gene transcription.