Impaired longitudinal systolic-diastolic coupling and cardiac response to exercise in patients with hypertrophic cardiomyopathy.

BACKGROUND: In patients with hypertrophic cardiomyopathy (HCM), impaired augmentation of stroke volume and diastolic dysfunction contribute to exercise intolerance. Systolic-diastolic (S-D) coupling characterizes how systolic contraction of the left ventricle (LV) primes efficient elastic recoil during early diastole. Impaired S-D coupling may contribute to the impaired cardiac response to exercise in patients with HCM. METHODS: Patients with HCM (n = 25, age = 47 ± 9 years) and healthy adults (n = 115, age = 49 ± 10 years) underwent a cardiopulmonary exercise testing (CPET) and echocardiogram. S-D coupling was defined as the ratio of LV longitudinal excursion of the mitral annulus during early diastole (EDexc) and systole (Sexc) and compared between groups. Peak oxygen uptake (peak V̇O2) (Douglas bags), cardiac index (C2H2 rebreathe), and stroke volume index (SVi) were assessed during CPET. Linear regression was performed between S-D coupling and peak V̇O2, peak cardiac index, and peak SVi. RESULTS: S-D coupling was lower in HCM (Controls: 0.63 ± 0.08, HCM: 0.56 ± 0.10, p < 0.001). Peak V̇O2 and stroke volume reserve were lower in patients with HCM (Peak VO2 Controls: 28.5 ± 5.5, HCM: 23.7 ± 7.2 mL/kg/min, p < 0.001, SV reserve: Controls 39 ± 16, HCM 30 ± 18 mL, p = 0.008). In patients with HCM, S-D coupling was associated with peak V̇O2 (r = 0.47, p = 0.018), peak cardiac index (r = 0.60, p = 0.002), and peak SVi (r = 0.63, p < 0.001). CONCLUSION: Systolic-diastolic coupling was impaired in patients with HCM and was associated with fitness and the cardiac response to exercise. Inefficient S-D coupling may link insufficient stroke volume generation, diastolic dysfunction, and exercise intolerance in HCM.

Remodeling of substrate consumption in the murine sTAC model of heart failure.

BACKGROUND: Energy metabolism and substrate selection are key aspects of correct myocardial mechanical function. Myocardial preference for oxidizable substrates changes in both hypertrophy and in overt failure. Previous work has shown that glucose oxidation is upregulated in overpressure hypertrophy, but its fate in overt failure is less clear. Anaplerotic flux of pyruvate into the tricarboxylic acid cycle (TCA) has been posited as a secondary fate of glycolysis, aside from pyruvate oxidation or lactate production. METHODS AND RESULTS: A model of heart failure that emulates both valvular and hypertensive heart disease, the severe transaortic constriction (sTAC) mouse, was assayed for changes in substrate preference using metabolomic and carbon-13 flux measurements. Quantitative measures of O2 consumption in the Langendorff perfused mouse heart were paired with 13C isotopomer analysis to assess TCA cycle turnover. Since the heart accommodates oxidation of all physiological energy sources, the utilization of carbohydrates, fatty acids, and ketones were measured simultaneously using a triple-tracer NMR method. The fractional contribution of glucose to acetyl-CoA production was upregulated in heart failure, while other sources were not significantly different. A model that includes both pyruvate carboxylation and anaplerosis through succinyl-CoA produced superior fits to the data compared to a model using only pyruvate carboxylation. In the sTAC heart, anaplerosis through succinyl-CoA is elevated, while pyruvate carboxylation was not. Metabolomic data showed depleted TCA cycle intermediate pool sizes versus the control, in agreement with previous results. CONCLUSION: In the sTAC heart failure model, the glucose contribution to acetyl-CoA production was significantly higher, with compensatory changes in fatty acid and ketone oxidation not reaching a significant level. Anaplerosis through succinyl-CoA is also upregulated, and is likely used to preserve TCA cycle intermediate pool sizes. The triple tracer method used here is new, and can be used to assess sources of acetyl-CoA production in any oxidative tissue.

Childhood and Adolescent Adversity and Cardiometabolic Outcomes: A Scientific Statement From the American Heart Association.

