Combined Endpoint Of Cardiovascular Death Research Articles

The role of fibrosis and inflammation for response and outcome prediction in candidates to cardiac resynchronization therapy: is response the right answer?

Abstract Background Cardiac resynchronization therapy (CRT) is an established treatment in selected patients suffering from heart failure with reduced ejection fraction (HFrEF). It has been proposed that myocardial fibrosis and inflammation could influence CRT "response" and outcome. Purpose Our study investigated the long-term prognostic significance of cardiac biomarkers in HFrEF patients with an indication for CRT. Methods 86 consecutive patients referred for CRT implantation were retrospectively evaluated. The soluble suppression of tumorigenicity 2 (sST2), galectin-3 (Gal-3), N-terminal portion of the B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR) were measured at baseline and after 1 year of follow-up. An echocardiographic reduction of LV end-systolic volume ≥15% was used to define a patient as responder to CRT. Multivariate analyses were performed to evaluate their correlation with the primary composite outcome of cardiovascular mortality and heart failure hospitalizations at a mean follow-up of 9 ± 2 years. Results 44% of patients experienced the primary outcome. the mean baseline values of NT-proBNP, Gal-3, and sST2 were significantly higher compared with the patients without cardiovascular events. At the multivariate analyses, baseline Gal-3 [cut-off: 38.5 ng/ml, AUC: 0.63, p=0.03, (OR 7.13 [1.12;45.41], p=0.03), together with TAPSE>17.5 mm (OR 10.86 [3.15;37.44], p<0.001) significantly correlated with the structural response to CRT in several prediction models. Baseline Gal-3 [cut-off: 16.6 ng/ml, AUC: 0.91, p<0.001, HR 8.33 (1.88–33.33), p = 0.005] and sST2 [cut-off: 35.6 ng/ml AUC: 0.91, p<0.001, HR 333 (250–1,000), p = 0.003] significantly correlated with the composite outcome in the prediction models with high likelihood (Table). At Kaplan-Meyer curve patients with both high baseline sST2 and Gal-3 had the lowest survival probability (Figure). Among the parameters evaluated at 1-year follow-up, sST2, eGFR, and the variation from baseline to 1-year of Gal-3 levels showed a strong association with the primary outcome [HR 1.15 (1.08–1.22), p < 0.001; HR: 0.84 (0.74–0.91), p = 0.04; HR: 1.26 (1.10–1.43), p ≤ 0.001, respectively]. Conversely, the echocardiographic definition of CRT response did not correlate with any outcome. Conclusion In HFrEF patients with CRT, sST2, Gal-3, and renal function were associated with the combined endpoint of cardiovascular death and HF hospitalizations at long term follow-up, while the echocardiographic CRT response did not seem to influence the outcome of the patients.

Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials

Heart failure with mildly reduced or preserved ejection fraction (hereafter referred to as HFpEF) is the most common type of heart failure and is associated with a high risk of hospitalisation and death, especially in patients with overweight, obesity, or type 2 diabetes. In the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide improved heart failure-related symptoms and physical limitations in participants with HFpEF. Whether semaglutide also reduces clinical heart failure events in this group remains to be established. We conducted a post-hoc pooled, participant-level analysis of four randomised, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) to examine the effects of once-weekly subcutaneous semaglutide (2·4 mg in SELECT, STEP-HFpEF, and STEP-HFpEF DM; 1·0 mg in FLOW) on heart failure events. The STEP-HFpEF and STEP-HFpF DM trials enrolled participants with obesity-related HFpEF, the SELECT trial enrolled participants with atherosclerotic cardiovascular disease and overweight or obesity, and the FLOW trial enrolled participants with type 2 diabetes and chronic kidney disease. Hence, for this analysis, we include all participants from the STEP-HFpEF trials and those with an investigator-reported history of HFpEF from SELECT and FLOW. The main outcomes for this analysis were the composite endpoint of time to cardiovascular death or first worsening heart failure event (defined as hospitalisation or urgent visit due to heart failure), time to first worsening heart failure event, and time to cardiovascular death. Efficacy and safety endpoints were analysed with the full analysis set (ie, all participants randomly assigned to treatment, according to the intention-to-treat principle). The SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials are registered at ClinicalTrials.gov, NCT03574597, NCT03819153, NCT04788511, and NCT04916470, respectively, and all are complete. Across the four trials, 3743 (16·8%) of 22 282 participants had a history of HFpEF (1914 assigned to semaglutide and 1829 assigned to placebo). In this group of participants with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or heart failure events (103 [5·4%] of 1914 in the semaglutide group had events vs 138 [7·5%] of 1829 in the placebo group; hazard ratio [HR] 0·69 [95% CI 0·53-0·89]; p=0·0045). Semaglutide also reduced the risk of worsening heart failure events (54 [2·8%] vs 86 [4·7%]; HR 0·59 [0·41-0·82]; p=0·0019). No significant effect on cardiovascular death alone was seen (59 [3·1%] vs 67 [3·7%]; HR 0·82 [0·57-1·16]; p=0·25). A lower proportion of patients treated with semaglutide had serious adverse events than did those who were treated with placebo (572 [29·9%] vs 708 [38·7%]). In patients with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or worsening heart failure events, and worsening heart failure events alone, whereas its effect on cardiovascular death alone was not significant. These data support the use of semaglutide as an efficacious therapy to reduce the risk of clinical heart failure events in patients with HFpEF, for whom few treatment options are currently available. Novo Nordisk.

