Ali Javaheri

Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure.

Background— The failing human heart is characterized by metabolic abnormalities, but these defects remains incompletely understood. In animal models of heart failure there is a switch from a predominance of fatty acid utilization to the more oxygen-sparing carbohydrate metabolism. Recent studies have reported decreases in myocardial lipid content, but the inclusion of diabetic and nondiabetic patients obscures the distinction of adaptations to metabolic derangements from adaptations to heart failure per se. Methods and Results— We performed both unbiased and targeted myocardial lipid surveys using liquid chromatography-mass spectroscopy in nondiabetic, lean, predominantly nonischemic, advanced heart failure patients at the time of heart transplantation or left ventricular assist device implantation. We identified significantly decreased concentrations of the majority of myocardial lipid intermediates, including long-chain acylcarnitines, the primary subset of energetic lipid substrate for mitochondrial fatty acid oxidation. We report for the first time significantly reduced levels of intermediate and anaplerotic acyl-coenzyme A (CoA) species incorporated into the Krebs cycle, whereas the myocardial concentration of acetyl-CoA was significantly increased in end-stage heart failure. In contrast, we observed an increased abundance of ketogenic &bgr;-hydroxybutyryl-CoA, in association with increased myocardial utilization of &bgr;-hydroxybutyrate. We observed a significant increase in the expression of the gene encoding succinyl-CoA:3-oxoacid-CoA transferase, the rate-limiting enzyme for myocardial oxidation of &bgr;-hydroxybutyrate and acetoacetate. Conclusions— These findings indicate increased ketone utilization in the severely failing human heart independent of diabetes mellitus, and they support the role of ketone bodies as an alternative fuel and myocardial ketone oxidation as a key metabolic adaptation in the failing human heart.

Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis

Macrophages specialize in removing lipids and debris present in the atherosclerotic plaque. However, plaque progression renders macrophages unable to degrade exogenous atherogenic material and endogenous cargo including dysfunctional proteins and organelles. Here we show that a decline in the autophagy–lysosome system contributes to this as evidenced by a derangement in key autophagy markers in both mouse and human atherosclerotic plaques. By augmenting macrophage TFEB, the master transcriptional regulator of autophagy–lysosomal biogenesis, we can reverse the autophagy dysfunction of plaques, enhance aggrephagy of p62-enriched protein aggregates and blunt macrophage apoptosis and pro-inflammatory IL-1β levels, leading to reduced atherosclerosis. In order to harness this degradative response therapeutically, we also describe a natural sugar called trehalose as an inducer of macrophage autophagy–lysosomal biogenesis and show trehaloses ability to recapitulate the atheroprotective properties of macrophage TFEB overexpression. Our data support this practical method of enhancing the degradative capacity of macrophages as a therapy for atherosclerotic vascular disease.

Constrictive Pericarditis Presenting as a Late Complication of Epicardial Ventricular Tachycardia Ablation

Radiofrequency epicardial ablation of ventricular tachycardia (VT) is a safe, effective modality for treatment of VT.1 Epicardial VT circuits were originally described in Chagas disease, but the importance of nonendocardial substrates for VT increasingly are recognized in other cardiomyopathies.2 In arrhythmogenic right ventricular cardiomyopathy (ARVC), failure of endocardial VT ablation often is related to epicardial VT origination, with high rates of success seen with epicardial VT ablation.3 While hemopericardium or pericardial inflammation are rare complications of epicardial VT ablation, to our knowledge no case of pericardial constriction and heart failure following epicardial VT ablation has been reported.4 Here we describe a case of pericardial constriction and severe heart failure requiring stripping and “bridge to recovery” right-ventricular assist-device (RVAD) support, which occurred subsequent to recurrent epicardial VT ablations. ### Case Presentation A 46-year-old male who presented with palpitations and episodic syncope underwent cardiac magnetic resonance imaging, which was consistent with ARVC, followed by implantable …

Intermittent Fasting Preserves Beta-Cell Mass in Obesity-induced Diabetes via the Autophagy-Lysosome Pathway