Adverse experiences in childhood and adolescence, defined as subjectively perceived threats to the safety or security of the child's bodily integrity, family, or social structures, are known to be associated with cardiometabolic outcomes over the life course into adulthood. This American Heart Association scientific statement reviews the scientific literature on the influence of childhood adversity on cardiometabolic outcomes that constitute the greatest public health burden in the United States, including obesity, hypertension, type 2 diabetes mellitus, and cardiovascular disease. This statement also conceptually outlines pathways linking adversity to cardiometabolic health, identifies evidence gaps, and provides suggestions for future research to inform practice and policy. We note that, despite a lack of objective agreement on what subjectively qualifies as exposure to childhood adversity and a dearth of prospective studies, substantial evidence documents an association between childhood adversity and cardiometabolic outcomes across the life course. Future studies that focus on mechanisms, resiliency, and vulnerability factors would further strengthen the evidence and provide much-needed information on targets for effective interventions. Given that childhood adversities affect cardiometabolic health and multiple health domains across the life course, interventions that ameliorate these initial upstream exposures may be more appropriate than interventions remediating downstream cardiovascular disease risk factor effects later in life.

Adiponectin protects against incident hypertension independent of body fat distribution: observations from the Dallas Heart Study.

BACKGROUND: Excess adipose tissue has been implicated in the pathogenesis of insulin resistance and atherosclerosis and is a key risk factor for blood pressure (BP) elevation. However, circulating levels of adiponectin, a protein produced by adipose tissue and widely implicated in the pathogenesis of insulin resistance and atherosclerosis, are inversely proportional to adiposity. The relationship between adiponectin and incident hypertension has not been determined in the general US population. METHODS: Normotensive participants (n = 1233) enrolled in the Dallas Heart Study, a multiethnic, probability-based population sample of Dallas County adults were followed for median of 7 years. Retroperitoneal, intraperitoneal, visceral, and subcutaneous adipose tissue were measured at baseline by magnetic resonance imaging. Liver fat content was measured by 1 H-magnetic resonance spectroscopy. Relative risk regression was used to determine the association of adiponectin with incident hypertension after adjustment for age, race, sex, BMI, smoking, diabetes, baseline systolic BP, total cholesterol, and regional fat depot. RESULTS: Of the 1233 study participants (median age 40 years, 40% black, and 56% women), 391 (32%) had developed hypertension over a median follow-up of 7 years. Adiponectin levels were associated with reduced risk of incident hypertension (RR 0.81, 95% CI [0.68-0.96]) in the fully adjusted model, which included liver fat. Similar results were observed after adjustment for subcutaneous or visceral fat depots when tested individually or simultaneously in the model. CONCLUSION: Our study suggested a protective role of adiponectin against incident hypertension independent of body fat distribution.

Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy.

BACKGROUND: Reperfusion accounts for a substantial fraction of the myocardial injury occurring with ischemic heart disease. Yet, no standard therapies are available targeting reperfusion injury. Here, we tested the hypothesis that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor approved for cancer treatment by the US Food and Drug Administration, will blunt reperfusion injury. METHODS AND RESULTS: Twenty-one rabbits were randomly assigned to 3 groups: (1) vehicle control, (2) SAHA pretreatment (1 day before and at surgery), and (3) SAHA treatment at the time of reperfusion only. Each arm was subjected to ischemia/reperfusion surgery (30 minutes coronary ligation, 24 hours reperfusion). In addition, cultured neonatal and adult rat ventricular cardiomyocytes were subjected to simulated ischemia/reperfusion to probe mechanism. SAHA reduced infarct size and partially rescued systolic function when administered either before surgery (pretreatment) or solely at the time of reperfusion. SAHA plasma concentrations were similar to those achieved in patients with cancer. In the infarct border zone, SAHA increased autophagic flux, assayed in both rabbit myocardium and in mice harboring an RFP-GFP-LC3 transgene. In cultured myocytes subjected to simulated ischemia/reperfusion, SAHA pretreatment reduced cell death by 40%. This reduction in cell death correlated with increased autophagic activity in SAHA-treated cells. RNAi-mediated knockdown of ATG7 and ATG5, essential autophagy proteins, abolished SAHA's cardioprotective effects. CONCLUSIONS: The US Food and Drug Administration-approved anticancer histone deacetylase inhibitor, SAHA, reduces myocardial infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during ischemia/reperfusion occur, at least in part, through the induction of autophagic flux.

Inaccuracy of estimated resting oxygen uptake in the clinical setting.

