Metra, Marco

Objective: Limited evidence is available regarding the impact of workload-indexed hypertensive response to exercise (HRE) in patients at different stages of the heart failure (HF) spectrum. We evaluated the prevalence, pathophysiologic and prognostic correlates of HRE, evaluated by the systolic blood pressure (SBP)/Workload slope, across the HF spectrum as defined by the American College of Cardiology/American Heart Association. Design and method: We prospectively enrolled 58 healthy controls, 201 subjects at risk of developing HF (HF Stages A-B), and 369 patients with a definite diagnosis of HF (Stage C) and either preserved (HFpEF) or reduced (HFrEF) left ventricular ejection fraction. All patients underwent a combined cardiopulmonary-exercise stress echocardiography test. We recorded two SBP measurements for each patient: the first within the first minute of exercise and the last at peak effort. The SBP/Workload slope was calculated as the difference in SBP over the corresponding increment in watts (W): (SBPpeak – SBPfirst)/(Wpeak – Wfirst). In each subgroup, we divided patients according to SBP/Workload slope tertiles, using sex-specific cut-off values; HRE was defined as the highest SBP/Workload slope tertile in each HF stage. A composite of all-cause mortality and hospitalization for cardiovascular reasons was chosen as the primary outcome. Results: The median SBP/Workload slope was 0.53 (interquartile range 0.36 - 0.72) mmHg/W and was steeper in women than men in all subgroups. After adjusting for age and sex, SBP/Workload slope in controls was similar to HFrEF but significantly lower than Stages A-B and HFpEF. In all HF stages, 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 (Hazard Ratio 2.05, 95% confidence interval 1.81 - 5.18). Kaplan-Meier analysis confirmed a worse survival probability in Stages A-B and HFpEF, but not HFrEF. After adjusting for clinical and echocardiographic variables, patients in the highest SBP/Workload tertile had a 47% higher risk of the primary outcome than subjects in the lowest tertile. Conclusions: HRE is associated with peculiar pathophysiological features and possibly worse prognosis in patients in the earliest stages of cardiovascular disease and in those with HFpEF.

Abstract Aims Current European heart failure (HF) guidelines suggest the use of risk score: among them, the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score has demonstrated to be one of the most accurate. However, the risk scores are still poorly implemented in clinical practice, also due to the lack of strong evidence regarding their external validation in different populations. Thus, the current study was designed as an external validation test of the MECKI score in an international multicentre setting. Methods and results The study cohort consisted of patients diagnosed with HF with reduced ejection fraction (HFrEF) across international centres (not Italian), retrospectively recruited. Collected data included demographics, HF aetiology, laboratory testing, electrocardiogram (ECG), echocardiographic findings, and cardiopulmonary exercise testing (CPET) results as described in the original MECKI score publication. A total of 1042 patients across 8 international centres (7 European and 1 Asian) were included and followed up from 1998 till 2019. Patients were divided according to the calculated MECKI scores into three subgroups: (i) MECKI score <10%, (ii) 10–20%, and (iii) ≥ 20%. Survival analysis comparison among the three MECKI score subgroups showed a worse prognosis in patients with higher MECKI score value: median event-free survival times were 4396 days for MECKI score <10%, 3457 days for 10–20%, and 1022 days for ≥20% (P < 0.0001). Receiver operating characteristic (ROC) curves and area under the ROC curves (AUC) were like those reported in the original internal validation studies. Conclusion In patients diagnosed with HFrEF, the power of the MECKI score was confirmed in terms of prognosis and risk stratification, supporting its implementation as advised by the HF guidelines.

Abstract Funding Acknowledgements Type of funding sources: None. Background Conflicting data exist regarding the prognostic significance of hypertensive response to exercise (HRE), commonly defined according to absolute peak systolic blood pressure (SBP) values. Limited evidence is available regarding the impact of workload-indexed HRE in patients at different stages of the heart failure (HF) spectrum as defined by the American College of Cardiology/American Heart Association HF staging system. Purpose We evaluated the SBP/Workload slope during exercise across the HF spectrum and investigated the haemodynamic, functional and prognostic correlates of HRE. Methods We prospectively enrolled 58 healthy controls, 201 subjects at risk of developing HF (HF Stages A-B), and 369 patients with a definite diagnosis of HF (Stage C); among the latter, 143 had preserved (HFpEF) and 226 reduced (HFrEF) left ventricular ejection fraction. All patients underwent a combined cardiopulmonary-exercise stress echocardiography test. For each patient, we recorded the first (i.e., within the first minute of exercise) and last (i.e., at peak effort) BP measurement during the ramp protocol. The SBP/Workload slope (Figure 1) was calculated as the ratio of the difference in SBP over the corresponding increment in watts (W): (SBPpeak – SBPfirst)/(Wpeak – Wfirst). In each subgroup, we divided patients according to SBP/Workload slope tertiles; HRE was defined as the highest sex-specific SBP/Workload slope tertile in each HF stage. The primary outcome was a composite of all-cause mortality and hospitalization for cardiovascular reasons. Results Median SBP/Workload slope was 0.53 mmHg/W, interquartile range 0.36-0.72 mmHg/W; the slope was 39% steeper in women than in men (p<0.0001). After adjusting for age and sex, SBP/Workload slope in controls (0.43, 0.35-0.57 mmHg/W) was similar to HFrEF (0.47, 0.30-0.63 mmHg/W) but significantly lower than Stages A-B (0.61, 0.47-0.75 mmHg/W) and HFpEF (0.63, 0.42-0.86 mmHg/W). In all HF stages, 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 (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. After adjusting for age, sex, body mass index, rest and peak SBP, rest and peak cardiac output, and rest and peak left ventricular ejection fraction, patients with the highest SBP/Workload slope had a 47% higher risk of the primary outcome than subjects in the lowest tertile (Figure 2). Conclusion HRE, as evaluated by the SBP/Workload slope, is associated with distinct pathophysiological features and impaired functional capacity across the HF spectrum, especially in Stages A-B and in patients with HFpEF. Patients with HRE in these subgroups may be at increased risk of adverse cardiovascular outcomes.

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