Dataset Information

Inhibition of KCa2 and Kv11.1 Channels in Pigs With Left Ventricular Dysfunction.

ABSTRACT: Background:Inhibition of KCa2 channels, conducting IKCa, can convert atrial fibrillation (AF) to sinus rhythm and protect against its induction. IKCa inhibition has been shown to possess functional atrial selectivity with minor effects on ventricles. Under pathophysiological conditions with ventricular remodeling, however, inhibiting IKCa can exhibit both proarrhythmic and antiarrhythmic ventricular effects. The aim of this study was to evaluate the effects of the IKCa inhibitor AP14145, when given before or after the IKr blocker dofetilide, on cardiac function and ventricular proarrhythmia markers in pigs with or without left ventricular dysfunction (LVD). Methods:Landrace pigs were randomized into an AF group (n = 6) and two control groups: SHAM1 (n = 8) and SHAM2 (n = 4). AF pigs were atrially tachypaced (A-TP) for 43 ± 4 days until sustained AF and LVD developed. A-TP and SHAM1 pigs received 20 mg/kg AP14145 followed by 100 µg/kg dofetilide whereas SHAM2 pigs received the same drugs in the opposite order. Proarrhythmic markers such as short-term variability of QT (STVQT) and RR (STVRR) intervals, and the number of premature ventricular complexes (PVCs) were measured at baseline and after administration of drugs. The influence on cardiac function was assessed by measuring cardiac output, stroke volume, and relevant echocardiographic parameters. Results:IKCa inhibition by AP14145 did not increase STVQT or STVRR in any of the pigs. IKr inhibition by dofetilide markedly increased STVQT in the A-TP pigs, but not in SHAM operated pigs. Upon infusion of AP14145 the number of PVCs decreased or remained unchanged both when AP14145 was infused after baseline and after dofetilide. Conversely, the number of PVCs increased or remained unchanged upon dofetilide infusion. Neither AP14145 nor dofetilide affected relevant echocardiographic parameters, cardiac output, or stroke volume in any of the groups. Conclusion:IKCa inhibition with AP14145 was not proarrhythmic in healthy pigs, or in the presence of LVD resulting from A-TP. In pigs already challenged with 100 µg/kg dofetilide there were no signs of proarrhythmia when 20 mg/kg AP14145 were infused. KCa2 channel inhibition did not affect cardiac function, implying that KCa2 inhibitors can be administered safely also in the presence of LV dysfunction.

SUBMITTER: Citerni C

PROVIDER: S-EPMC7219273 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Inhibition of KCa2 and Kv11.1 Channels in Pigs With Left Ventricular Dysfunction.

Citerni Carlotta C Kirchhoff Jeppe J Olsen Lisbeth Høier LH Sattler Stefan Michael SM Grunnet Morten M Edvardsson Nils N Bentzen Bo Hjorth BH Diness Jonas Goldin JG

Frontiers in pharmacology 20200506

<h4>Background</h4>Inhibition of KCa2 channels, conducting IKCa, can convert atrial fibrillation (AF) to sinus rhythm and protect against its induction. IKCa inhibition has been shown to possess functional atrial selectivity with minor effects on ventricles. Under pathophysiological conditions with ventricular remodeling, however, inhibiting IKCa can exhibit both proarrhythmic and antiarrhythmic ventricular effects. The aim of this study was to evaluat ...[more]

PMID: 32435191

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Project description:BackgroundPatients with left ventricular (LV) systolic dysfunction after myocardial infarction are at a high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system inhibition may result in greater attenuation of adverse LV remodeling as a result of increased levels of substrates for neprilysin with vasodilatory, antihypertrophic, antifibrotic, and sympatholytic effects.MethodsWe performed a prospective, multicenter, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103 mg twice daily with valsartan 160 mg twice daily in patients ≥3 months after myocardial infarction with a LV ejection fraction ≤40% who were taking a renin angiotensin system inhibitor (equivalent dose of ramipril ≥2.5 mg twice daily) and a β-blocker unless contraindicated or intolerant. Patients in New York Heart Association class ≥II or with signs and symptoms of heart failure were excluded. The primary outcome was change from baseline to 52 weeks in LV end-systolic volume index measured using cardiac magnetic resonance imaging. Secondary outcomes included other magnetic resonance imaging measurements of LV remodeling, change in NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin I, and a patient global assessment of change questionnaire.ResultsFrom July 2018 to June 2019, we randomized 93 patients with the following characteristics: mean age, 60.7±10.4 years; median time from myocardial infarction, 3.6 years (interquartile range, 1.2-7.2); mean LV ejection fraction, 36.8%±7.1%; and median NT-proBNP, 230 pg/mL (interquartile range, 124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LV end-systolic volume index; adjusted between-group difference, -1.9 mL/m2 (95% CI, -4.9 to 1.0); P=0.19. There were no significant between-group differences in NT-proBNP, high-sensitivity cardiac troponin I, LV end-diastolic volume index, left atrial volume index, LV ejection fraction, LV mass index, or patient global assessment of change.ConclusionsIn patients with asymptomatic LV systolic dysfunction late after myocardial infarction, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03552575.

Project description:BackgroundCardiac magnetic resonance (CMR) has been used to diagnose and risk-stratify patients with left ventricular noncompaction (LVNC). The prognostic value of CMR parameters for LVNC, especially feature tracking (CMR-FT), is not well known in LVNC patients with left ventricular dysfunction. The present study aimed to investigate whether the combination of CMR-FT with traditional CMR parameters can increase the prognostic value of CMR for LVNC patients with reduced left ventricular ejection fraction (LVEF).MethodsA total of 123 candidates were retrospectively included in this multicenter study and 55 LVNC patients (mean age, 45.7 ± 16.2 years; 61.8% men) remained after applying the exclusion criteria. Clinical features, left ventricular (LV) function parameters, global and segment myocardial strain, and late gadolinium enhancement (LGE) were evaluated. The outcomes include the composite events of cardiovascular death, heart transplantation, hospitalization for heart failure, thromboembolic events, and ventricular arrhythmias.ResultsAfter a median follow-up of 5.17 years (interquartile range: 0.17 to 10.58 years), 24 (36.8%) patients experienced at least one major adverse cardiovascular event (MACE). The myocardial strain parameters of patients with events were lower than those of patients without events. In the univariable Cox analysis, LVEF, the presence of LGE, global longitudinal strain (GLS) and segmental strains, including longitudinal strain at the apical level and radial and circumferential strain at the basal level, were significantly associated with MACEs. In the multivariate analysis, LGE (hazard ratio (HR) 3.452, 95% CI 1.133 to 10.518, p = 0.029) was a strong predictor of MACEs and significantly improved the predictive value (chi-square of the model after adding LGE: 7.51 vs. 13.47, p = 0.009). However, myocardial strain parameters were not statistically significant for the prediction of MACEs after adjusting for age, body mass index, LVEF and the presence of LGE and did not increase the prognostic value (chi-square of the model after adding GLS: 13.47 vs. 14.14, p = 0.411) in the multivariate model.ConclusionsThe combination of CMR-FT with traditional CMR parameters may not increase the prognostic value of CMR in LVNC patients with reduced LVEF, while the presence of LGE was a strong independent predictor of MACEs and significantly improved the predictive value.

Dataset Information

Inhibition of KCa2 and Kv11.1 Channels in Pigs With Left Ventricular Dysfunction.

Publications

Inhibition of K<sub>Ca</sub>2 and K<sub>v</sub>11.1 Channels in Pigs With Left Ventricular Dysfunction.

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