BACKGROUND: The Fick principle (cardiac output = oxygen uptake ( O2)/systemic arterio-venous oxygen difference) is used to determine cardiac output in numerous clinical situations. However, estimated rather than measured O2 is commonly used because of complexities of the measurement, though the accuracy of estimation remains uncertain in contemporary clinical practice. METHODS AND RESULTS: From 1996 to 2005, resting O2 was measured via the Douglas bag technique in adult patients undergoing right heart catheterization. Resting O2 was estimated by each of 3 published formulae. Agreement between measured and estimated O2 was assessed overall, and across strata of body mass index, sex, and age. The study included 535 patients, with mean age 55 yrs, mean body mass index 28.4 kg/m2; 53% women; 64% non-white. Mean (±standard deviation) measured O2 was 241 ± 57 ml/min. Measured O2 differed significantly from values derived from all 3 formulae, with median (interquartile range) absolute differences of 28.4 (13.1, 50.2) ml/min, 37.7 (19.4, 63.3) ml/min, and 31.7 (14.4, 54.5) ml/min, for the formulae of Dehmer, LaFarge, and Bergstra, respectively (P<0.0001 for each). The measured and estimated values differed by >25% in 17% to 25% of patients depending on the formula used. Median absolute differences were greater in severely obese patients (body mass index > 40 kg/m2), but were not affected by sex or age. CONCLUSIONS: Estimates of resting O2 derived from conventional formulae are inaccurate, especially in severely obese individuals. When accurate hemodynamic assessment is important for clinical decision-making, O2 should be directly measured.

A Prospective Analysis of Plasma Adiponectin and Risk of Incident Cancer: The Dallas Heart Study.

BACKGROUND: Adiponectin dysregulation is postulated to affect cancer risk via modulation of insulin resistance and inflammation. Epidemiologic studies evaluating this relationship have conflicting results and data from non-white cohorts are lacking. We examined the association between adiponectin and risk of cancer incidence in the multiethnic Dallas Heart Study (DHS). METHODS: Participants enrolled in the DHS and known adiponectin values were included. Incident cancer cases were identified through a systematic linkage of the DHS and the Texas Cancer Registry. Univariate/multivariate analysis were performed to test the association between adiponectin and incident cancer after adjusting for age, diabetes status, gender, ethnicity, C-reactive protein level, smoking status, and body mass index. Adiponectin level was evaluated both as a continuous variable and in race/ethnicity specific quartiles. RESULTS: Of 3444 individuals, there were 152 incident cancers. The study population was comprised of 44.4% men, and 51.05% were black. Baseline median adiponectin levels were 6.43 mcg/mL (interquartile range [IQR], 4.37-9.45 mcg/mL) in the incident cancer group versus 6.33 mcg/mL (IQR, 4.57-9.97 mcg/mL) in those without cancer. In multivariable analysis, adiponectin level was not associated with cancer incidence after adjusting for covariates. In analyses stratified by race/ethnic group, no association was observed in white, Hispanic, or African American subgroups. CONCLUSIONS: In this study of a predominant ethnic minority population, no association between adiponectin and cancer incidence was demonstrated. Despite preclinical rationale and confirmatory findings in other studies, this association may not replicate across all ethnic populations. Additional studies with strong minority representation are warranted to further examine this association.

Adipose tissue biology and cardiomyopathy: translational implications.

It is epidemiologically established that obesity is frequently associated with the metabolic syndrome and poses an increased risk for the development of type 2 diabetes mellitus and cardiovascular disease. The molecular links that connect the phenomenon of obesity, per se, with insulin resistance and cardiovascular disease are still not fully elucidated. It is increasingly apparent that fully functional adipose tissue can be cardioprotective by reducing lipotoxic effects in other peripheral tissues and by maintaining a healthy balance of critical adipokines, thereby allowing the heart to maintain its full metabolic flexibility. The present review highlights both basic and clinical findings that emphasize the complex interplay of adipose tissue physiology and adipokine-mediated effects on the heart exerted by either direct effects on cardiac myocytes or indirect actions via central mechanisms through sympathetic outflow to the heart.

Using metabolomics to assess myocardial metabolism and energetics in heart failure.

