Pressure overload is associated with right ventricular dyssynchrony in heart failure with reduced ejection fraction.

AIMS: The determinants and relevance of right ventricular (RV) mechanical dyssynchrony in heart failure with reduced ejection fraction (HFrEF) are poorly understood. We hypothesized that increased afterload may adversely affect the synchrony of RV contraction. METHODS AND RESULTS: A total of 148 patients with HFrEF and 36 controls underwent echocardiography, right heart catheterization, and gated single-photon emission computed tomography to measure RV chamber volumes and mechanical dyssynchrony (phase standard deviation of systolic displacement timing). Exams were repeated after preload (N = 135) and afterload (N = 15) modulation. Patients with HFrEF showed higher RV dyssynchrony compared with controls (40.6 ± 17.5° vs. 27.8 ± 9.1°, P < 0.001). The magnitude of RV dyssynchrony in HFrEF correlated with larger RV and left ventricular (LV) volumes, lower RV ejection fraction (RVEF) and LV ejection fraction, reduced intrinsic contractility, increased heart rate, higher pulmonary artery (PA) load, and impaired RV-PA coupling (all P ≤ 0.01). Low RVEF was the strongest predictor of RV dyssynchrony. Left bundle branch block (BBB) was associated with greater RV dyssynchrony than right BBB, regardless of QRS duration. RV afterload reduction by sildenafil improved RV dyssynchrony (P = 0.004), whereas preload change with passive leg raise had modest effect. Patients in the highest tertiles of RV dyssynchrony had an increased risk of adverse clinical events compared with those in the lower tertile [T2/T3 vs. T1: hazard ratio 1.98 (95% confidence interval 1.20-3.24), P = 0.007]. CONCLUSIONS: RV dyssynchrony is associated with RV remodelling, dysfunction, adverse haemodynamics, and greater risk for adverse clinical events. RV dyssynchrony is mitigated by acute RV afterload reduction and could be a potential therapeutic target to improve RV performance in HFrEF.

Catheter ablation of atrial fibrillation and atrial tachycardia in patients with pulmonary hypertension: a randomized study.

AIMS: Atrial fibrillation (AF), typical atrial flutter (AFL), and other atrial tachycardias (ATs) are common in patients with pulmonary hypertension. Frequently, several supraventricular arrhythmias are successively observed in individual patients. We investigated the hypothesis of whether more extensive radiofrequency catheter ablation of the bi-atrial arrhythmogenic substrate instead of clinical arrhythmia ablation alone results in superior clinical outcomes in patients with pulmonary arterial hypertension (PH) and supraventricular arrhythmias. METHODS AND RESULTS: Patients with combined post- and pre-capillary or isolated pre-capillary PH and supraventricular arrhythmia indicated to catheter ablation were enrolled in three centres and randomized 1:1 into two parallel treatment arms. Patients underwent either clinical arrhythmia ablation only (Limited ablation group) or clinical arrhythmia plus substrate-based ablation (Extended ablation group). The primary endpoint was arrhythmia recurrence >30 s without antiarrhythmic drugs after the 3-month blanking period. A total of 77 patients (mean age 67 ± 10 years; 41 males) were enrolled. The presumable clinical arrhythmia was AF in 38 and AT in 36 patients, including typical AFL in 23 patients. During the median follow-up period of 13 (interquartile range: 12; 19) months, the primary endpoint occurred in 15 patients (42%) vs. 17 patients (45%) in the Extended vs. Limited ablation group (hazard ratio: 0.97, 95% confidence interval: 0.49-2.0). There was no excess of procedural complications and clinical follow-up events including an all-cause death in the Extended ablation group. CONCLUSION: Extensive ablation, compared with a limited approach, was not beneficial in terms of arrhythmia recurrence in patients with AF/AT and PH. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov; NCT04053361.

Pulmonary Vasculature Responsiveness to Phosphodiesterase-5A Inhibition in Heart Failure With Reduced Ejection Fraction: Possible Role of Plasma Potassium.