Clinical significance and prognostic value of right bundle branch block in permanent pacemaker patients.

In patients undergoing pacemaker implantation with no prior history of heart failure (HF), the presence of left bundle branch block (LBBB) has been identified as an independent predictor of HF-related death or hospitalization, while the prognostic significance of right bundle branch block (RBBB) remains uncertain. We aimed to assess the long-term risk of all-cause mortality in patients with a standard indication for permanent pacing and normal or moderately depressed left ventricular function when RBBB is detected at the time of implantation. We retrospectively enrolled 1348 consecutive patients who had undergone single- or dual-chamber pacemaker implantation at the study center, from January 1990 to December 2022. Patients with a left ventricular ejection fraction ≤35% or a prior diagnosis of HF were excluded. The baseline 12-lead electrocardiogram revealed an RBBB in 241 (18%) and an LBBB in 98 (7%) patients. During a median follow-up of 65 [25th-75th percentile: 32-117] months, 704 (52%) patients died. The combined endpoint of cardiovascular death or HF hospitalization was reached by 173 (13%) patients. On multivariate analysis, RBBB was confirmed as an independent predictor of death [hazard ratio, 1.33; 95% confidence interval (CI), 1.09-1.63; P = 0.005]. However, when considering the combined endpoint of cardiovascular death and HF hospitalization, this endpoint was independently associated with LBBB (hazard ratio, 2.13; 95% CI, 1.38-3.29; P < 0.001), but not with RBBB. In patients with standard pacemaker indications and normal or moderately depressed left ventricular function, the presence of basal RBBB was an independent predictor of mortality. However, it was not associated with the combined endpoint of cardiovascular death and HF hospitalization.

Clinical significance and prognostic value of right bundle branch block in permanent pacemaker patients

Abstract Aim In patients undergoing pacemaker implantation with no prior history of heart failure (HF), the presence of left bundle branch block (LBBB) has been identified as an independent predictor of HF-related death or hospitalization, while the prognostic significance of right bundle branch block (RBBB) remains uncertain. We aimed to assess the long-term risk of all-cause mortality in patients with a standard indication for permanent pacing and normal or moderately depressed left ventricular function when RBBB is detected at the time of implantation. Methods We retrospectively enrolled 1348 consecutive patients who had undergone single- or dual-chamber pacemaker implantation at the study center, from January 1990 to December 2022. Patients with a left ventricular ejection fraction ≤35% or a prior diagnosis of HF were excluded. Results The baseline 12-lead electrocardiogram revealed an RBBB in 241 (18%) and an LBBB in 98 (7%) patients. During a median follow-up of 65 [25th-75th percentile: 32-117] months, 704 (52%) patients died. The combined endpoint of cardiovascular death or HF hospitalization was reached by 173 (13%) patients. On multivariate analysis, RBBB was confirmed as independent predictor of death (Hazard Ratio, 1.33; 95% CI, 1.09–1.63; P=0.005). However, when considering the combined endpoint of cardiovascular death and HF hospitalization, this endpoint was independently associated with LBBB (Hazard Ratio, 2.13; 95% CI, 1.38–3.29; P&amp;lt;0.001), but not with RBBB. Conclusions In patients with standard pacemaker indications and normal or moderately depressed LV function the presence of basal RBBB was an independent predictor of mortality. However, it was not associated with the combined endpoint of cardiovascular death and HF hospitalization.Time to event

Clinical and prognostic implications of left ventricular dilatation in heart failure.

