Ahmet Güçlü

Gene-specific increase in the energetic cost of contraction in hypertrophic cardiomyopathy caused by thick filament mutations

AIMS Disease mechanisms regarding hypertrophic cardiomyopathy (HCM) are largely unknown and disease onset varies. Sarcomere mutations might induce energy depletion for which until now there is no direct evidence at sarcomere level in human HCM. This study investigated if mutations in genes encoding myosin-binding protein C (MYBPC3) and myosin heavy chain (MYH7) underlie changes in the energetic cost of contraction in the development of human HCM disease. METHODS AND RESULTS Energetic cost of contraction was studied in vitro by measurements of force development and ATPase activity in cardiac muscle strips from 26 manifest HCM patients (11 MYBPC3mut, 9 MYH7mut, and 6 sarcomere mutation-negative, HCMsmn). In addition, in vivo, the ratio between external work (EW) and myocardial oxygen consumption (MVO2) to obtain myocardial external efficiency (MEE) was determined in 28 pre-hypertrophic mutation carriers (14 MYBPC3mut and 14 MYH7mut) and 14 healthy controls using [(11)C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging. Tension cost (TC), i.e. ATPase activity during force development, was higher in MYBPC3mut and MYH7mut compared with HCMsmn at saturating [Ca(2+)]. TC was also significantly higher in MYH7mut at submaximal, more physiological [Ca(2+)]. EW was significantly lower in both mutation carrier groups, while MVO2 did not differ. MEE was significantly lower in both mutation carrier groups compared with controls, showing the lowest efficiency in MYH7 mutation carriers. CONCLUSION We provide direct evidence that sarcomere mutations perturb the energetic cost of cardiac contraction. Gene-specific severity of cardiac abnormalities may underlie differences in disease onset and suggests that early initiation of metabolic treatment may be beneficial, in particular, in MYH7 mutation carriers.

Myocardial efficiency is an important determinant of functional improvement after aortic valve replacement in aortic valve stenosis patients: a combined PET and CMR study

AIMS The pathophysiology underlying aortic valve stenosis (AVS)-induced cardiac dysfunction and reduced exercise capacity is unclear. We hypothesize that improvement of myocardial external efficiency (MEE)--the ratio between external work and myocardial oxygen consumption (MVO2)--underlies functional improvement of AVS patients after aortic valve replacement (AVR). Therefore, the aim of this proof-of-concept study was to investigate whether myocardial efficiency is reduced in patients with cardiac hypertrophy caused by AVS and to assess the effect of AVR on myocardial efficiency in relation to exercise capacity. METHODS AND RESULTS Echocardiography, cardiopulmonary exercise test, [(11)C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging were performed in 10 AVS patients prior to (pre-AVR) and 4 months after AVR (post-AVR). Fourteen healthy individuals served as control group. MEE was significantly lower in pre-AVR patients (32 ± 7%) than in controls (49 ± 6%). AVR significantly decreased left ventricle mass and MVO2. Also, external work significantly decreased post-AVR reaching similar values as in controls. AVR significantly improved MEE from 32 ± 7 to 37 ± 5% (P = 0.02). Moreover, significant correlations were present between the AVR-induced increase in MEE and changes in both exercise work (r = 0.74, P = 0.01) and peak VO2 (r = 0.67, P = 0.03). However, four AVS patients did not show improved MEE, which was associated with no or minimal improvement in exercise parameters. CONCLUSION MEE is significantly reduced in patients with AVS-induced hypertrophy. Improved MEE is an important predictor of AVR-induced improvement of exercise capacity in AVS patients. Future investigation is needed to confirm our observations in a large prospective, multicenter clinical trial.

Left ventricular outflow tract gradient is associated with reduced capillary density in hypertrophic cardiomyopathy irrespective of genotype.

Coronary microvascular dysfunction (CMD) is an important feature of hypertrophic cardiomyopathy (HCM), which contributes negatively to symptoms and long‐term outcome. Previous in vivo imaging studies in HCM suggest that left ventricular outflow tract (LVOT) gradient and genetic status are important contributors to CMD. CMD may be caused by reduced capillary density. Here, we investigated whether a reduction in capillary density is related to genetic status or LVOT gradient severity in an in vitro study of HCM cardiac samples.

Disease Stage–Dependent Changes in Cardiac Contractile Performance and Oxygen Utilization Underlie Reduced Myocardial Efficiency in Human Inherited Hypertrophic CardiomyopathyCLINICAL PERSPECTIVE

Background— Reduced myocardial efficiency represents a target for therapy in hypertrophic cardiomyopathy although therapeutic benefit may depend on disease stage. Here, we determined disease stage–dependent changes in myocardial efficiency and effects of myectomy surgery. Methods and Results— Myocardial external efficiency (MEE) was determined in 27 asymptomatic mutation carriers (genotype positive/phenotype negative), 10 patients with hypertrophic obstructive cardiomyopathy (HOCM), 10 patients with aortic valve stenosis, and 14 healthy individuals using [11C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging. Follow-up measurements were performed in HOCM and aortic valve stenosis patients 4 months after surgery. External work did not differ in HOCM compared with controls, whereas myocardial oxygen consumption was lower in HOCM. Because of a higher cardiac mass, total cardiac oxygen consumption was significantly higher in HOCM than in controls and genotype positive/phenotype negative. MEE was significantly lower in genotype positive/phenotype negative than in controls (28±6% versus 42±6%) and was further decreased in HOCM (22±5%). In contrast to patients with aortic valve stenosis, MEE was not improved in patients with HOCM after surgery, which was explained by opposite changes in the septum (decrease) and lateral (increase) wall. Conclusions— Different mechanisms underlie reduced MEE at the early and advanced stage of hypertrophic cardiomyopathy. The initial increase and subsequent reduction in myocardial oxygen consumption during disease progression indicates that energy deficiency is a primary mutation-related event, whereas mechanisms secondary to disease remodeling underlie low MEE in HOCM. Our data highlight that the benefit of therapies to improve energetic status of the heart may vary depending on the disease stage and that treatment should be initiated before cardiac remodeling.

Sex-dependent pathophysiological mechanisms in hypertrophic cardiomyopathy: Implications for rhythm disorders

Differences in cardiac physiology are seen between men and women in terms of health and disease. Sex differences start to develop at puberty and are maintained during aging. The prevalence of almost all cardiovascular diseases is found to be higher in men than in women, and disease progression tends to be more rapid in male than in female patients. In cohorts of patients with hypertrophic cardiomyopathy (HCM), the most common autosomal inherited cardiac disease, men are overrepresented, suggesting increased penetrance of HCM-causing mutations in male patients. Cardiac remodeling in patients with HCM is higher in men than in women, the same is seen in HCM animal models. Patients with HCM are at increased risk of sudden cardiac death (SCD) and developing rhythm disorders. There seems to be no sex effect on the risk of SCD or arrhythmias in patients with HCM; however, animal studies suggest that certain mutations predispose men to SCD.

SEPTAL MYECTOMY DOES NOT IMPROVE SEPTAL MYOCARDIAL EFFICIENCY IN HYPERTROPHIC CARDIOMYOPATHY

Next to left ventricular hypertrophy, hypertrophic obstructive cardiomyopathy (HOCM) is characterized by reduced myocardial external efficiency. Septal myectomy improves symptoms and prognosis. This study was conducted to study the effects of septal myectomy on regional (septal and lateral)