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Heart failure modulates electropharmacological characteristics of sinoatrial nodes.

ABSTRACT: The impact of heart failure (HF) on sinoatrial node (SAN) channel regulation and electropharmacological responses has remained elusive. The present study aimed to investigate the effects of HF on the electrical activity of SANs with and without pharmacological interventions. Action potentials (APs) were recorded in isolated SANs from normal rabbits (control) and those with HF (rapid ventricular pacing for 4 weeks) prior to and after administration of a funny current blocker (ivabradine; 0.1, 0.3, 3 or 10 µM), a calmodulin kinase II inhibitor (KN-93; 0.3 or 3 µM), a sarcoplasmic reticulum Ca2+ release inhibitor (ryanodine; 0.3 or 3 µM), a sodium current inhibitor (tetrodotoxin; 1, 3 or 10 µM) and a late sodium current inhibitor (ranolazine; 10 µM). Western blot analysis was used to investigate the protein expression in SANs from normal rabbits and those with HF. Control SANs had a higher beating rate than SANs from rabbits with HF (2.3±0.1 vs. 1.5±0.1 Hz; P<0.001). Similarly, ivabradine (10 µM), KN-93 (3 µM), ranolazine (10 µM) and ryanodine (3 µM) decreased the beating rates of SANs in the control (n=6) and HF (n=6) groups. Ivabradine treatment resulted in a higher incidence of AP block in HF vs. control SANs (66.7 vs. 0%; P<0.05). Tetrodotoxin (1, 3 or 10 µM) decreased the beating rate to a higher extent in SANs from rabbits with HF than in those from control rabbits and induced a higher incidence of AP block (66.7 vs. 0%; P<0.05). Furthermore, SANs from rabbits with HF had higher protein levels of phospholamban (PLB) and lower levels of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4, ryanodine receptor and phosphorylated PLB than control SANs. In conclusion, HF modulates electropharmacological responses in the SAN by channel regulation, which may result in SAN dysfunction.

SUBMITTER: Chang SL

PROVIDER: S-EPMC5348682 | biostudies-other | 2017 Feb

REPOSITORIES: biostudies-other

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Heart failure modulates electropharmacological characteristics of sinoatrial nodes.

Chang Shih-Lin SL Chuang Hui-Lun HL Chen Yao-Chang YC Kao Yu-Hsun YH Lin Yung-Kuo YK Yeh Yung-Hsin YH Chen Shih-Ann SA Chen Yi-Jen YJ

Experimental and therapeutic medicine 20161230 2

The impact of heart failure (HF) on sinoatrial node (SAN) channel regulation and electropharmacological responses has remained elusive. The present study aimed to investigate the effects of HF on the electrical activity of SANs with and without pharmacological interventions. Action potentials (APs) were recorded in isolated SANs from normal rabbits (control) and those with HF (rapid ventricular pacing for 4 weeks) prior to and after administration of a funny current blocker (ivabradine; 0.1, 0.3 ...[more]

PMID: 28352365

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Project description:AimWe present the baseline characteristics of the PREFERS Stockholm epidemiological study on the natural history and course of new onset heart failure (HF) aiming to improve phenotyping focusing on HF with preserved left ventricular ejection fraction (HFpEF) pathophysiology.Methods and resultsNew onset HF patients diagnosed in hospital or at outpatient HF clinics were included at five Stockholm hospitals 2015-2018 and characterized by N-terminal pro brain natriuretic peptide (NT-proBNP), biomarkers, echocardiography, and cardiac magnetic resonance imaging (subset). HFpEF [left ventricular ejection fraction (LVEF) ≥ 50%] was compared with HF with mildly reduced LVEF (HFmrEF; LVEF 41-49%) and with HF with reduced LVEF (HFrEF; LVEF ≤ 40%). We included 547 patients whereof HFpEF (n = 137; 25%), HFmrEF (n = 61; 11%), and HFrEF (n = 349; 64%). HFpEF patients were older (76; 70-81 years; median; interquartile range) than HFrEF (67; 58-74; P < 0.001), more often women (49% vs. 30%; P < 0.001), and had significantly higher comorbidity burden. They more often had atrial fibrillation, hypertension, and renal dysfunction. NT-proBNP was lower in HFpEF (896; 462-1645 ng/L) than in HFrEF (1160; 563-2370; P = 0.005). In HFpEF, left ventricular (LV) diameters and volumes were smaller (P < 0.001) and septal and posterior wall thickness and relative wall thickness higher (P < 0.001). E/é ≥ 14 was present in 26% of HFpEF vs. 32% of HFrEF (P = 0.017) and left atrial volume index > 34 mL/m2 in 57% vs. 61% (P = 0.040). HFmrEF patients were intermediary between HFpEF and HFrEF for LV mass, LV volumes, and RV volumes but had the highest proportion of left ventricular hypertrophy and the lowest proportion of elevated E/é.ConclusionsPhenotype data in new onset HF patients recruited in a broad clinical setting showed that 25% had HFpEF, were older, more often women, and had greater comorbidity burden. PREFERS is well suited to further explore biomarker and imaging components of HFpEF pathophysiology and may contribute to the emerging knowledge of HF epidemiology.Clinical trial registrationClinicaltrials.gov identifier: NCT03671122.

Project description:BackgroundFactors associated with sympathetic and parasympathetic sinoatrial reinnervation after heart transplantation (HTx) are inadequately studied.MethodsFifty transplant recipients were examined at 7 to 12 wk (index visit), 6, 12, 24, and 36 mo after HTx. Supine rest heart rate variability in the low-frequency (LF) domain (sympathetic and parasympathetic sinoatrial reinnervation) and the high-frequency (HF) domain (parasympathetic sinoatrial reinnervation) were measured repeatedly and related to selected recipient, donor, and perisurgical characteristics. We primarily aimed to identify index visit factors that affect the sinoatrial reinnervation process. Secondarily, we examined overall associations between indices of reinnervation and repeatedly measured recipient characteristics to generate new hypotheses regarding the consequences of reinnervation.ResultsLF and HF variability increased time dependently. In multivariate modeling, a pretransplant diagnosis of nonischemic cardiomyopathy (P = 0.038) and higher index visit handgrip strength (P = 0.028) predicted improved LF variability. Recipient age, early episodes of rejection, and duration of extracorporeal circulation were not associated with indices of reinnervation. Study average handgrip strength was positively associated with LF and HF variability (respectively, P = 0.005 and P = 0.029), whereas study average C-reactive protein was negatively associated (respectively, P = 0.015 and P = 0.008).ConclusionsIndices of both sympathetic and parasympathetic sinoatrial reinnervation increased with time after HTx. A pretransplant diagnosis of nonischemic cardiomyopathy and higher index visit handgrip strength predicted higher indices of mainly sympathetic reinnervation, whereas age, rejection episodes, and duration of extracorporeal circulation had no association. HTx recipients with higher indices of reinnervation had higher average handgrip strength, suggesting a link between reinnervation and improved frailty. The more reinnervated participants had lower average C-reactive protein, suggesting an inhibitory effect of reinnervation on inflammation, possibly through enhanced function of the inflammatory reflex. These potential effects of reinnervation may affect long-term morbidity in HTx patients and should be scrutinized in future research.

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Heart failure modulates electropharmacological characteristics of sinoatrial nodes.

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Heart failure modulates electropharmacological characteristics of sinoatrial nodes.

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