To assess the agreement between left ventricular end-diastolic diameter index (LVEDDi) and volume index (LVEDVi) to define LV dilatation and to investigate the respective prognostic implications in patients with heart failure (HF). Patients with HF symptoms and LV ejection fraction (LVEF) < 50% undergoing cardiac magnetic resonance were evaluated retrospectively. LV dilatation was defined as LVEDDi or LVEDVi above the upper normal limit according to published reference values. Patients were followed up for the combined endpoint of cardiovascular death or HF hospitalization during 5 years. A total of 564 patients (median age 64 years; 79% men) were included. LVEDDi had a modest correlation with LVEDVi (r = 0.682, P < 0.001). LV dilatation was noted in 84% of patients using LVEDVi-based definition and in 73% using LVEDDi-based definition, whereas 20% of patients displayed discordant definitions of LV dilatation. During a median follow-up of 2.8 years, patients with both dilated LVEDDi and LVEDVi had the highest cumulative event rate (HR 3.00, 95% CI 1.15-7.81, P = 0.024). Both LVEDDi and LVEDVi were independently associated with the primary outcome (hazard ratio 3.29, 95%, P < 0.001 and 2.8, P = 0.009; respectively). The majority of patients with HF and LVEF < 50% present both increased LVEDDi and LVEDVi whereas 20% show discordant linear and volumetric definitions of LV dilatation. Patients with increased LVEDDi and LVEDVi have the worst clinical outcomes suggesting that the assessment of these two metrics is needed for better risk stratification.

The role of fibrosis, inflammation, and congestion biomarkers for outcome prediction in candidates to cardiac resynchronization therapy: is "response" the right answer?

Cardiac resynchronization therapy (CRT) is an established treatment in selected patients suffering from heart failure with reduced ejection fraction (HFrEF). It has been proposed that myocardial fibrosis and inflammation could influence CRT "response" and outcome. Our study investigated the long-term prognostic significance of cardiac biomarkers in HFrEF patients with an indication for CRT. Consecutive patients referred for CRT implantation were retrospectively evaluated. The soluble suppression of tumorigenicity 2 (sST2), galectin-3 (Gal-3), N-terminal portion of the B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR) were measured at baseline and after 1 year of follow-up. Multivariate analyses were performed to evaluate their correlation with the primary composite outcome of cardiovascular mortality and heart failure hospitalizations at a mean follow-up of 9 ± 2 years. Among the 86 patients enrolled, 44% experienced the primary outcome. In this group, the mean baseline values of NT-proBNP, Gal-3, and sST2 were significantly higher compared with the patients without cardiovascular events. At the multivariate analyses, baseline Gal-3 [cut-off: 16.6 ng/ml, AUC: 0.91, p < 0.001, HR 8.33 (1.88-33.33), p = 0.005] and sST2 [cut-off: 35.6 ng/ml AUC: 0.91, p < 0.001, HR 333 (250-1,000), p = 0.003] significantly correlated with the composite outcome in the prediction models with high likelihood. Among the parameters evaluated at 1-year follow-up, sST2, eGFR, and the variation from baseline to 1-year of Gal-3 levels showed a strong association with the primary outcome [HR 1.15 (1.08-1.22), p < 0.001; HR: 0.84 (0.74-0.91), p = 0.04; HR: 1.26 (1.10-1.43), p ≤ 0.001, respectively]. Conversely, the echocardiographic definition of CRT response did not correlate with any outcome. In HFrEF patients with CRT, sST2, Gal-3, and renal function were associated with the combined endpoint of cardiovascular death and HF hospitalizations at long-term follow-up, while the echocardiographic CRT response did not seem to influence the outcome of the patients.