There is a long history of investigation into the metabolism of the failing heart. Congestive heart failure is marked both by severe disruptions in myocardial energy supply and an inability of the heart to efficiently uptake and oxidize fuels. Despite the many advancements in our understanding, there are still even more outstanding questions in the field. Metabolomics has the power to assist our understanding of the metabolic derangements which accompany myocardial dysfunction. Metabolomic investigations in animal models of heart failure have already highlighted several novel, potentially important pathways of substrate selection and toxicity. Metabolomic biomarker studies in humans, already successfully applied to other forms of cardiovascular disease, have the potential to improve diagnosis and patient care. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".

Correlations between physician-perceived functional status, patient-perceived health status, and cardiopulmonary exercise results in hypertrophic cardiomyopathy.

BACKGROUND: Dyspnea and the resulting functional impairment are a common complication in hypertrophic cardiomyopathy (HCM). The relationship between physician-perceived functional status, patient-perceived health status, and objective exercise test results has not been evaluated in this condition. PURPOSE: To evaluate the correlation between the Kansas City Cardiomyopathy Questionnaire (KCCQ) and (1) physician's perceived (NYHA class) and (2) objective measurement (cardiopulmonary exercise test) of functional capacity in patients with HCM. METHODS: In 24 outpatients with HCM at a single, referral center, the KCCQ instrument was administered and cardiopulmonary exercise testing (CPX) was performed. Severity of symptoms as determined by physician (NYHA classification) and patient (KCCQ instrument) was obtained before exercise test results were known. Pearson correlation was used to assess the independent correlation between KCCQ score and the various exercise parameters; Spearman correlation was used to assess correlation between KCCQ score and NYHA class. RESULTS: KCCQ results demonstrated moderate reductions in all domains, with greatest reduction in quality-of-life domain. CPX testing showed reduction in peak oxygen consumption (mean absolute VO2 20.5 ± 7.8 ml/kg/min and percent predicted VO2 76.8 ± 4.1 %). There were negative correlations between NYHA class and all KCCQ components except the self-efficacy score. The strongest correlations were between NYHA class and the overall summary score (r = -0.623, p = 0.001) as well as the physical limitation score (r = -0.604, p = 0.002). Similarly, there were statistically significant positive correlations between the KCCQ components and percent predicted peak VO2. The strongest correlation was between percent predicted peak VO2 and the physical limitation score (r = 0.474, p = 0.019), but there was also correlation between percent predicted peak VO2 and the quality-of-life score (r = 0.456, p = 0.025), the functional status score (r = 0.455, p = 0.025), and the clinical summary score (r = 0.444, p = 0.030). CONCLUSIONS: The multiple domains of the KCCQ provide data on patient-perceived health status, which correlate with physician-perceived and objective measurement of functional capacity in HCM. Additional studies are needed to evaluate the sensitivity of the KCCQ to changes in functional capacity over time or in response to therapies for this condition.

Randomized Controlled Trial of Moderate- and High-Intensity Exercise Training in Patients With Hypertrophic Cardiomyopathy: Effects on Fitness and Cardiovascular Response to Exercise.

Background Moderate intensity exercise training (MIT) is safe and effective for patients with hypertrophic cardiomyopathy, yet the efficacy of high intensity training (HIT) remains unknown. This study aimed to compare the efficacy of HIT compared with MIT in patients with hypertrophic cardiomyopathy. Methods and Results Patients with hypertrophic cardiomyopathy were randomized to either 5 months of MIT, or 1 month of MIT followed by 4 months of progressive HIT. Peak oxygen uptake (V˙O2; Douglas bags), cardiac output (acetylene rebreathing), and arteriovenous oxygen difference (Fick equation) were measured before and after training. Left ventricular outflow gradient and volumes were measured by echocardiography. Fifteen patients completed training (MIT, n=8, age 52±7 years; HIT, n=7, age 42±8 years). Both HIT and MIT improved peak V˙O2 by 1.3 mL/kg per min (P=0.009). HIT (+1.5 mL/kg per min) had a slightly greater effect than MIT (+1.1 mL/kg per min) but with no statistical difference (group×exercise P=0.628). A greater augmentation of arteriovenous oxygen difference occurred with exercise (Δ1.6 mL/100 mL P=0.005). HIT increased left ventricular end-diastolic volume (+17 mL, group×exercise P=0.015) compared with MIT. No serious arrhythmias or adverse cardiac events occurred. Conclusions This randomized trial of exercise training in patients with hypertrophic cardiomyopathy demonstrated that both HIT and MIT improved fitness without clear superiority of either. Although the study was underpowered for safety outcomes, no serious adverse events occurred. Exercise training resulted in salutary peripheral and cardiac adaptations. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03335332.

