Jan Christian Reil

Heart rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction

AIMS In diabetes mellitus, heart failure with preserved ejection fraction (HFPEF) is a significant comorbidity. No therapy is available that improves cardiovascular outcomes. The aim of this study was to characterize myocardial function and ventricular-arterial coupling in a mouse model of diabetes and to analyse the effect of selective heart rate (HR) reduction by If-inhibition in this HFPEF-model. METHODS AND RESULTS Control mice, diabetic mice (db/db), and db/db mice treated for 4 weeks with the If-inhibitor ivabradine (db/db-Iva) were compared. Aortic distensibility was measured by magnetic resonance imaging. Left ventricular (LV) pressure-volume analysis was performed in isolated working hearts, with biochemical and histological characterization of the cardiac and aortic phenotype. In db/db aortic stiffness and fibrosis were significantly enhanced compared with controls and were prevented by HR reduction in db/db-Iva. Left ventricular end-systolic elastance (Ees) was increased in db/db compared with controls (6.0 ± 1.3 vs. 3.4 ± 1.2 mmHg/µL, P < 0.01), whereas other contractility markers were reduced. Heart rate reduction in db/db-Iva lowered Ees (4.0 ± 1.1 mmHg/µL, P < 0.01), and improved the other contractility parameters. In db/db active relaxation was prolonged and end-diastolic capacitance was lower compared with controls (28 ± 3 vs. 48 ± 8 μL, P < 0.01). These parameters were ameliorated by HR reduction. Neither myocardial fibrosis nor hypertrophy were detected in db/db, whereas titin N2B expression was increased and phosphorylation of phospholamban was reduced both being prevented by HR reduction in db/db-Iva. CONCLUSION In db/db, a model of HFPEF, selective HR reduction by If-inhibition improved vascular stiffness, LV contractility, and diastolic function. Therefore, If-inhibition might be a therapeutic concept for HFPEF, if confirmed in humans.

Abdominal obesity is associated with microalbuminuria and an elevated cardiovascular risk profile in patients with hypertension.

Background Overweight and obesity are frequently associated with preventable death and have emerged as a major challenge to public health. There is an ongoing debate on the role of abdominal obesity and its value in predicting cardiovascular and renal outcomes. The present analysis evaluates the prevalence of microalbuminuria (MAU) and conventional cardiovascular risk factors in relation to measures of general and abdominal obesity. Methods In this multinational, observational study, 20828 hypertensive out-patients from 26 countries including Europe, North and Latin America, Middle East, and Asia were analyzed. Urinary dipstick screening for MAU was performed as well as data on patient demographics, anthropometric measures, cardiovascular risk factors, comorbid conditions, and cardiovascular drug therapy collected. MAU prevalence was determined by a stepwise logistic regression analysis with cardiovascular risk factors as univariate. Results In the univariate analysis, MAU prevalence systematically increased with body mass index (BMI) from 54.4% (1st tertial) to 62.1% (3rd tertial) (p < 0.0001), an increase which was also observed for waist circumference (WC). At any level of BMI, MAU increased with WC from 53.5%, 54.8%, and 55.0% (1st tertial of WC in all three BMI tertials) to 61.4%, 62.1%, and 64.0% (3rd tertial of WC in all BMI tertials) (p < 0.0001). In the multivariate analysis, WC, but not BMI was independently associated with MAU. Furthermore, overweight/obesity were associated with the presence of modifiable and nonmodifiable risk factors. Conclusion An abnormal WC, but not BMI appears to be independently associated with MAU, an early marker of cardiovascular and renal risk. Increasing WC confers an incremental risk for MAU at any level of BMI, underlining the prognostic importance of abdominal fat accumulation beyond general obesity.

Association of heart rate with microalbuminuria in cardiovascular risk patients: Data from I-SEARCH

Background Microalbuminuria (MAU) is an indicator of impaired renal function and a relevant risk predictor for cardiovascular events. An increased heart rate is closely correlated with increased cardiovascular mortality. The International Survey Evaluating Microalbuminuria Routinely by Cardiologists in Patients with Hypertension (I-SEARCH) investigated 21 050 patients with hypertension and risk factors for cardiovascular disease. In patients in sinus rhythm (n = 18 900) the relationship between increased heart rate and the prevalence of MAU was analysed. Methods and results The study was performed in 26 countries worldwide from September 2005 to March 2006. Heart rate, blood pressure, urine albumin and serum creatinine were measured as key parameters. With increasing heart rate (> 80 bpm to < 120 bpm) the proportion of patients with MAU increased from 63 to 69% (P < 0.0001). The odds ratio (OR) for MAU increased with increasing heart rate [heart rate 80–100 bpm compared with 60 bpm: OR, 1.47; 95% confidence interval (CI), 1.29–1.68; P < 0.0001; and heart rate 100–120 bpm compared with 60 bpm: OR, 1.56; 95% CI, 1.22–1.99; P = 0.0004]. The prevalence of MAU was similar whether or not patients were receiving beta-blockers; but MAU was significantly reduced in physically active patients compared with sedentary patients (OR, 0.78; 95% CI, 0.73–0.84; P < 0.0001). Summary These results show that heart rate is an independent predictor for the prevalence of MAU in hypertensive patients with cardiovascular risk factors. In contrast to beta-blocker therapy, physical activity markedly decreased MAU with increasing heart rates. Further controlled and prospective studies are needed to show that lowered heart rates in combination with MAU can significantly reduce kidney damage, as well as cardiovascular events.