Definition of left ventricular dilation in heart failure using cardiovascular magnetic resonance: prognostic implications of end-diastolic diameter and volume assessment

Abstract Background Patients with heart failure (HF) and reduced or mildly reduced ejection fraction (HFrEF/HFmrEF) display variable grades of left ventricular (LV) dilation. LV end-diastolic diameter (LVEDD) and volume (LVEDV) may not be concomitantly increased. The respective prognostic implications of LV dilation have not been explored. Purpose To assess the prognostic implications of LVEDD and LVEDV index (LVEDVi) in HFrEF/HFmrEF. Methods Data from consecutive HF outpatients undergoing cardiovascular magnetic resonance (CMR) and with LV ejection fraction &amp;lt;50% were analyzed. LVEDD was measured in a basal short axis slice. Established age- and gender-specific cut-offs for LVEDVi and a cut-off of 58 mm for LVEDD were used to define LV dilation. Patients were followed for the occurrence of the combined endpoint of cardiovascular death or HF hospitalization. Results A total of 564 patients (79% men, median age 65 years [56–73], ischaemic aetiology in 32%) were included. HFrEF was present in 85% of patients, and HFmrEF in 15%. Median values for LVEDD and LVEDVi were 63 mm (58–69) and 124 mL/m2 (104–149) respectively. LVEDD was significantly correlated with LVEDVi (r=0.804, p&amp;lt;0.001). Sixty-nine percent of patients had concomitant dilation of LV based on LVEDD and LVEDVi. In contrast, 18% of patients did not have concordant definition of LV dilation based on LVEDVi and LVEDD, including 14% with small LVEDD and large LVEDVi. LV dilation based on LVEDVi was associated with a shorter survival free from CV death or HF hospitalization (log-rank 4.6, p=0.032), while LVEDD &amp;gt;58 mm was not (p=0.278). There was a trend toward an independent association between LV dilation based on LVEDVi and outcome adjusting for HFrEF/HFmrEF status and ischaemic aetiology (hazard ratio 2.10, 95% confidence interval 1.00–4.41, p=0.050). An independent association was not found for LV dilation based on LVEDD. An LVEDD &amp;gt;66 mm was associated with increased risk of CV death or HF hospitalization on spline curve analysis (Figure 11). All patients with an LVEDD &amp;gt;66 mm had also LV dilation based on LVEDVi. Conclusions In patients with HFrEF and HFmrEF, LV dilation based on LVEDVi does not always coincide with a dilated LVEDD. The cut-off value of LVEDD associated with an excess of the combined endpoint is much larger than the value used in clinical practice. However, in patients with dilated LV based on LVEDVi, LVEDD does not add to the risk stratification. Funding Acknowledgement Type of funding sources: None.

The ISCHEMIA trial: optimal medical therapy against PTCA in the stable patient: the endless story.

In patients with acute coronary syndrome, an aggressive approach with coronary angiography and revascularization leads to important benefits compared to medical therapy alone. On the contrary, the prognostic impact of coronary revascularization in patients suffering from stable coronary artery disease has long been the subject of debate. The pivotal study in this area is COURAGE, published in 2007, in which coronary revascularization showed no benefit about the combined endpoint of death from all causes and acute myocardial infarction (AMI), compared to medical therapy. The ISCHEMIA study, published in 2020, compared selective coronary angiography and revascularization vs. a non-invasive approach. By protocol, the patients were initially evaluated with coronary computed axial tomography angiography: in case of coronary stenosis >50%, they were then randomized to the two strategies. While in the invasive arm patients were revascularized, in the non-invasive arm revascularization was used only in case of patient destabilization. As in COURAGE, the results of ISCHEMIA did not demonstrate superiority of revascularization over medical therapy alone for a combined endpoint of cardiovascular death, AMI, or hospitalization for unstable angina, heart failure, or cardiac arrest. Based on recent evidence from ISCHEMIA, it is therefore confirmed that coronary revascularization in stable patients does not seem to improve the prognosis compared to medical therapy alone.

Endovascular renal sympathetic denervation to improve heart failure with reduced ejection fraction: the IMPROVE-HF-I study.

