Heart rate-reducing therapy with add-on ivabradine and bisoprolol before coronary computed tomographic angiography in a fast-track ambulatory setting.

Objective This study was performed to determine whether add-on oral ivabradine in patients treated with beta blockers 1 hour before coronary computed tomographic angiography (CCTA) is effective in lowering the heart rate and thus improving CCTA quality. Methods In this single-center cohort study, the data of 294 patients referred for ambulant CCTA were retrospectively screened. Patients with an initial heart rate of ≥75 bpm (n = 112) were pretreated with either a combination of bisoprolol and ivabradine or with bisoprolol alone. Results During the scan, there was no difference in heart rate between the two groups Likewise, there was no significant difference in additionally administered intravenous bradycardic agents, the number of motion artifacts, or the radiation dose. Both drug regimens were tolerated well. Conclusion Additive oral ivabradine 1 hour before CCTA does not result in a further reduction of the heart rate. Consequently, neither movement artifacts nor radiation dose can be reduced. Therefore, pretreatment with ivabradine does not seem reasonably appropriate in an outpatient clinical setting with short patient contact.

CHA2DS2-VASc score and blood biomarkers to identify patients with atrial high-rate episodes and paroxysmal atrial fibrillation.

AIMS: Paroxysmal atrial fibrillation (PAF) is often asymptomatic but nonetheless harmful. We evaluated the performance of disease-related blood biomarkers and CHA2DS2-VASc score to discriminate for PAF in patients with continuous rhythm monitoring. METHODS AND RESULTS: Clinical data and blood samples were obtained from patients with dual-chamber pacemakers selected according to the absence (no_AHRE) or presence of Atrial High-Rate Episodes (AHRE) >6 min in recent device history (case-control approach). We included 93 patients (n = 49 AHRE, n = 44 no_AHRE). In a subgroup with high AHRE burden and confirmed PAF 15 biomarkers were evaluated (n = 19 AHRE-AF vs. n = 20 no_AHRE). Significantly regulated biomarkers were then tested in all patients to distinguish no_AHRE from AHRE (receiver operating characteristics analysis). Hsp27, TGFß1, cystatin C, matrix metalloproteinases MMP-2,-3,-9, albumin, and serum uric acid were not altered in the subgroup. Tissue inhibitors of metalloproteinases (TIMP) -1,-2,-4; NT-proANP, NT-proBNP, IL-6 and serum amyloid protein A were significantly different in AHRE vs. no_AHRE (subgroup and whole cohort), with best discriminatory performance for TIMP-4. Biomarkers performed better than CHADS2-VASc for AHRE discrimination. Intracardial electrograms and medical history from seven AHRE patients suggested atrial tachycardia and not AF (AHRE-AT). Four of the most relevant regulated biomarkers (TIMP-4, TIMP-2, SAA, NT-proBNP) behaved similarly in AHRE-AT and AHRE-AF. NT-proBNP >150 pg/mL indicated an odds ratio of 12.9 for AHRE. Combining two biomarkers significantly improved discrimination of AHRE. CONCLUSION: TIMP-4, NT-proANP, NT-proBNP were strongest associated with PAF and AHRE. The discriminatory performance of CHADS2-VASc for PAF was increased by addition of selected biomarkers.

Novel pathomechanisms of cardiomyocyte dysfunction in a model of heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is increasingly common, but the underlying cellular mechanisms are not well understood. We investigated cardiomyocyte function and the role of SEA0400, an Na(+) /Ca(2+) exchanger (NCX) inhibitor in a rat model of chronic kidney disease (CKD) with HFpEF. METHODS AND RESULTS: Male Wistar rats were subjected to subtotal nephrectomy (NXT) or sham operation (Sham). After 8 and 24 weeks, in vivo (haemodynamics, echocardiography) and in vitro function (LV cardiomyocyte cell shortening (CS), and Ca(2+) transients (CaT)) were determined without and with SEA0400. In a subgroup of rats, SEA0400 or vehicle was given p.o. (1 mg/kg b.w.) between week 8 and 24. NXT resulted in stable compensated CKD and HFpEF [hypertrophied left ventricle, prolonged LV isovolumetric relaxation constant TAU (IVRc TAU), elevated end diastolic pressure (EDP), increased lung weight (pulmonary congestion), and preserved LV systolic function (EF, dP/dt)]. In NXT cardiomyocytes, the amplitude of CS and CaT were unchanged but relaxation and CaT decay were progressively prolonged at 8 and 24 weeks vs. Sham, individually correlating with diastolic dysfunction in vivo. NCX forward mode activity (caffeine response) was progressively reduced, while NCX protein expression was up-regulated, suggesting increased NCX reverse mode activity in NXT. SEA0400 acutely improved relaxation in NXT in vivo and in cardiomyocytes and improved cardiac remodelling and diastolic function when given chronically. CONCLUSIONS: This model of renal HFpEF is associated with slowed relaxation of LV cardiomyocytes. Treatment with SEA0400 improved cardiomyocyte function, remodelling, and HFpEF.