Cardiac CaM Kinase II Genes δ and γ Contribute to Adverse Remodeling but Redundantly Inhibit Calcineurin-Induced Myocardial Hypertrophy

Background— Ca2+-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear. Methods and Results— We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes &dgr; and &ggr; specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca2+ handling nor functional and structural changes. On pathological pressure overload and &bgr;-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling. Conclusions— We established a mouse model in which CaMKII’s activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure.1 Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany. 2 Department of Cardiology, Saarland University, Homburg, Germany 3 Department of Internal Medicine II, University of Regensburg, Regensburg, Germany 4 British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom 5 Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas, TX, USA 6 Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany 7 Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany 8 Department of Cardiology, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg, Germany 9 Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas, TX, USA

Relationship between heart rate and mortality and morbidity in the irbesartan patients with heart failure and preserved systolic function trial (I-Preserve)

Higher heart rate is associated with poorer outcomes in patients with heart failure and reduced ejection fraction (HF‐REF). Less is known about the association between heart rate and outcomes in patients with heart failure and preserved ejection fraction (HF‐PEF). Therefore, we examined the relationship between heart rate and outcomes in the irbesartan in patients with heart failure and preserved systolic function trial (I‐Preserve) in patients with an ejection fraction >45% aged >60 years.

Atrial fibrillation and heart rate independently correlate to microalbuminuria in hypertensive patients

AIMS To investigate the relationship between microalbuminuria (MAU) and atrial fibrillation (AF) and to further evaluate whether the heart rate dependency of MAU in patients without AF is maintained in patients with a history of AF. METHODS AND RESULTS The International Survey Evaluating Microalbuminuria Routinely by Cardiologists in patients with Hypertension (I-SEARCH) included 18,900 patients without and 1705 patients with a history of AF suffering from hypertension and other risk factors for cardiovascular disease in 26 countries worldwide from September 2005 to March 2006. Heart rate, blood pressure, urinary albumin excretion, and an estimated glomerular filtration rate were determined among other parameters. The prevalence of MAU was higher at higher heart rate in both patients with and without a history of AF. Prevalence of MAU was about 10% higher in patients with a history of AF (P < 0.001). Male gender, the presence of diabetes mellitus, a higher heart rate, and a higher diastolic blood pressure were independently associated with increased odds for MAU in patients without and with a history of AF. CONCLUSION The prevalence of MAU in hypertensive patients with cardiovascular risk factors is related to heart rate and significantly higher in patients with a history of AF.

A background Ca2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling.

AIMS Pathological cardiac hypertrophy is a major predictor for the development of cardiac diseases. It is associated with chronic neurohumoral stimulation and with altered cardiac Ca(2+) signalling in cardiomyocytes. TRPC proteins form agonist-induced cation channels, but their functional role for Ca(2+) homeostasis in cardiomyocytes during fast cytosolic Ca(2+) cycling and neurohumoral stimulation leading to hypertrophy is unknown. METHODS AND RESULTS In a systematic analysis of multiple knockout mice using fluorescence imaging of electrically paced adult ventricular cardiomyocytes and Mn(2+)-quench microfluorimetry, we identified a background Ca(2+) entry (BGCE) pathway that critically depends on TRPC1/C4 proteins but not others such as TRPC3/C6. Reduction of BGCE in TRPC1/C4-deficient cardiomyocytes lowers diastolic and systolic Ca(2+) concentrations both, under basal conditions and under neurohumoral stimulation without affecting cardiac contractility measured in isolated hearts and in vivo. Neurohumoral-induced cardiac hypertrophy as well as the expression of foetal genes (ANP, BNP) and genes regulated by Ca(2+)-dependent signalling (RCAN1-4, myomaxin) was reduced in TRPC1/C4 knockout (DKO), but not in TRPC1- or TRPC4-single knockout mice. Pressure overload-induced hypertrophy and interstitial fibrosis were both ameliorated in TRPC1/C4-DKO mice, whereas they did not show alterations in other cardiovascular parameters contributing to systemic neurohumoral-induced hypertrophy such as renin secretion and blood pressure. CONCLUSIONS The constitutively active TRPC1/C4-dependent BGCE fine-tunes Ca(2+) cycling in beating adult cardiomyocytes. TRPC1/C4-gene inactivation protects against development of maladaptive cardiac remodelling without altering cardiac or extracardiac functions contributing to this pathogenesis.

