High diastolic stiffness of failing myocardium results from interstitial fibrosis and elevated resting tension ( F _passive ) of cardiomyocytes. A shift in titin isoform expression from N2BA to N2B isoform, lower overall phosphorylation of titin, and a shift in titin phosphorylation from N2B to N2BA isoform can raise F _passive of cardiomyocytes. In left ventricular biopsies of heart failure (HF) patients, aortic stenosis (AS) patients, and controls (CON), we therefore related F _passive of isolated cardiomyocytes to expression of titin isoforms and to phosphorylation of titin and titin isoforms. Biopsies were procured by transvascular technique (44 HF, 3 CON), perioperatively (25 AS, 4 CON), or from explanted hearts (4 HF, 8 CON). None had coronary artery disease. Isolated, permeabilized cardiomyocytes were stretched to 2.2-μm sarcomere length to measure F _passive . Expression and phosphorylation of titin isoforms were analyzed using gel electrophoresis with ProQ Diamond and SYPRO Ruby stains and reported as ratio of titin (N2BA/N2B) or of phosphorylated titin (P-N2BA/P-N2B) isoforms. F _passive was higher in HF (6.1±0.4 kN/m ² ) than in CON (2.3±0.3 kN/m ² ; P <0.01) or in AS (2.2±0.2 kN/m ² ; P <0.001). Titin isoform expression differed between HF (N2BA/N2B=0.73±0.06) and CON (N2BA/N2B=0.39±0.05; P <0.001) and was comparable in HF and AS (N2BA/N2B=0.59±0.06). Overall titin phosphorylation was also comparable in HF and AS, but relative phosphorylation of the stiff N2B titin isoform was significantly lower in HF (P-N2BA/P-N2B=0.77±0.05) than in AS (P-N2BA/P-N2B=0.54±0.05; P <0.01). Relative hypophosphorylation of the stiff N2B titin isoform is a novel mechanism responsible for raised F _passive of human HF cardiomyocytes.

Background—: Aortic stenosis (AS) and diabetes mellitus (DM) are frequent comorbidities in aging populations. In heart failure, DM worsens diastolic left ventricular (LV) dysfunction, thereby adversely affecting symptoms and prognosis. Effects of DM on diastolic LV function were therefore assessed in aortic stenosis, and underlying myocardial mechanisms were identified. Methods and Results—: Patients referred for aortic valve replacement were subdivided into patients with AS and no DM (AS; n=46) and patients with AS and DM (AS-DM; n=16). Preoperative Doppler echocardiography and hemodynamics were implemented with perioperative LV biopsies. Histomorphometry and immunohistochemistry quantified myocardial collagen volume fraction and myocardial advanced glycation end product deposition. Isolated cardiomyocytes were stretched to 2.2-μm sarcomere length to measure resting tension (F _passive ). Expression and phosphorylation of titin isoforms were analyzed with gel electrophoresis with ProQ Diamond and SYPRO Ruby stains. Reduced LV end-diastolic distensibility in AS-DM was evident from higher LV end-diastolic pressure (21±1 mm Hg for AS versus 28±4 mm Hg for AS-DM; P =0.04) at comparable LV end-diastolic volume index and attributed to higher myocardial collagen volume fraction (AS, 12.9±1.1% versus AS-DM, 18.2±2.6%; P <0.001), more advanced glycation end product deposition in arterioles, venules, and capillaries (AS, 14.4±2.1 score per 1 mm ² versus AS-DM, 31.4±6.1 score per 1 mm ² ; P =0.03), and higher F _passive (AS, 3.5±1.7 kN/m ² versus AS-DM, 5.1±0.7 kN/m ² ; P =0.04). Significant hypophosphorylation of the stiff N2B titin isoform in AS-DM explained the higher F _passive and normalization of F _passive after in vitro treatment with protein kinase A. Conclusions—: Worse diastolic LV dysfunction in AS-DM predisposes to heart failure and results from more myocardial fibrosis, more intramyocardial vascular advanced glycation end product deposition, and higher cardiomyocyte F _passive , which was related to hypophosphorylation of the N2B titin isoform.

Heart failure (HF) is a complex and progressive syndrome associated with high morbidity, mortality, impaired quality of life, and substantial healthcare costs. Globally, more than 55 million people live with HF, and prevalence is steadily rising, largely driven by population ageing, improved survival after cardiovascular events, and the increasing burden of comorbidities. While the prevalence of HF with reduced EF (HFrEF) appears to be stable or declining, most likely due to improved treatment of ischaemic heart disease, HF with preserved EF (HFpEF) is steadily increasing and may become the most common form of HF in the future. Overall HF incidence has remained stable or even declined in many Western countries, although rising trends have been reported in younger populations and in specific regions. However, incidence of HFpEF is rising rapidly and has nearly doubled over two decades due to ageing and increased prevalence of comorbidities, whereas HFrEF incidence has declined slightly. Considerable geographic variation exists in HF epidemiology, with data from low- and middle-income countries being still limited, although HF in these settings often differs in terms of causes, age at onset, and outcomes. Despite substantial advances in life-saving, evidence-based therapies, prognosis remains poor: depending on the population and care setting 1-year mortality ranges from 5% to 34%, 1-year rehospitalization is ∼30%, and non-cardiovascular mortality is rising, particularly among patients with HFpEF. In this review, we provide an updated and comprehensive overview of HF epidemiology, summarizing recent evidence on prevalence, incidence, aetiologies, outcomes, and costs across diverse populations and regions worldwide.

Persistent left ventricular (LV) hypertrophy after surgery is frequent, but its clinical relevance is controversial. We evaluated if residual LV hypertrophy (LVH) is associated with clinical outcomes after aortic valve replacement (AVR) for severe aortic stenosis (AS). We analysed clinical and echocardiographic parameters before and after AVR, in a prospective cohort of 132 patients with severe AS. The mean follow-up was 6.0 ± 1.5 years. Clinical endpoints were all-cause death and combination of as in all-cause death and non-fatal cardiovascular hospitalization. At AVR, myocardial biopsies for collagen volume fraction (CVF) evaluation were done in 56 random patients. Residual LVH was present in 44% of patients after AVR. Patients with residual LVH were older, more frequently women and had hypertension (HT). Preoperatively, they had higher LV mass indices (LVMI), higher E/e′ and left atrial volume indices, as well as lower peak systolic annular velocity. Female gender, HT, LVMI and E/e′ were independent predictors of persistent LVH. CVF at the time of surgery was higher in those with residual LVH (20.0 ± 14.6 vs 13.2 ± 11.5%, P = 0.027). The risk of all-cause death and non-fatal cardiovascular hospitalization was higher in patients with residual LVH [OR 2.89 (95% CI 1.12–7.44); P = 0.035], but there were no differences in all-cause mortality. Residual LVH was associated with a worse outcome in women but not in men. Residual LVH after AVR is common and is associated with worse prognosis, particularly in women. In addition, HT, higher baseline LVM and worse diastolic dysfunction can help to identify patients at risk for incomplete normalization of LVM.

(2010). Correlation between plasma levels of apelin and myocardial hypertrophy in rats and humans: possible target for treatment? Expert Opinion on Therapeutic Targets: Vol. 14, No. 3, pp. 231-241. doi: 10.1517/14728220903485685