IntroductionThe aim of the present study was to assess the safety and efficacy of renal sympathetic denervation (RDN) in patients with heart failure with reduced ejection fraction (HFrEF).MethodsWe randomly assigned 50 patients with a left ventricular ejection fraction (LVEF) ≤ 35% and NYHA class ≥ II, in a 1:1 ratio, to either RDN and optimal medical therapy (OMT) or OMT alone. The primary safety endpoint was the occurrence of a combined endpoint of cardiovascular death, rehospitalisation for heart failure, and acute kidney injury at 6 months. The primary efficacy endpoint was the change in iodine-123 meta-iodobenzylguanidine (123I‑MIBG) heart-to-mediastinum ratio (HMR) at 6 months.ResultsMean age was 60 ± 9 years, 86% was male and mean LVEF was 33 ± 8%. At 6 months, the primary safety endpoint occurred in 8.3% vs 8.0% in the RDN and OMT groups, respectively (p = 0.97). At 6 months, the mean change in late HMR was −0.02 (95% CI: −0.08 to 0.12) in the RDN group, versus −0.02 (95% CI: −0.09 to 0.12) in the OMT group (p = 0.95) whereas the mean change in washout rate was 2.34 (95% CI: −6.35 to 1.67) in the RDN group versus −2.59 (95% CI: −1.61 to 6.79) in the OMT group (p-value 0.09).ConclusionRDN with the Vessix system in patients with HFrEF was safe, but did not result in significant changes in cardiac sympathetic nerve activity at 6 months as measured using 123I‑MIBG.Supplementary InformationThe online version of this article (10.1007/s12471-021-01633-z) contains supplementary material, which is available to authorized users.

Risk stratification and prognostic value of CMR in DCM; parametric mapping and GLS- value beyond EF and LGE?

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Dr Pamela Brown was suppoerted by funding from Alliance Medical. Background; Arrhythmia risk stratification and device implantation in dilated cardiomyopathy (DCM) poses significant challenges and as demonstrated by the DANISH trial appears to have reached the asymptote of clinical efficacy. A body of evidence now demonstrates that risk stratification of and device selection for DCM patients may be enhanced by inclusion of patients" LGE-status. Furthermore, it has been suggested that CMR based parametric mapping and strain analysis may further advance risk stratification. Methods; 703 patients with DCM undergoing clinically indicated CMR scans and prospectively enrolled into the UHSM-CMR study (NCT02326324) between 03/2015-12/2018 were analysed. Multivariable Cox proportional hazard models and Youden index driven C-statistics were used to assess additive prognostic value of GLS, T1 and ECV mapping on the combined endpoint of cardiovascular death, cardiac transplantation, LVAD insertion or hospitalisation for heart failure in models incorporating NHYA class, EF and LGE status. Additionally. the value of GLS, T1, and ECV on predicting significant arrhythmic events (SAV) (ventricular arrhythmia (VA), resuscitated cardiac arrest (rCA) or sudden cardiac death (SCD)) was assessed. Results; Patients (mean age 59, 66% male, 60% ≥NYHA II, mean EF 42%, mean GLS -12%, mean ECV 27%) were on good medical therapy (beta blocker 74%%, ACE 79%, MRA 38%, Entresto 5%, CRT 23%). Mean follow-up was 21 months; the combined endpoint occurred in 34 patients (5%). On univariate analysis NYHA class (HR 2.44 (1.67-3.57), p &amp;lt; 0.001), ECV (HR 1.14 (1.05-1.22), p &amp;lt; 0.001), GLS% (HR 1.14 (1.07-1.21) p &amp;lt; 0.001,) T1 (HR 1.06 (1.005-1.1), p = 0.03), RVEF (HR 0.95 (0.93-0.98), p &amp;lt; 0.001), LVEF (HR 0.92 (0.9-0.95), p &amp;lt; 0.001) were all significantly associated with outcome. On multivariate analysis only EF and NYHA class was associated with outcome. SAV occurred as the first manifestation of disease or during follow up in 27 patients (4%). At univariate analysis LGE, ECV, GLS, EF and NYHA class were all associated with SAV. However, on multivariable analysis only EF, LGE and ECV (HR 1.11 (1.01-1.22), p = 0.03) but not GLS remained independently predictive in a model already incorporating EF, NYHA and LGE. Conclusion Optimally treated DCM populations have very low event rates. CMR based assessment of fibrosis status/burden with both LGE and ECV assessment has the potential to enhance patient selection for ICD therapy. Whilst GLS is increasingly recognised as a sensitive imaging biomarker of early disease detection it provides no additive value, likely because of it’s high co-linearity with EF, in models already containing EF, NYHA class and LGE status.