Effect of ivabradine in dobutamine induced sinus tachycardia in a case of acute heart failure

Sirs, In heart failure, heart rate (HR) is related to cardiac decompensations and overall mortality [1]. Low baseline HR and HR reduction by beta-blockers are significantly associated with a better prognosis [1, 2]. Currently in acute heart failure the inotrope dobutamine is frequently used to increase cardiac output and to lower filling pressures [3]. Dobutamine stimulates myocardial s1-adrenergic receptors thereby improving myocardial contractility and reducing wall stress. Sometimes increases in heart rate may outweigh the reduction in wall stress and produce a net increase in myocardial oxygen consumption. Thus, in heart failure, patients with low ejection fraction and hypotension inotropic agents, such as, dobutamine can increase mortality in particular when tachycardia develops [4]. The If channel inhibitor ivabradine reduces intrinsic pacemaker activity in the sinuatrial node thereby reducing HR without affecting contractility [5]. Thus, HR reduction with ivabradine may be useful for treatment of acute heart failure, especially in patients on dobutamine with concomitant HR increases.

Inhibition of NHE3-mediated Sodium Absorption in the Gut Reduced Cardiac End-organ Damage Without Deteriorating Renal Function in Obese Spontaneously Hypertensive Rats.

Abstract: Increased sodium absorption in the gut is one mechanism contributing to hypertensive blood pressure values. The sodium-proton-exchanger subtype 3 (NHE3) is an important mediator of intestinal sodium absorption. The compound SAR is a new specific NHE3 inhibitor with extremely low oral absorbability leading to decreased sodium absorption in the gut and substantial systolic blood pressure reduction. The effects of intestinal NHE3 inhibition on cardiac and renal hypertensive end-organ damage are unknown. The effects of SAR (1 mg·kg−1·d−1 in chow) on left ventricular (LV) and renal remodeling processes were studied by magnetic resonance imaging and biochemical and histological analysis in obese spontaneously hypertensive rats (SHR-ob SAR) compared with placebo-treated SHR-ob (SHR-ob PLAC). Inhibition of intestinal NHE3 by SAR lowered blood pressure and reduced LV end-diastolic pressure from 21 ± 3.0 to 15 ± 2.0 mm Hg (P = 0.0016), whereas heart rate kept unchanged. LV mass indices, LV myocyte diameters, and LV fibrosis formation were lower in SHR-ob SAR compared with SHR-ob PLAC. SAR did not influence urinary albumin to creatinine ratio or glomerular filtration rate. Renal interstitial fibrosis formation, as well as podocyte damage and glomerulosclerosis remained unchanged. Reduction of intestinal sodium absorption by selective NHE3 inhibition in the gut lowered high blood pressure and reduced LV remodeling without deteriorating renal functional and structural parameters in SHR-ob.

Overview of the i-SEARCH global study: Cardiovascular risk factors and microalbuminuria in hypertensive individuals

Microalbuminuria (MAU) is a highly predictive, sensitive, inexpensive and easily repeatable marker of cardiovascular risk and all-cause mortality in hypertensive patients. The international, observational, practice-based study i-SEARCH (Survey for Evaluating Microalbuminuria Routinely by Cardiologists in patients with Hypertension) was designed to assess the frequency with which MAU occurred in a large outpatient population who were currently treated or newly diagnosed with hypertension and were under professional care. The primary aim of the study was to define the prevalence of MAU in hypertensive outpatients attending a cardiologist or internist (i-SEARCH A) and to compare hypertensive outpatients with or without coronary artery disease (i-SEARCH B). A secondary objective was to establish a correlation between MAU and known cardiovascular risk factors. A total of 21 050 patients from 26 countries were included in the primary analysis. Overall, this study demonstrated a very high worldwide prevalence (58.4%) of MAU in high-risk cardiovascular patients, but with a considerable variation across countries. MAU was more prevalent in patients with coronary artery disease than in those without. It was also significantly related to the presence of specific predictors, including male gender, abnormally high waist circumference, increased blood pressure levels (systolic ≥120 mmHg, diastolic ≥100 mmHg), creatinine clearance ≥50 mL/min, or clinical conditions such as diabetes mellitus, congestive heart failure, history of cerebral pathology, and peripheral arterial disease. Since the presence of MAU reflects long-term detrimental effects on the cardiovascular system, these results indicate the high, and in many cases hidden, burden of cardiovascular diseases among the hypertensive patients seen by cardiologists. This article discusses the main results of the study and the potential implications of ongoing analyses included in the core clinical study programme.