Citations

Background: There are no specific treatments for patients with HFpEF and pulmonary hypertension (PH-HFpEF). Increased central and pulmonary venous pressures (CVP, PCWP) are believed to contribute importantly to symptoms at rest and during exercise. Levosimendan (LEVO), a calcium sensitizer/KATP channel activator, is known to reduce CVP and PCWP in patients with reduced LVEF. We hypothesized that LEVO would have similar effects in PH-HFpEF. Methods: 44 PH-HFpEF patients with mean pulmonary artery (mPAP) ≥35 mmHg, PCWP ≥20 mmHg, LVEF ≥40% and NYHA II or III symptoms underwent hemodynamic measurements at rest, during passive leg raise (PLR) and during supine bicycle exercise for 3 minutes at 25 Watts (EX) at baseline and following a continuous 24-hour infusion of LEVO (0.1 μg/kg/min) as part of a multicenter clinical trial. Measurements included CVP, mPAP, PCWP, mean arterial pressure (MAP) and cardiac index (CI); pulmonary and systemic vascular resistances (PVR, SVR) were calculated. Hemodynamic tracings were analyzed in a core lab blinded to condition and timepoint. The primary endpoint was the change of PCWP at 25 Watts. Results: Patients averaged 69±9.1 years old, 61.4% were female and had a mPAP of 41.0±9.3 mmHg at rest. LEVO decreased mPAP at rest, CVP and PCWP at rest and EX, and increased CI with EX; there were no significant changes in mPAP, PVR or SVR. Resting and EX hemodynamic data are summarized in the Table. 37 of the 44 patients (84%) were considered hemodynamic “responders” based on a pre-specified ≥4 mmHg decrease of EX PCWP. Conclusions: In patients with PH-HFpEF, a 24 hour levosimendan infusion at 0.1 μg/kg/min decreased CVP and PCWP and increased CI at rest and EX, despite no significant effect on SVR or PVR. A majority of patients exhibited acute hemodynamic response. While the underlying mechanism(s) remain to be clarified, LEVO’s effects on CVP and PCWP warrant further study of this drug as a treatment for PH-HFpEF.

Abstract Aims A hallmark of heart failure with preserved ejection fraction (HFpEF) is impaired exercise capacity of varying severity. The main determinant of exercise capacity is cardiac output (CO), however little information is available about the relation between the constituents of CO – heart rate and stroke volume – and exercise capacity in HFpEF. We sought to determine if a heterogeneity in heart rate and stroke volume response to exercise exists in patients with HFpEF and describe possible clinical phenotypes associated with differences in these responses. Methods and results Data from two prospective trials of HFpEF ( n = 108) and a study of healthy participants ( n = 42) with invasive haemodynamic measurements during exercise were utilized. Differences in central haemodynamic responses were analysed with regression models. Chronotropic incompetence was present in 39–56% of patients with HFpEF and 3–56% of healthy participants depending on the definition used, but some ( n = 47, 44%) had an increase in heart rate similar to that of healthy controls. Patients with HFpEF had a smaller increase in their stroke volume index (SVI) (HFpEF: +4 ± 10 mL/m 2 , healthy participants: +24 ± 12 mL/m 2 , P < 0.0001), indeed, SVI fell in 28% of patients at peak exercise. Higher body mass index and lower SVI at rest were associated with smaller increases in heart rate during exercise, whereas higher resting heart rate, and angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker use were associated with a greater increase in SVI in patients with HFpEF. Conclusion The haemodynamic response to exercise was very heterogeneous among patients with HFpEF, with chronotropic incompetence observed in up to 56%, and 28% had impaired increase in SVI. This suggests that haemodynamic exercise testing may be useful to identify which HFpEF patients may benefit from interventions targeting stroke volume and chronotropic response.

Approximately 50% of patients with heart failure have preserved ejection fraction. Although a wide variety of conditions cause or contribute to heart failure with preserved ejection fraction, elevated left ventricular filling pressures, particularly during exercise, are common to all causes. Acute elevation in left‐sided filling pressures promotes lung congestion and symptoms of dyspnea, while chronic elevations often lead to pulmonary vascular remodeling, right heart failure, and increased risk of mortality. Pharmacologic therapies, including neurohormonal modulation and drugs that modify the nitric oxide/cyclic GMP‐protein kinase G pathway have thus far been limited in reducing symptoms or improving outcomes in patients with heart failure with preserved ejection fraction. Hence, alternative means of reducing the detrimental rise in left‐sided heart pressures are being explored. One proposed method of achieving this is to create an interatrial shunt, thus unloading the left heart at rest and during exercise. Currently available studies have shown 3‐ to 5‐mm Hg decreases of pulmonary capillary wedge pressure during exercise despite increased workload. The mechanisms underlying the hemodynamic changes are just starting to be understood. In this review we summarize results of recent studies aimed at elucidating the potential mechanisms of improved hemodynamics during exercise tolerance following interatrial shunt implantation and the current interatrial shunt devices under investigation.