Transcatheter Valve-in-Valve Aortic Valve Replacement as an Alternative to Surgical Re-Replacement

BackgroundValve-in-valve (VIV) transcatheter aortic valve replacement (TAVR) and redo surgical aortic valve replacement (SAVR) represent the 2 treatments for aortic bioprosthesis failure. Clinical comparison of both therapies remains limited by the number of patients analyzed. ObjectivesThe purpose of this study was to analyze the outcomes of VIV TAVR versus redo SAVR at a nationwide level in France. MethodsBased on the French administrative hospital-discharge database, the study collected information for patients treated for aortic bioprosthesis failure with isolated VIV TAVR or redo SAVR between 2010 and 2019. Propensity score matching was used for the analysis of outcomes. ResultsA total of 4,327 patients were found in the database. After matching on baseline characteristics, 717 patients were analyzed in each arm. At 30 days, VIV TAVR was associated with lower rates of the composite of all-cause mortality, all-cause stroke, myocardial infarction, and major or life-threatening bleeding (odds ratio: 0.62; 95% confidence interval: 0.44 to 0.88; p = 0.03). During follow-up (median 516 days), the combined endpoint of cardiovascular death, all-cause stroke, myocardial infarction, or rehospitalization for heart failure was not different between the 2 groups (odds ratio: 1.18; 95% confidence interval: 0.99 to 1.41; p = 0.26). Rehospitalization for heart failure and pacemaker implantation were more frequently reported in the VIV TAVR group. A time-dependent interaction between all-cause and cardiovascular mortality following VIV TAVR was reported (p-interaction <0.05). ConclusionsVIV TAVR was observed to be associated with better short-term outcomes than redo SAVR. Major cardiovascular outcomes were not different between the 2 treatments during long-term follow-up.

Severity of Cardiovascular Autonomic Neuropathy Is a Predictor Associated With Major Adverse Cardiovascular Events in Adults With Type 2 Diabetes Mellitus: A 6-Year Follow-up Study

ObjectivesCardiovascular autonomic function impairment has been reported in patients with type 2 diabetes mellitus and is associated with cardiovascular events. In this study, we test the hypothesis that the severity of cardiovascular autonomic neuropathy is a predictor associated with subsequent 3-point major adverse cardiovascular events (3-P MACE; combined endpoint of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke). MethodsIn this prospective study, we enrolled 168 patients with type 2 diabetes mellitus over a 6-year follow-up period. We constructed the Composite Autonomic Scoring Scale as a measure of the severity of cardiovascular autonomic neuropathy and examined baseline clinical and laboratory data of 168 patients with diabetes. Cardiovascular autonomic testing included heart rate response to deep breathing, Valsalva ratio and baroreflex sensitivity. Therapeutic outcome was defined as 3-P MACE. ResultsThe overall incidence of new 3-P MACE was 23.2% and overall fatality rate was 9.5% during the 6-year follow-up period. Only underlying coronary heart disease and Composite Autonomic Scoring Scale were independently associated with subsequent 3-P MACE in the Cox proportional hazards model. Any increase of 1 point in Composite Autonomic Scoring Scale would increase the risk of new 3-P MACE by 9.7%. Area under the curve on receiver-operating characteristic curve analysis was 0.72 in predicting subsequent 3-point MACE in combined heart rate response to deep breathing and Valsalva ratio. ConclusionsBesides underlying coronary heart disease, the severity of cardiovascular autonomic neuropathy is strongly associated with subsequent 3-P MACE. Combined heart rate response to deep breathing and Valsalva ratio testing can increase sensitivity and specificity in predicting subsequent 3-point MACE, and it can serve as a time-effective cardiovascular autonomic screening service in the outpatient clinic sitting.

