Metra, Marco

Abstract Aims Limited evidence is available regarding the role of hypertensive response to exercise (HRE) in heart failure (HF). We evaluated the systolic blood pressure (SBP) to workload slope during exercise across the HF spectrum, investigating haemodynamic and prognostic correlates of HRE. Methods and results We prospectively enrolled 369 patients with HF Stage C (143 had preserved [HFpEF], and 226 reduced [HFrEF] ejection fraction), 201 subjects at risk of developing HF (HF Stages A–B), and 58 healthy controls. We performed a combined cardiopulmonary exercise stress echocardiography testing. We defined HRE as the highest sex-specific SBP/workload slope tertile in each HF stage. Median SBP/workload slope was 0.53 mmHg/W (interquartile range 0.36–0.72); the slope was 39% steeper in women than men (p < 0.0001). After adjusting for age and sex, SBP/workload slope in HFrEF (0.47, 0.30–0.63) was similar to controls (0.43, 0.35–0.57) but significantly lower than Stages A–B (0.61, 0.47–0.75) and HFpEF (0.63, 0.42–0.86). Patients with HRE showed significantly lower peak oxygen consumption and peripheral oxygen extraction. After a median follow-up of 16 months, HRE was independently associated with adverse outcomes (all-cause mortality and hospitalization for cardiovascular reasons: hazard ratio 2.05, 95% confidence interval 1.81–5.18), while rest and peak SBP were not. Kaplan–Meier analysis confirmed a worse survival probability in Stages A–B (p = 0.005) and HFpEF (p < 0.001), but not HFrEF. Conclusion A steeper SBP/workload slope is associated with impaired functional capacity across the HF spectrum and could be a more sensitive predictor of adverse events than absolute SBP values, mainly in patients in Stages A–B and HFpEF.

Background In heart failure, the exercise gas exchange Weber (A to D) and ventilatory classifications (VC‐1 to VC‐4) historically define disease severity and prognosis. However, their applications in the modern heart failure population of any left ventricular ejection fraction combined with hemodynamics are undefined. We aimed at revisiting and implementing these classifications by cardiopulmonary exercise testing imaging. Methods and Results 269 patients with heart failure with reduced (n=105), mid‐range (n=88) and preserved (n=76) ejection fraction underwent cardiopulmonary exercise testing imaging, primarily assessing the cardiac output (CO), mitral regurgitation, and mean pulmonary arterial pressure (mPAP)/CO slope. Within both classes, a progressively lower exercise CO, higher mPAP/CO slopes, and mitral regurgitation ( P <0.01 all) were observed. After adjustment for age and sex, Cox proportional hazard regression analyses showed that Weber (hazard ratio [HR], 2.9; 95% CI, 1.8–4.7; P <0.001) and ventilatory classes (HR, 1.4; 95% CI, 1.1–2.0; P =0.017) were independently associated with outcome. The best stratification was observed when combining Weber (A/B or C/D) with severe ventilation inefficiency (VC‐4) (HR, 2.7; 95% CI, 1.6–4.8; P <0.001). At multivariable analysis the best hemodynamic determinants of peak oxygen consumption and ventilation to carbon dioxide production slope were CO (β‐coefficient, 0.72±0.16; P <0.001) and mPAP/CO slope (β‐coefficient, 0.72±0.16; P <0.001), respectively. Conclusions In the contemporary heart failure population, the Weber and ventilatory classifications maintain their prognostic ability, especially when combined. Exercise CO and mPAP/CO slope are the best predictors of peak oxygen consumption and ventilation to carbon dioxide production slope classifications representing the main targets of interventions to impact functional class and, likely, event rate.