Phase 2 Study of Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients. OBJECTIVES: This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM. METHODS: Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout. RESULTS: From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: -40 ± 27 mm Hg, and -43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (-36 ± 27 mm Hg and -53 ± 44 mm Hg, P = 0.001 and <0.0001 vs placebo, respectively). There were modest reductions in EF (-6% ± 7.5% and -12% ± 5.9%, P = 0.007 and P < 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro-B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms. CONCLUSIONS: Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM.

Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults.

CONTEXT: The risk of type 2 diabetes mellitus is heterogeneous among obese individuals. Factors that discriminate prediabetes or diabetes risk within this population have not been well characterized. A dysfunctional adiposity phenotype, characterized by excess visceral fat and insulin resistance, may contribute to diabetes development in those with obesity. OBJECTIVE: To investigate associations between adiposity phenotypes and risk for incident prediabetes and diabetes in a multiethnic, population-based cohort of obese adults. DESIGN, SETTING, AND PARTICIPANTS: Among 732 obese participants (body mass index ≥30) aged 30 to 65 years without diabetes or cardiovascular disease enrolled between 2000 and 2002 in the Dallas Heart Study, we measured body composition by dual energy x-ray absorptiometry and magnetic resonance imaging (MRI); circulating adipokines and biomarkers of insulin resistance, dyslipidemia, and inflammation; and subclinical atherosclerosis and cardiac structure and function by computed tomography and MRI. MAIN OUTCOME MEASURES: Incidence of diabetes through a median 7.0 years (interquartile range, 6.6-7.6) of follow-up. In a subgroup of 512 participants with normal fasting glucose values at baseline, incidence of the composite of prediabetes or diabetes was determined. RESULTS: Of the 732 participants (mean age, 43 years; 65% women; 71% nonwhite), 84 (11.5%) developed diabetes. In multivariable analysis, higher baseline visceral fat mass (odds ratio [OR] per 1 SD [1.4 kg], 2.4; 95% CI, 1.6-3.7), fructosamine level (OR per 1 SD [1.1 µmol/L], 2.0; 95% CI, 1.4-2.7), fasting glucose level (OR per 1 SD [1.1 µmol/L], 1.9; 95% CI, 1.4-2.6), family history of diabetes (OR, 2.3; 95% CI, 1.3-4.3), systolic blood pressure (OR per 10 mm Hg, 1.3; 95% CI, 1.1-1.5), and weight gain over follow-up (OR per 1 kg, 1.06; 95% CI, 1.02-1.10) were independently associated with diabetes, with no associations observed for body mass index, total body fat, or abdominal subcutaneous fat. Among the 512 participants with normal baseline glucose values, the composite outcome of prediabetes or diabetes occurred in 39.1% and was independently associated with baseline measurements of visceral fat mass; levels of fasting glucose, insulin, and fructosamine; older age; nonwhite race; family history of diabetes; and weight gain over follow-up (P < .05 for each) but not with measurements of general adiposity. CONCLUSION: Excess visceral fat and insulin resistance, but not general adiposity, were independently associated with incident prediabetes and type 2 diabetes mellitus in obese adults.

Limits to submaximal and maximal exercise in patients with hypertrophic cardiomyopathy.