Long-term outcome of prosthesis-patient mismatch after transcatheter aortic valve replacement

BackgroundIncidence and long-term clinical consequences of prosthesis-patient mismatch (PPM) after transcatheter aortic valve replacement (TAVR) are still unclear. MethodsWe enrolled 710 consecutive patients who underwent TAVR. PPM was defined as absent if the index orifice area (iEOA) was >0.85 cm2/m2, moderate if the iEOA was between 0.65 and 0.85 cm2/m2 or severe if the iEOA was <0.65 cm2/m2. ResultsAmong the 566 patients fulfilling the study criteria, the distribution of PPM was as follows: 50.5% none (n = 286), 43% moderate PPM (n = 243) and 6.5% severe PPM (n = 37). At 5-year follow-up, patients with severe PPM had a significantly higher incidence of the combined endpoint of cardiovascular death, acute myocardial infarction and stroke (p = .025) compared with the other patients. After adjusting the results for possible confounders, severe PPM remained an independent predictor of long-term adverse outcome (HR: 2.46; 95% Confidence Interval: 1.10–5.53). The independent predictors of severe PPM were valve-in-valve procedure and body mass index. Balloon-expandable valves were not associated with higher rates of severe PPM in comparison with self-expandable valves (8% vs. 5%, respectively, p = .245). ConclusionsIn our study severe PPM emerged as a risk factor for long-term major adverse cardiac and cerebrovascular events.

Valve-in-valve transcatheter aortic valve implantation after failed surgically implanted aortic bioprosthesis versus native transcatheter aortic valve implantation for aortic stenosis: Data from a nationwide analysis

Valve-in-valve transcatheter aortic valve implantation (TAVI) has emerged as a treatment for aortic bioprosthesis failure in case of prohibitive risk for redo surgery. However, clinical evaluation of valve-in-valve TAVI remains limited by the number of patients analysed. To evaluate outcomes of valve-in-valve TAVI compared with native aortic valve TAVI at a nationwide level in France. Based on the French administrative hospital discharge database, the study collected information for all consecutive patients treated with TAVI for aortic stenosis or with isolated valve-in-valve TAVI for aortic bioprosthesis failure between 2010 and 2019. Propensity score matching was used for the analysis of outcomes. A total of 44,218 patients were found in the database. After matching on baseline characteristics, 2749 patients were analysed in each arm. At 30 days, no significant differences were observed regarding the occurrence of major clinical events (composite of cardiovascular mortality, all-cause stroke, myocardial infarction, major or life-threatening bleeding and conversion to open heart surgery) (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.68-1.01; P=0.32). During follow-up (mean 516 days), the combined endpoint of cardiovascular death, all-cause stroke or rehospitalization for heart failure was not different between the valve-in-valve TAVI and native TAVI groups (RR 1.03, 95% CI 0.94-1.13; P=1.00). We observed that valve-in-valve TAVI was associated with good short- and long-term outcomes. No significant differences were observed compared with native valve TAVI regarding clinical follow-up.

Relationship between body mass index and outcomes of coronary artery disease in Asian population: Insight from the FOCUS registry

BackgroundObesity is often considered as a risk factor of cardiovascular events, but recent researches showed conflicting results regarding to the effect of body weight on prognosis of coronary artery disease (CAD). This study aimed to evaluate the relationship between body mass index (BMI) and clinical outcomes of CAD in Asian population. MethodsA total of 4315 patients from the FOCUS registry were enrolled into this analysis. Patients were divided into 4 groups according to BMI: lean group (BMI<18.5 kg/m2), normal group (BMI 18.5–24.9 kg/m2), overweight group (BMI 25–30 kg/m2) and obesity group (BMI>30 kg/m2). Follow-up was continued to 3 years to evaluate clinical outcomes, and the primary endpoint was a composite of all-cause death and myocardial infarction (MI). ResultsPatients with higher BMI were more likely to be associated with cardiovascular risk factors like hypertension, hypercholesterolemia and diabetes, but not smoking. At the end of the follow-up period, however, the incidence of a composite endpoint of all-cause death and MI was significantly lower in the higher BMI (overweight and obese) subsets, as compared with the lower BMI group (5.2% vs. 8.0%, p < 0.001). So did the cumulative rates of all-cause death (p < 0.001), cardiovascular death (p < 0.001), and a combined endpoint of cardiovascular death and MI (p = 0.001). ConclusionsIn Asian patients with CAD, an inverse association between BMI and long-term prognosis was observed. Although overweight or obese patients were associated with more metabolism-associated comorbidities, they had significantly lower adverse events at 3-year follow up after percutaneous coronary intervention.