Background Interatrial shunt device (IASD) effects have been described in patients with heart failure and ejection fractions (EFs) ≥40%. However, baseline characteristics that correlate with greatest hemodynamic effects are unknown. On the basis of fundamental principles, we hypothesized that larger pressure gradients between left and right atria would yield greater shunt flow and greater hemodynamic effects. Methods and Results REDUCE LAP-HF (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a multicenter study that investigated IASD safety and performance. Sixty-four patients with EF ≥40% underwent device implantation followed by hemodynamic assessments at rest and exercise, including pulmonary capillary wedge pressure (PCWP, surrogate for left atrial pressure) and central venous pressure (CVP). At 6 months, IASD resulted in an average pulmonary-to-systemic blood flow ratio of 1.27 and increased exercise tolerance. The PCWP-CVP gradient (ie, the driving pressure for shunt flow) decreased at peak exercise from 16.8±6.9 to 11.4±5.5 mm Hg, because of increased CVP (17.5±5.4 to 20.3±7.9 mm Hg; P =0.04) and decreased PCWP (34.1±7.6 to 31.6±8.0 mm Hg; P =0.025). Baseline PCWP-CVP gradient during exercise correlated with changes of both PCWP-CVP and PCWP: Δ(PCWP-CVP)=10.0−0.89·(PCWP-CVP) baseline ( r 2 =0.56) and ΔPCWP=7.54−0.60·(PCWP-CVP) baseline ( P =0.001). Hemodynamics of patients with EF ≥50% and those with EF <50% responded similarly to IASD. Conclusions In heart failure patients with EF ≥40%, IASD significantly reduced PCWP and PCWP-CVP at peak exercise. Patients with higher baseline PCWP-CVP gradient had greater reductions in both parameters at follow-up. Results were sustained through 12 months and were independent of whether EF was ≥50% or between 40% and 49%. Additional studies will help further define the baseline hemodynamic predictors of exercise, hemodynamic, and clinical efficacy of the IASD. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01913613.

Abstract Aims Patients with heart failure and preserved ejection fraction (HFpEF) are characterized by functional impairment and an abnormal haemodynamic response to exercise. The six-minute walk test (6MWT) serves as a standardized test for functional capacity quantification in heart failure patients, and is associated with cardiovascular outcomes. However, as the association between 6MWT and haemodynamic parameters during rest and exercise in HFpEF patients is unknown, we sought to elucidate this relationship. Methods and results Overall, 64 patients enrolled in the REDUCE LAP-HF trial completed a 6MWT at baseline. Univariate and multivariable linear regression models were used to assess the associations between 6MWT and measured or derived haemodynamic variables at baseline, during light/moderate exercise (20 W), and at peak supine exercise. The average 6MWT distance was 318 ± 106 m. At rest, in a multivariable model, only pulmonary capillary wedge pressure (PCWP) was significantly associated with 6MWT [coefficient: –5.4, 95% confidence interval (CI) –10.4, –0.5, P = 0.033]. During light/moderate exercise, mean pulmonary artery pressure was associated with 6MWT in a multivariable model (coefficient: –3.5, 95% CI –6.8, –0.3, P = 0.033). During peak exercise, central venous pressure, cardiac index (CI), and PCWP/CI correlated with 6MWT; however, workload corrected PCWP was the only variable independently associated with 6MWT (coefficient: –0.8, 95% CI –1.3, –0.4, P &lt; 0.001). The variance in 6MWT was modestly explained by measured or derived haemodynamic variables at rest or at any stage of exercise (r2 = 7–17%). Conclusion Workload corrected PCWP correlated best with 6MWT performance in HFpEF patients. Baseline haemodynamic variables were modestly correlated with 6MWT, suggesting that 6MWT performance in HFpEF patients may be significantly influenced by extra-cardiac factors.