Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. METHODS: We performed a comprehensive multiomics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). RESULTS: Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and phosphocreatine) and a reduction in mitochondrial genes involved in creatine kinase and ATP synthesis. Accompanying these metabolic derangements, electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. CONCLUSIONS: Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.

Anesthetic considerations during minimally invasive mitral valve surgery.

Advances in instruments and visualization tools as well as circulatory systems for cardiopulmonary bypass during the late 1990s have stimulated widespread adoption of minimally invasive mitral valve surgery (MIMVS). Today, MIMVS is the standard approach for many surgeons and institutions. There are multiple benefits of MIMVS. Patient satisfaction and improved cosmesis are important. Additionally, studies have consistently shown faster recovery times and less associated pain with MIMVS. Statistically significant improvement in bleeding, transfusion, incidence of atrial fibrillation, and time to resumption of normal activities with MIMVS has also been shown when comparing MIMVS with conventional mitral surgery. Most important, these benefits have been achieved without sacrificing perioperative safety or durability of surgical repair. Although a steep learning curve still exists given the high level of case complexity, continued development fueled by increasing patient demand may allow for even further expansion in the use of minimal invasive techniques.

Surgical ablation of refractory ventricular tachycardia in patients with nonischemic cardiomyopathy.

BACKGROUND: The surgical approach for the treatment of ventricular tachycardia (VT) has been largely replaced by percutaneous, catheter-based techniques. However, some VT circuits, particularly in patients with nonischemic cardiomyopathy, remain inaccessible to percutaneous ablation. Surgical therapy of these VTs is an alternative approach; however, its methodology has not been well defined. The purpose of this study was to evaluate the efficacy of preoperative electroanatomic and electrophysiological characterization of the VT substrate and circuit to guide surgical ablation. METHODS AND RESULTS: Eight patients with recurrent sustained VT refractory to antiarrhythmic drugs underwent endocardial and/or epicardial ablation procedures. Electroanatomic mapping was performed, and the VT substrate and circuit(s) were defined using voltage, activation, entrainment, and pace mapping. All 8 patients underwent detailed endocardial mapping; 6 patients also underwent epicardial mapping. Radiofrequency ablation was performed with the use of an open-irrigation catheter. After the unsuccessful percutaneous approach, surgical cryoablation was applied to the sites previously identified and targeted during the percutaneous procedure. There were no significant perioperative complications. During a mean follow-up period of 23 ± 6 months (range, 15 to 34 months), 6 patients had significant reduction in VT burden as evident by a reduced number of implantable cardioverter-defibrillator shocks after ablation (6.6 to 0.6 shocks per patient; P = 0.026). Two patients died, one of progressive heart failure and one of sepsis. CONCLUSIONS: VT circuits inaccessible to percutaneous ablation techniques are rare but can be encountered in patients with nonischemic cardiomyopathy. These VTs can be successfully targeted by surgical cryoablation guided by preoperative electroanatomic and electrophysiological mapping.

Clinically silent cerebral ischemic events after cardiac surgery: their incidence, regional vascular occurrence, and procedural dependence.

BACKGROUND: The reported frequency of stroke after coronary artery bypass grafting varies between 1.5% and 6%, approaches 10% after aortic valve replacement, and may occur in between 40 to 70% in high-risk groups. Clinically silent infarction may be far more frequent and could contribute to long-term cognitive dysfunction in patients after cardiac procedures. Using diffusion-weighted magnetic resonance imaging we document the occurrence, vascular distribution, and procedural dependence of silent infarction after cardiac surgery with cardiopulmonary bypass. We also document the association of preexisting white matter lesions with new postoperative ischemic lesions. METHODS: Thirty-four patients underwent T2-weighted fluid attenuated inversion recovery and diffusion-weighted magnetic resonance imaging before and after cardiac surgery with cardiopulmonary bypass for coronary artery bypass grafting, aortic valve replacement, and mitral valve repair or replacement surgery. Images were evaluated by experienced neuroradiologists for number, size, and vascular distribution of lesions. RESULTS: Mean age of participants was 67 +/- 15 years. Imaging occurred before and 6 +/- 2 days after surgery. New cerebral infarctions were evident in 6 of 34 patients (18%), were often multiple, and in 67% of patients were clinically silent. The occurrence of new infarctions by surgical procedure was as follows: aortic valve replacement (2 of 6), coronary artery bypass grafting and aortic valve replacement (3 of 8), aortic valve replacement with root replacement (1 of 1), coronary artery bypass grafting and mitral valve repair or replacement (0 of 4), mitral valve repair or replacement (0 of 2), and isolated coronary artery bypass grafting (0 of 13). New infarction occurred in 6 of 15 (40%) of all procedures involving aortic valve replacement. The severity of preexisting white matter lesions trended toward predicting the occurrence of new lesions (p = 0.055). CONCLUSIONS: Diffusion-weighted imaging reveals new cerebral infarctions in nearly 40% of patients after aortic valve replacement.