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Ventricular Arrhythmias Underlie Sudden Death in Rats With Heart Failure and Preserved Ejection Fraction.

ABSTRACT: BACKGROUND:Heart failure (HF) with preserved ejection fraction (HFpEF) is increasingly common clinically, now rivaling or exceeding HF with reduced ejection fraction . Sudden death is the leading mode of exodus in patients with HFpEF, but the underlying causes are largely unknown. Using ambulatory recordings in a rat model, we test the hypothesis that ventricular arrhythmias (VA) underlie sudden death in HFpEF. METHODS:Dahl salt-sensitive rats (7 weeks of age) were fed a high-salt diet to induce HFpEF (n=13) or a normal-salt diet (controls, n=9). Transthoracic echocardiography was performed to check systolic and diastolic function at 14 to 18 weeks of age. Telemetric electrocardiographic recordings were analyzed for QT interval duration, burden of premature ventricular contractions, spontaneous VA, and heart rate variability. Survival was monitored twice daily. RESULTS:High-salt-fed rats with clear diastolic dysfunction, preserved ejection fraction, and HF signs were diagnosed with HFpEF at 14 to 15 weeks of age. QT and QTc intervals were prolonged in HFpEF rats compared with controls. Heart rate variability was reduced in HFpEF rats compared with controls. Spontaneous VA were more prevalent in HFpEF rats (6/13=46.1% versus 0/9=0% in controls; P<0.05), and sudden death was observed in 4 of 13 HFpEF rats. Three of the 4 sudden deaths were associated with VA as the terminal rhythm. CONCLUSIONS:In this rat model with phenotypically verified HFpEF, sudden death was common and generally associated with VA. Further clinical studies are warranted to determine whether these insights translate to sudden death in HFpEF patients.

SUBMITTER: Cho JH

PROVIDER: S-EPMC6091890 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

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Ventricular Arrhythmias Underlie Sudden Death in Rats With Heart Failure and Preserved Ejection Fraction.

Cho Jae Hyung JH Zhang Rui R Aynaszyan Stephan S Holm Kevin K Goldhaber Joshua I JI Marbán Eduardo E Cingolani Eugenio E

Circulation. Arrhythmia and electrophysiology 20180801 8

<h4>Background</h4>Heart failure (HF) with preserved ejection fraction (HFpEF) is increasingly common clinically, now rivaling or exceeding HF with reduced ejection fraction . Sudden death is the leading mode of exodus in patients with HFpEF, but the underlying causes are largely unknown. Using ambulatory recordings in a rat model, we test the hypothesis that ventricular arrhythmias (VA) underlie sudden death in HFpEF.<h4>Methods</h4>Dahl salt-sensitive rats (7 weeks of age) were fed a high-salt ...[more]

PMID: 30030266

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Project description:BACKGROUND:Heart failure with preserved ejection fraction (HFpEF) represents approximately half of heart failure, and its incidence continues to increase. The leading cause of mortality in HFpEF is sudden death, but little is known about the underlying mechanisms. METHODS:Dahl salt-sensitive rats were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF (n=38). Rats fed a normal-salt diet (0.3% NaCl) served as controls (n=13). Echocardiograms were performed to assess systolic and diastolic function from 14 weeks of age. HFpEF-verified and control rats underwent programmed electrical stimulation. Corrected QT interval was measured by surface ECG. The mechanisms of ventricular arrhythmias (VA) were probed by optical mapping, whole-cell patch clamp to measure action potential duration and ionic currents, and quantitative polymerase chain reaction and Western blotting to investigate changes in ion channel expression. RESULTS:After 7 weeks of a high-salt diet, 31 of 38 rats showed diastolic dysfunction and preserved ejection fraction along with signs of heart failure and hence were diagnosed with HFpEF. Programmed electric stimulation demonstrated increased susceptibility to VA in HFpEF rats (P<0.001 versus controls). The arrhythmogenicity index was increased (P<0.001) and the corrected QT interval on ECG was prolonged (P<0.001) in HFpEF rats. Optical mapping of HFpEF hearts demonstrated prolonged action potentials (P<0.05) and multiple reentry circuits during induced VA. Single-cell recordings of cardiomyocytes isolated from HFpEF rats confirmed a delay of repolarization (P=0.001) and revealed downregulation of transient outward potassium current (Ito; P<0.05). The rapid components of the delayed rectifier potassium current (IKr) and the inward rectifier potassium current (IK1) were also downregulated (P<0.05), but the current densities were much lower than for Ito. In accordance with the reduction of Ito, both Kcnd3 transcript and Kv4.3 protein levels were decreased in HFpEF rat hearts. CONCLUSIONS:Susceptibility to VA was markedly increased in rats with HFpEF. Underlying abnormalities include QT prolongation, delayed repolarization from downregulation of potassium currents, and multiple reentry circuits during VA. Our findings are consistent with the hypothesis that potassium current downregulation leads to abnormal repolarization in HFpEF, which in turn predisposes to VA and sudden cardiac death.