Exenatide exerts a PKA-dependent positive inotropic effect in human atrial myocardium: GLP-1R mediated effects in human myocardium.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are a rapidly growing class of drugs developed for treating type-2 diabetes mellitus. Patients with diabetes carry an up to 5-fold greater mortality risk compared to non-diabetic patients, mainly as a result of cardiovascular diseases. Although beneficial cardiovascular effects have been reported, exact mechanisms of GLP-1R-agonist action in the heart, especially in human myocardium, are poorly understood. The effects of GLP-1R-agonists (exenatide, GLP-1(7-36)NH2, PF-06446009, PF-06446667) on cardiac contractility were tested in non-failing atrial and ventricular trabeculae from 72 patients. The GLP-1(7-36)NH2 metabolite, GLP-1(9-36)NH2, was also examined. In electrically stimulated trabeculae, the effects of compounds on isometric force were measured in the absence and presence of pharmacological inhibitors of signal transduction pathways. The role of ß-arrestin signaling was examined using a ß-arrestin partial agonist, PF-06446667. Expression levels were tested by immunoblots. Translocation of GLP-1R downstream molecular targets, Epac2, GLUT-1 and GLUT-4, were assessed by fluorescence microscopy. All tested GLP-1R-agonists significantly increased developed force in human atrial trabeculae, whereas GLP-1(9-36)NH2 had no effect. Exendin(9-39)NH2, a GLP-1R-antagonist, and H-89 blunted the inotropic effect of exenatide. In addition, exenatide increased PKA-dependent phosphorylation of phospholamban (PLB), GLUT-1 and Epac2 translocation, but not GLUT-4 translocation. Exenatide failed to enhance contractility in ventricular myocardium. Quantitative real-time PCR (qRT-PCR) revealed a significant higher GLP-1R expression in the atrium compared to ventricle. Exenatide increased contractility in a dose-dependent manner via GLP-1R/cAMP/PKA pathway and induced GLUT-1 and Epac2 translocation in human atrial myocardium, but had no effect in ventricular myocardium. Therapeutic use of GLP-1R-agonists may therefore impart beneficial effects on myocardial function and remodelling.

Interrelated aldosterone and parathyroid hormone mutually modify cardiovascular mortality risk.

BACKGROUND: Inappropriate aldosterone and parathyroid hormone (PTH) secretion is associated with increased cardiovascular risk. Accumulating evidence suggests bidirectional interplay between aldosterone and PTH. METHODS: We evaluated the cross-sectional relationship between plasma aldosterone concentration (PAC), aldosterone to renin ratio (ARR) and PTH and subsequently tested whether the interaction between PAC and PTH modified the risk of cardiovascular death. PAC [78.0 (48.0-123.0) pg/mL], ARR [6.4 (2.9-12.9) pg/mL/pg/mL] and PTH concentration [median: 29.0 (22.0-40.0) pg/mL] were measured in 3074 patients (mean age: 62.5 ± 10.6 years; 30.3% women) referred to coronary angiography in a tertiary care center in Southwest Germany. RESULTS: Using multiple linear regression analysis, PAC and ARR emerged as an independent predictor of higher PTH concentrations (ß=0.12 and 0.21, P<0.001 for both) irrespective of intake of antihypertensive treatment, 25(OH)D, kidney function, serum calcium, phosphate, magnesium, cortisol, NT-pro-BNP, soluble α-klotho and FGF-23 concentration. After a median follow-up of 9.9 years, 512 (16.7%) participants had died due to fatal cardiovascular events. Multivariate Cox proportional hazard analysis revealed that both PAC and PTH were independently associated with cardiovascular mortality, with a potential synergistic interaction (P=0.028). PAC and PTH are exclusively associated with cardiovascular death in subjects with PTH and PAC concentrations above the median, respectively (PAC: HR per log SD: 1.14; 95% CI 1.02-1.29; P=0.026; PTH: HR per log SD: 1.18; 95% CI 1.02-1.37; P=0.031). CONCLUSIONS: Higher PAC and ARR were independently associated with PTH. PAC was independently related to incident cardiovascular mortality exclusively in patients with elevated PTH and vice versa.