ABSTRACT Obesity-induced diabetes is characterized by hyperglycemia, insulin resistance, and progressive beta cell failure. In islets of mice with obesity-induced diabetes, we observe increased beta cell death and impaired autophagic flux. We hypothesized that intermittent fasting, a clinically sustainable therapeutic strategy, stimulates autophagic flux to ameliorate obesity-induced diabetes. Our data show that despite continued high-fat intake, intermittent fasting restores autophagic flux in islets and improves glucose tolerance by enhancing glucose-stimulated insulin secretion, beta cell survival, and nuclear expression of NEUROG3, a marker of pancreatic regeneration. In contrast, intermittent fasting does not rescue beta-cell death or induce NEUROG3 expression in obese mice with lysosomal dysfunction secondary to deficiency of the lysosomal membrane protein, LAMP2 or haplo-insufficiency of BECN1/Beclin 1, a protein critical for autophagosome formation. Moreover, intermittent fasting is sufficient to provoke beta cell death in nonobese lamp2 null mice, attesting to a critical role for lysosome function in beta cell homeostasis under fasting conditions. Beta cells in intermittently-fasted LAMP2- or BECN1-deficient mice exhibit markers of autophagic failure with accumulation of damaged mitochondria and upregulation of oxidative stress. Thus, intermittent fasting preserves organelle quality via the autophagy-lysosome pathway to enhance beta cell survival and stimulates markers of regeneration in obesity-induced diabetes.

Apolipoprotein A-I and Cholesterol Efflux The Good, the Bad, and the Modified

High-density lipoprotein (HDL) cholesterol is strongly and inversely associated with coronary heart disease. However, recent developments have raised major questions about the causal nature of this relationship. Several randomized controlled clinical trials of HDL-raising interventions have failed to demonstrate reduction in risk of major adverse cardiac events.1–4 Furthermore, in 1 Mendelian randomization study, genetic variants associated with increased HDL cholesterol were not associated with protection from coronary heart disease.5 It has been proposed that HDL can be dysfunctional and that this might cloud the relationship between HDL cholesterol and coronary heart disease. In this issue of Circulation Research , Shao et al6 further our understanding of the concept of HDL dysfunction by showing that oxidative modifications of apoA-I, the main protein constituent of HDL, impair its ability to accept cholesterol from macrophages. Article, see p 1733 HDL may protect against atherogenesis via several potential mechanisms. HDL has been shown to inhibit inflammation,7 regulate nitric oxide production,8 function in innate immunity,9 and, in its most extensively studied property, remove excess cholesterol from macrophages in the process of reverse cholesterol transport. During cholesterol efflux, lipid-poor apoA-I and mature HDL interact with integral membrane proteins ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1, respectively, to accept cholesterol from cells.10 Our group and others have shown that the cholesterol efflux capacity of HDL inversely correlates with atherosclerotic vascular disease.6,11,12 The addition of niacin to statin therapy failed to improve cardiovascular outcomes but also did not improve HDL cholesterol efflux capacity,13 providing a …

Reconstituted High-Density Lipoprotein Therapies A Cause for Optimism

Despite epidemiological studies showing that increased levels of high-density lipoprotein cholesterol (HDL-C) are associated with a reduced risk of future coronary heart disease, neither monogenic diseases characterized by extreme HDL-C levels nor genetic variants associated with higher HDL-C levels are associated with coronary heart disease risk reduction.1,2 Most importantly, increasing HDL-C levels as a therapeutic approach to reduce cardiovascular risk has been called into question by the recent failure of several randomized trials in which therapies aimed at increasing HDL-C levels, such as niacin and cholesteryl ester transferase protein inhibitors, have failed to improve cardiovascular outcomes.3–5 See accompanying article on page 2106 However, it remains clear that HDL has multiple potential antiatherogenic functions,6 including its well-described role in reverse cholesterol transport (RCT)7 (Figure [A]). Thus, a novel approach toward coronary heart disease prevention and HDL-targeting therapies focuses on enhancing HDL function rather than HDL-C levels. That cholesterol efflux capacity of HDL isolated from human subjects is inversely correlated with coronary heart disease status8 reinforces the concept that atheroprotection is associated with HDL function rather than HDL-C levels. In this issue of Arteriosclerosis Thrombosis and Vascular Biology , Gille et al9 present evidence that in healthy volunteers, infusion of CSL112, a reconstituted HDL (rHDL) containing apolipoprotein AI (apoAI) and phospholipids improves biomarkers of RCT and cholesterol efflux when measured ex vivo. Figure. A , Reverse cholesterol transport. Apolipoprotein AI (apoAI; synthesized in the liver and intestines) acquires phospholipid and a small amount of free cholesterol via the ATP-binding cassette transporter A1 (ABCA1) to …

Cholesterol efflux capacity of high-density lipoprotein correlates with survival and allograft vasculopathy in cardiac transplant recipients

