Cardiomyopathies Due to Left Ventricular Noncompaction, Mitochondrial and Storage Diseases, and Inborn Errors of Metabolism

There is a constant high demand for energy to sustain the continuous contractile activity of the heart, which is met primarily by the beta-oxidation of long-chain fatty acids. The control of fatty acid beta-oxidation is complex and is aimed at ensuring that the supply and oxidation of the fatty acids is sufficient to meet the energy demands of the heart. The metabolism of fatty acids via beta-oxidation is not regulated in isolation; rather, it occurs in response to alterations in contractile work, the presence of competing substrates (i.e., glucose, lactate, ketones, amino acids), changes in hormonal milieu, and limitations in oxygen supply. Alterations in fatty acid metabolism can contribute to cardiac pathology. For instance, the excessive uptake and beta-oxidation of fatty acids in obesity and diabetes can compromise cardiac function. Furthermore, alterations in fatty acid beta-oxidation both during and after ischemia and in the failing heart can also contribute to cardiac pathology. This paper reviews the regulation of myocardial fatty acid beta-oxidation and how alterations in fatty acid beta-oxidation can contribute to heart disease. The implications of inhibiting fatty acid beta-oxidation as a potential novel therapeutic approach for the treatment of various forms of heart disease are also discussed.

The network for cardiac fuel metabolism contains intricate sets of interacting pathways that result in both ATP-producing and non-ATP-producing end points for each class of energy substrates. The most salient feature of the network is the metabolic flexibility demonstrated in response to various stimuli, including developmental changes and nutritional status. The heart is also capable of remodeling the metabolic pathways in chronic pathophysiological conditions, which results in modulations of myocardial energetics and contractile function. In a quest to understand the complexity of the cardiac metabolic network, pharmacological and genetic tools have been engaged to manipulate cardiac metabolism in a variety of research models. In concert, a host of therapeutic interventions have been tested clinically to target substrate preference, insulin sensitivity, and mitochondrial function. In addition, the contribution of cellular metabolism to growth, survival, and other signaling pathways through the production of metabolic intermediates has been increasingly noted. In this review, we provide an overview of the cardiac metabolic network and highlight alterations observed in cardiac pathologies as well as strategies used as metabolic therapies in heart failure. Lastly, the ability of metabolic derivatives to intersect growth and survival are also discussed.

We sought to describe characteristics and outcome in adults with isolated ventricular noncompaction (IVNC). Isolated ventricular noncompaction is an unclassified cardiomyopathy due to intrauterine arrest of compaction of the loose interwoven meshwork. Knowledge regarding diagnosis, morbidity and prognosis is limited. Echocardiographic criteria for IVNC include-in the absence of significant heart lesions-segmental thickening of the left ventricular myocardial wall consisting of two layers: a thin, compacted epicardial and an extremely thickened endocardial layer with prominent trabeculations and deep recesses. Thirty-four adults (age >16 years, 25 men) fulfilled the diagnostic criteria and were followed prospectively. At diagnosis, mean age was 42 + 17 years, and 12 patients (35%) were in New York Heart Association class III/IV. Left ventricular end-diastolic diameter was 65 + 12 mm and ejection fraction 33 + 13%. Apex and/or midventricular segments of both the inferior and lateral wall were involved in >80% of patients. Follow-up was 44 + 40 months. Major complications were heart failure in 18 patients (53%), thromboembolic events in 8 patients (24%) and ventricular tachycardias in 14 patients (41%). There were 12 deaths: sudden in six, end-stage heart failure in four and other causes in two patients. Four patients underwent heart transplantation. Automated cardioverter/defibrillators were implanted in four patients. Diagnosis of IVNC by echocardiography using strict criteria is feasible. Its mortality and morbidity are high, including heart failure, thrombo-embolic events and ventricular arrhythmias. Risk stratification includes heart failure therapy, oral anticoagulation, heart transplantation and implantation of an automated defibrillator/cardioverter. As IVNC is a distinct entity, its classification as a specific cardiomyopathy seems to be more appropriate.