Abstract Aims This study aims to explore long-term clinical outcomes of cardiopoiesis-guided stem cell therapy for ischaemic heart failure assessed in the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial. Methods and results CHART-1 is a multinational, randomized, and double-blind trial conducted in 39 centres in heart failure patients (n = 315) on standard-of-care therapy. The ‘active’ group received cardiopoietic stem cells delivered intramyocardially using a retention-enhanced catheter. The ‘control’ group underwent patient-level sham procedure. Patients were followed up to 104 weeks. In the entire study population, results of the primary hierarchical composite outcome were maintained neutral at Week 52 [Mann–Whitney estimator 0.52, 95% confidence interval (CI) 0.45–0.59, P = 0.51]. Landmark analyses suggested late clinical benefit in patients with significant left ventricular enlargement receiving adequate dosing. Specifically, beyond 100 days of follow-up, patients with left ventricular end-diastolic volume of 200–370 mL treated with ≤19 injections of cardiopoietic stem cells showed reduced risk of death or cardiovascular hospitalization (hazard ratio 0.38, 95% CI 0.16–0.91, P = 0.031) and cardiovascular death or heart failure hospitalization (hazard ratio 0.28, 95% CI 0.09–0.94, P = 0.040). Cardiopoietic stem cell therapy was well tolerated long term with no difference in safety readouts compared with sham at 2 years. Conclusions Longitudinal follow-up documents that cardiopoietic stem cell therapy is overall safe, and post hoc analyses suggest benefit in an ischaemic heart failure subpopulation defined by advanced left ventricular enlargement on tolerable stem cell dosing. The long-term clinical follow-up thus offers guidance for future targeted trials.

Abstract Aims Left ventricular (LV) reverse remodelling is an important marker of improved outcomes in patients with advanced heart failure (HF). We examined the impact of the intramyocardial administration of bone-marrow-derived, lineage-directed, autologous cardiopoietic mesenchymal stem cells (C3BS-CQR-1) on LV remodelling in patients with advanced HF enrolled in the CHART-1 study. Methods and results Patients (n=351) with symptomatic advanced HF secondary to ischaemic heart disease, and reduced LV ejection fraction (LVEF &lt;35%) were randomized to receive C3BS-CQR-1 or a sham procedure. In a post hoc analysis we examined the effect of C3BS-CQR-1 on LV reverse remodelling within 1 year of the procedure and the influence of C3BS-CQR-1 dosing in the 271 patients treated as randomized. Delivery of C3BS-CQR-1 was associated with a progressive decrease in both LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) within 52 weeks after treatment. At 1 year, the LVEDV and LVESV of treated patients decreased by 17.0 mL and 12.8 mL greater than controls (P=0.006 and P=0.017, respectively). The effect on LVEDV was maintained after multivariable adjustment for baseline age, systolic blood pressure, LVEDV, LVEF and history of myocardial infarction. The largest reverse remodelling was evident in the patients receiving a moderate number of injections (&lt;20). Conclusion In CHART-1, intramyocardial administration of cardiopoietic stem cells led to reverse remodelling as evidenced by significant progressive decreases in LVEDV and LVESV through the 52 weeks of follow-up. Further studies are needed to explore the dose response with regard to cell number and injected volume, and reverse remodelling.

Abstract Aims Cardiopoiesis is a conditioning programme that aims to upgrade the cardioregenerative aptitude of patient-derived stem cells through lineage specification. Cardiopoietic stem cells tested initially for feasibility and safety exhibited signs of clinical benefit in patients with ischaemic heart failure (HF) warranting definitive evaluation. Accordingly, CHART-1 is designed as a large randomized, sham-controlled multicentre study aimed to validate cardiopoietic stem cell therapy. Methods Patients (n = 240) with chronic HF secondary to ischaemic heart disease, reduced LVEF (&lt;35%), and at high risk for recurrent HF-related events, despite optimal medical therapy, will be randomized 1:1 to receive 600 × 106 bone marrow-derived and lineage-directed autologous cardiopoietic stem cells administered via a retention-enhanced intramyocardial injection catheter or a sham procedure. The primary efficacy endpoint is a hierarchical composite of mortality, worsening HF, Minnesota Living with Heart Failure Questionnaire score, 6 min walk test, LV end-systolic volume, and LVEF at 9 months. The secondary efficacy endpoint is the time to cardiovascular death or worsening HF at 12 months. Safety endpoints include mortality, readmissions, aborted sudden deaths, and serious adverse events at 12 and 24 months. Conclusion The CHART-1 clinical trial is powered to examine the therapeutic impact of lineage-directed stem cells as a strategy to achieve cardiac regeneration in HF populations. On completion, CHART-1 will offer a definitive evaluation of the efficacy and safety of cardiopoietic stem cells in the treatment of chronic ischaemic HF. Trial registration: NCT01768702