Patients with hypertrophic cardiomyopathy (HCM) often have reduced exercise capacity, and it is unclear whether cardiovascular regulation during exercise is intact in these patients. We aimed to determine the relationship between cardiac output (Q̇c) and oxygen uptake (V̇o2), and stroke volume (SV) reserve in HCM compared with healthy participants and participants with left ventricular hypertrophy (LVH) but not HCM. Sixteen patients with HCM (48 ± 7 yr, 44% female), 16 participants with LVH (49 ± 5 yr, 44% female), and 61 healthy controls (CON: 52 ± 5 yr, 52% female) completed submaximal steady-state treadmill exercise followed by a maximal exercise test. V̇o2, Q̇c, SV, and arteriovenous oxygen difference were measured during rest and exercise, and Q̇c/V̇o2 slopes were constructed, The Q̇c/V̇o2 slope was blunted in HCM compared with CON and LVH [HCM 4.9 ± 0.7 vs. CON 5.5 ± 1.0 (P = 0.027) vs. LVH 6.0 ± 1.0 AU (P = 0.002)] and participants with HCM had a lower SV reserve (HCM 53 ± 33%, controls 83 ± 33%, LVH 82 ± 22%; HCM vs. controls P = 0.002; HCM vs. LVH P = 0.015). Despite a blunted Q̇c/V̇o2 slope, 75% of patients with HCM achieved ≥80% predicted V̇o2max by augmenting a-vo2 difference at maximal exercise (16.0 ± 0.8 mL/100 mL vs. 13.8 ± 2.7 mL/100 mL, P = 0.021). Patients with HCM do not appropriately match Q̇c to metabolic demand, primarily due to inadequate stroke volume augmentation. Despite this central limitation, many patients achieve normal exercise capacities by significantly increasing peripheral oxygen extraction.NEW & NOTEWORTHY Through state-of-the-art hemodynamic and oxygen uptake methodologies, this study found the cardiac output response to increasing metabolic demand is blunted among patients with hypertrophic cardiomyopathy (HCM), primarily due to a reduced stroke volume reserve. Many patients with HCM augment their peripheral oxygen extraction during maximal exercise to achieve normal exercise capacity and overcome ineffective matching of cardiac output. Peripheral adaptations that compensate for cardiac limitations may contribute to the heterogeneity of functional limitations observed within this patient population.

Autophagy as a therapeutic target in cardiovascular disease.

The epidemic of heart failure continues apace, and development of novel therapies with clinical efficacy has lagged. Now, important insights into the molecular circuitry of cardiovascular autophagy have raised the prospect that this cellular pathway of protein quality control may be a target of clinical relevance. Whereas basal levels of autophagy are required for cell survival, excessive levels - or perhaps distinct forms of autophagic flux - contribute to disease pathogenesis. Our challenge will be to distinguish mechanisms that drive adaptive versus maladaptive autophagy and to manipulate those pathways for therapeutic gain. Recent evidence suggests this may be possible. Here, we review the fundamental biology of autophagy and its role in a variety of forms of cardiovascular disease. We discuss ways in which this evolutionarily conserved catabolic mechanism can be manipulated, discuss studies presently underway in heart disease, and provide our perspective on where this exciting field may lead in the future. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.''

Anatomic and clinical correlates of septal morphology in hypertrophic cardiomyopathy.

UNLABELLED: Aim The presence of septal hypertrophy in hypertrophic cardiomyopathy (HCM) is common. To date, there has been no accepted classification of septal morphology in HCM. Furthermore, the possible relationship between septal morphology and clinical features of HCM is undefined. METHODS AND RESULTS: Seventy-five consecutive adult patients with HCM were enrolled. Septal morphologies were retrospectively categorized into one of four patterns of hypertrophy based on transthoracic echocardiography. Left ventricular diastolic function by Doppler echocardiography and late gadolinium enhancement (LGE) by magnetic resonance imaging were assessed in all patients. Patients were followed for a mean of 45 ± 32 months. Catenoid septum was the most common morphologic subtype (46 of 75, 61%), followed by simple sigmoid (22 of 75, 29%), neutral (4 of 75, 5%), and apical (3 of 75, 4%). Inter-observer reproducibility of septal classifications was high (κ = 0.95). Patients with the catenoid subtype presented at a younger age, had worse diastolic function, and high rates of LGE. The presence of catenoid septal morphology was independently associated with LGE in multivariable logistic regression analysis. Implantable cardioverter-defibrillator implantation for prevention of sudden cardiac death occurred only in patients with this septal morphology. CONCLUSION: We propose a simple, reproducible classification system of patterns of septal hypertrophy in HCM. These patterns of hypertrophy are associated with significant differences in clinical, haemodynamic, and myocardial characteristics. Further studies are needed to evaluate the relationship between septal morphology and outcome or response to therapies in HCM.

Preemptive Alcohol Septal Ablation Prior to Valve-in-Valve Transcatheter Mitral Valve Replacement With Bioprosthetic Balloon Fracture.

A 78-year-old woman with bioprosthetic mitral valve degeneration at high risk for reoperation was referred for transcatheter mitral valve replacement. We describe the use of a preemptive alcohol septal ablation pre-procedurally to minimize the risk of acute left ventricular outflow tract obstruction given the anticipated need for a bioprosthetic valve fracture. (Level of Difficulty: Advanced.).