BACKGROUND Cardiac allograft vasculopathy (CAV) is a major cause of mortality after cardiac transplantation. High-density lipoprotein (HDL) cholesterol efflux capacity (CEC) is inversely associated with coronary artery disease. In 2 independent studies, we tested the hypothesis that reduced CEC is associated with mortality and disease progression in CAV. METHODS We tested the relationship between CEC and survival in a cohort of patients with CAV (n = 35). To determine whether reduced CEC is associated with CAV progression, we utilized samples from the Clinical Trials in Organ Transplantation 05 (CTOT05) study to determine the association between CEC and CAV progression and status at 1 year (n = 81), as assessed by average change in maximal intimal thickness (MIT) on intravascular ultrasound. RESULTS Multivariable Cox proportional hazard models demonstrated that higher levels of CEC were associated with improved survival (hazard ratio 0.26, 95% confidence interval 0.11 to 0.63) per standard deviation CEC, p = 0.002). Patients who developed CAV had reduced CEC at baseline and 1-year post-transplant. We observed a significant association between pre-transplant CEC and the average change in MIT, particularly among patients who developed CAV at 1 year (β = -0.59, p = 0.02, R2 = 0.35). CONCLUSION Reduced CEC is associated with disease progression and mortality in CAV patients. These findings suggest the hypothesis that interventions to increase CEC may be useful in cardiac transplant patients for prevention or treatment of CAV.

High-Density Lipoprotein: NO Failure in Heart Failure

Despite numerous epidemiological studies demonstrating that high-density lipoprotein cholesterol (HDL-C) levels are inversely associated with cardiovascular risk,1–3 several lines of evidence now indicate that targeting HDL-C levels to reduce the risk of cardiovascular events is unlikely to be effective. Studies of pharmacological interventions to raise HDL-C, such as niacin4,5 and 2 cholesteryl ester transfer protein inhibitors,6,7 have shown no benefit in reducing cardiovascular events. In addition, data from a large Mendelian randomization study have shown that some genetic variants associated with HDL-C seem to have little relationship to coronary heart disease.8 As a result, there is currently skepticism about whether interventions specifically to raise HDL-C levels will decrease the risk of cardiovascular events. Article, see p 1345 This failure of the so-called HDL cholesterol hypothesis has been accompanied by a shift toward a more rigorous, basic understanding of HDL as a molecule with multiple functions that can be differentiated from simple measures of HDL cholesterol mass. One of the important functions of HDL is its role in promoting cellular cholesterol efflux and reverse cholesterol transport. Our group and others have shown that the capacity of HDL to promote cholesterol efflux from macrophages ex vivo is inversely related to the risk of coronary heart disease even after controlling for HDL-C levels.9,10 Furthermore, niacin therapy does not augment cholesterol efflux despite raising HDL levels in statin-treated patients,11 which could explain the lack of efficacy of niacin despite increased HDL-C levels. Although more studies are certainly warranted, one hypothesis is that therapies that improve cholesterol efflux capacity and reverse cholesterol transport, such as infusion of a reconstituted HDL12 composed of apolipoprotein A1 and phospholipids, may improve cardiovascular outcomes. Beyond promoting cholesterol efflux, HDL is known to have anti-inflammatory, …

How to Approach the Assessment of Cardiac Allograft Vasculopathy in the Modern Era: Review of Invasive Imaging Modalities

Heart transplantation is one of the most definitive therapies for end-stage heart failure. The therapy is unfortunately marred by the devastating complications of cardiac allograft vasculopathy (CAV). Non-invasive screening and assessment for CAV has been greatly limited by both low sensitivity and poor correlation with adverse outcomes. As such, invasive imaging with coronary angiography has emerged as the gold standard for detection of CAV. Although conventional coronary angiography serves well for larger lesions, the modality has been significantly enhanced with adjunct imaging to visualize the intimal hyperplasia that is a hallmark of the disease process. These modalities include intravascular ultrasound (IVUS) and optical coherence tomography (OCT). In the following review, we summarize both the invasive and non-invasive assessments of CAV. We further conclude that the current evidence poorly supports the use of non-invasive testing for early CAV and that a transition should be considered to routine early angiography with adjunctive intravascular imaging.

Fatal accelerated rejection with a prominent natural killer cell infiltrate in a heart transplant recipient with peripartum cardiomyopathy

Accelerated rejection is uncommon after cardiac transplantation. The mechanism is hypothesized to be mediated by cytotoxic T cells and anti-HLA antibodies resulting from a memory response to the donor allograft in sensitized patients. A role for Natural Killer (NK) cell in cellular rejection has also been suggested. We report a case of fulminant accelerated rejection in a heart transplant recipient, with a history of peripartum cardiomyopathy (PPMC). The patient had no pre-transplant donor specific antibody and flow cytometric T and B cell crossmatches were negative. Autopsy revealed left ventricular subendocardial and intramyocardial hemorrhage with diffuse lymphocytic infiltrates and myocyte damage (Grade 3R rejection). Immunohistochemistry revealed a large proportion (50-70%) of mature CD16+ NK cells with cytotoxic potential in the interstitium and the intra capillary compartments. This case highlights the need for evaluating the potential role of NK cells in accelerated rejection in heart transplant recipients.