Project description:BackgroundSudden death (SD) and pump failure death (PFD) are leading modes of death in heart failure and preserved ejection fraction (HFpEF). Risk stratification for mode-specific death may aid in patient enrichment for new device trials in HFpEF.MethodsModels were derived in 4116 patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-Preserve), using competing risks regression analysis. A series of models were built in a stepwise manner, and were validated in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved and Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trials.ResultsThe clinical model for SD included older age, men, lower LVEF, higher heart rate, history of diabetes or myocardial infarction, and HF hospitalization within previous 6 months, all of which were associated with a higher SD risk. The clinical model predicting PFD included older age, men, lower LVEF or diastolic blood pressure, higher heart rate, and history of diabetes or atrial fibrillation, all for a higher PFD risk, and dyslipidaemia for a lower risk of PFD. In each model, the observed and predicted incidences were similar in each risk subgroup, suggesting good calibration. Model discrimination was good for SD and excellent for PFD with Harrell's C of 0.71 (95% CI 0.68-0.75) and 0.78 (95% CI 0.75-0.82), respectively. Both models were robust in external validation. Adding ECG and biochemical parameters, model performance improved little in the derivation cohort but decreased in validation. Including NT-proBNP substantially increased discrimination of the SD model, and simplified the PFD model with marginal increase in discrimination.ConclusionsThe clinical models can predict risks for SD and PFD separately with good discrimination and calibration in HFpEF and are robust in external validation. Adding NT-proBNP further improved model performance. These models may help to identify high-risk individuals for device intervention in future trials.Clinical trial registrationI-Preserve: ClinicalTrials.gov NCT00095238; TOPCAT: ClinicalTrials.gov NCT00094302; CHARM-Preserved: ClinicalTrials.gov NCT00634712.

Project description:ObjectivesTo determine clinical and prognostic differences between preserved and deteriorated systolic function (defined as left ventricular (LV) ejection fractions > or = 50% and < 50%, respectively) in patients with heart failure satisfying modified Framingham criteria.Patients and methodsRecords were studied of 1252 patients with congestive heart failure (CHF) (mean (SD) age 69.4 (11.7) years; 485 women, 767 men) who had been admitted to a cardiology service for CHF in the period 1991-2002 and whose LV systolic function had been echocardiographically evaluated within two weeks of admission. Data were collected on the main clinical findings, supplementary examinations, treatment, and duration of hospitalisation. Whether the patient was alive in the spring of 2003 was evaluated by searching the general archives of the hospital and by telephone survey.ResultsLV systolic function was preserved in 39.8% of patients. Age, female to male sex ratio, and prevalence of atrial fibrillation, valve disease, and other non-ischaemic, non-dilated cardiopathies were all significantly greater in the group with preserved systolic function. New York Heart Association functional class IV, third heart sound, jugular vein congestion, cardiomegaly, radiological signs of lung oedema, pathological Q waves, left bundle branch block, sinus rhythm, ischaemic cardiopathy, and dilated cardiomyopathy were all significantly more prevalent in the group with deteriorated systolic function, as was treatment with angiotensin converting enzyme inhibitors and most other antihypertensive drugs on discharge from hospital. There was no significant difference in survival between the groups with preserved and deteriorated systolic function (either survival regardless of age at admission or in subgroups aged < 75 and > or = 75 years at admission). In the whole group, survival rates after one, three, and five years were 84.0%, 66.7%, and 50.9%, respectively.ConclusionIn view of the poor prognosis of patients with CHF with preserved LV systolic function, who are currently treated empirically, it is to be hoped that relevant controlled clinical trials under way will afford information allowing optimisation of their treatment.

Dataset Information

Ventricular Arrhythmias Underlie Sudden Death in Rats With Heart Failure and Preserved Ejection Fraction.

Publications

Ventricular Arrhythmias Underlie Sudden Death in Rats With Heart Failure and Preserved Ejection Fraction.

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