Introduction: Phosphodiesterase-5a inhibition (PDE5i) leads to favorable changes in pulmonary hemodynamic and cardiac output (CO) in patients with advanced heart failure (HF) and reduced ejection fraction (HFrEF). The hemodynamic response to PDE5i could be heterogeneous and the clinical variables associated with these changes are scarcely investigated. Materials and Methods: Of 260 patients with advanced HFrEF referred for advanced therapies [cardiac transplant/left ventricular assist device (LVAD)], 55 had pulmonary hypertension (PH) and fulfilled the criteria for the PDE5i vasoreactivity test. Right heart catheterization (RHC) was performed as a part of clinical evaluation before and after 20-mg intravenous sildenafil. Absolute and relative changes in pulmonary vascular resistance (PVR) were evaluated to assess hemodynamic response to PDE5i. Clinical, biochemical, and hemodynamic factors associated with PVR changes were identified. Results: Sildenafil administration reduced PVR (- 45.3%) and transpulmonary gradient (TPG; - 34.8%) and increased CO (+ 13.6%). Relative change analysis showed a negative moderate association between baseline plasma potassium and changes in PVR (r = - 0.48; p = 0.001) and TPG (r = - 0.43; p = 0.005) after PDE5i. Aldosterone concentration shows a direct moderate association with PVR changes after PDE5i. A significant moderate association was also demonstrated between CO improvement and the severity of mitral (r = 0.42; p = 0.002) and tricuspid (r = 0.39; p = 0.004) regurgitation. Conclusion: We identified plasma potassium, plasma aldosterone level, and atrioventricular valve regurgitations as potential cofounders of hemodynamic response to acute administration of PDE5i. Whether modulation of potassium levels could enhance pulmonary vasoreactivity in advanced HFrEF deserves further research.

Acute Unloading Effects of Sildenafil Enhance Right Ventricular-Pulmonary Artery Coupling in Heart Failure.

BACKGROUND: Phosphodiesterase-5A inhibitors (PDE5i) are sometimes used in patients with advanced heart failure with reduced ejection fraction before heart transplant or left ventricular assist device implantation to decrease right ventricular (RV) afterload and mitigate the risk of right heart failure. Conflicting evidence exists regarding the impact of these drugs on RV contractility. The aim of this study was to explore the acute effects of PDE5i on ventricular-vascular coupling and load-independent RV contractility. METHODS: Twenty-two patients underwent right heart catheterization and gated equilibrium blood pool single photon emission computed tomography, before and after 20 mg intravenous sildenafil. Single photon emission computed tomography and right heart catheterization-derived data were used to calculate RV loading and contractility. RESULTS: PDE5i induced a decrease in the right atrial pressure (-43%), pulmonary artery (PA) mean pressure (-26%), and PA wedge pressure (PAWP; -23%), with favorable reductions in pulmonary vascular resistance (-41%) and PA elastance (-40%), and increased cardiac output (+13%) (all P < 0.01). The RV ejection fraction increased with sildenafil (+20%), with no change of RV contractility (P = 0.74), indicating that the improvement in the RV ejection fraction was related to enhanced RV-PA coupling (r = 0.59, P = 0.004) by a decrease in the ventricular load. RV diastolic compliance increased with sildenafil. The decrease in the PAWP correlated with RV end-diastolic volume decrease; no relationship was observed with the change in LV transmural pressure, suggesting decreased pericardial constraint. CONCLUSIONS: Acute PDE5i administration has profound RV afterload-reducing effects, improves the RVEF, decreases RV volumes, and decreases the PAWP, predominantly through relief of pericardial constraint, without effects on RV chamber contractility. These findings support further study of PDE5i in protection of RV function in advanced heart failure with reduced ejection fraction who are at risk of RV failure.

The effects of phosphodiesterase 5 inhibition on hemodynamics, functional status and survival in advanced heart failure and pulmonary hypertension: a case-control study.

BACKGROUND: The goal was to examine the hemodynamic and clinical effects of long-term therapy with PDE5 inhibitor sildenafil (SILD) in patients with advanced, pre-transplant heart failure (HF) and severe pulmonary hypertension (PH), in comparison to a similar control group (CON). METHODS: In this non-randomized, retrospective case-control study, 32 middle-aged patients (81% males) with advanced systolic HF (80%≥ NYHA III, 56% ischemic) and severe pre-capillary PH (transpulmonary pressure gradient>15 mm Hg) were studied before and after initiation of SILD (dose 73 ± 25 mg/day) and were compared to 15 CON patients, matched for key clinical characteristics (including PH severity, age and co-morbidities), not exposed to SILD. Changes at 3 months and the long-term outcome were compared between groups. RESULTS: SILD significantly reduced pulmonary vascular resistance (-32% vs. baseline), transpulmonary gradient (-25%) and increased cardiac output (+15%) compared to controls, without affecting systemic or ventricular filling pressures. SILD-treated subjects experienced an improvement in NYHA class and had a steady body weight which contrasted with significant weight loss in the CON group (by -4.8%, absolutely by 4.3 ± 6 kg). During follow-up (median 349 days from baseline), 60% of patients underwent heart transplantation. Two patients in CON group had severe post-transplant failure of the right ventricle, none in SILD group. Overall pre- and peritransplant survival (censored 30 days after transplantation) was significantly better in SILD than CON group (93.7 vs 60%, p=0.0048). CONCLUSIONS: In patients with advanced HF and severe PH, SILD therapy has beneficial effects on hemodynamics, clinical status, cardiac cachexia, and contributes to improved peri-transplant survival.