Beneficial effects of ivabradine in patients with heart failure, low ejection fraction, and heart rate above 77 b.p.m.

AimsIvabradine has been approved in heart failure with reduced ejection fraction (HFrEF) and elevated heart rate despite guideline‐directed medical therapy (GDMT) to reduce cardiovascular (CV) death and hospitalization for worsening HF. The median value of 77 b.p.m. is the lower bound selected for the regulatory approval in Canada, South Africa, and Australia. Patient‐reported outcomes (PROs) including symptoms, quality of life, and global assessment are considered of major interest in the global plan of care of patients with HF. However, the specific impact of GDMT, and specifically ivabradine, on PRO remains poorly studied. In the subgroup of patients from the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) who had heart rate above the median of 77 b.p.m. (pre‐specified analysis) and for whom the potential for improvement was expected to be larger, we aimed (i) to evaluate the effects of ivabradine on PRO (symptoms, quality of life, and global assessment); (ii) to consolidate the effects of ivabradine on the primary composite endpoint of CV death and hospitalization for HF; and (iii) to reassess the effects of ivabradine on left ventricular (LV) remodelling.Methods and resultsComparisons were made according to therapy, and proportional hazards models (adjusted for baseline beta‐blocker therapy) were used to estimate the association between ivabradine and various outcomes. In SHIFT, n = 3357 (51.6%) patients had a baseline heart rate > 77 b.p.m. After a median follow‐up of 22.9 months (inter‐quartile range 18–28 months), ivabradine on top of GDMT improved symptoms (28% vs. 23% improvement in New York Heart Association functional class, P = 0.0003), quality of life (5.3 vs. 2.2 improvement in Kansas City Cardiomyopathy Questionnaire overall summary score, P = 0.005), and global assessment [from both patient (improved in 72.3%) and physician (improved in 61.0%) perspectives] significantly more than did placebo (both P < 0.0001). Ivabradine induced a 25% reduction in the combined endpoint of CV death and hospitalization for HF (hazard ratio 0.75; P < 0.0001), which translates into a number of patients needed to be treated for 1 year of 17. Patients under ivabradine treatment demonstrated a significant reduction in LV dimensions when reassessed at 8 months (P < 0.05).ConclusionsIn patients with chronic HFrEF, sinus rhythm, and a heart rate > 77 b.p.m. while on GDMT, the present analysis brings novel insights into the role of ivabradine in improving the management of HFrEF, particularly with regard to PRO (ISRCTN70429960).

Cardiovascular Effects of Sodium-Glucose Cotransporter-2 Inhibitors in Adults With Type 2 Diabetes.

Adults with type 2 diabetes mellitus can benefit from pharmacotherapies that lower their risk for cardiovascular disease. This review describes the salient findings from sodium-glucose cotransporter-2 (SGLT2) inhibitor cardiovascular outcome trials that serendipitously revealed the cardiorenal benefits of SGLT2 inhibitors in adults with type 2 diabetes mellitus who either have established cardiovascular disease or multiple cardiovascular risk factors. It also summarizes the findings from other phase 3 clinical studies that measured the cardiovascular effects of SGLT2 inhibitors and real-world evidence reports that compared the cardiovascular impact of SGLT2 inhibitors with other antihyperglycemic agents. The collective data indicate that SGLT2 inhibitors are pleiotropic agents that offer important cardiovascular, metabolic and renal benefits beyond glucose lowering with low incidences of hypoglycemia. Specifically, the placebo-controlled SGLT2 inhibitor cardiovascular outcome trials documented either fewer major adverse cardiac events (nonfatal myocardial infarction, nonfatal stroke and cardiovascular death) or a reduction in the composite endpoint of cardiovascular death or hospitalization for heart failure in participants with type 2 diabetes mellitus and established cardiovascular disease. Amongst those with type 2 diabetes mellitus who did not have established cardiovascular disease but did present with multiple risk factors, SGLT2 inhibitors lowered the combined endpoint of cardiovascular death or hospitalization for heart failure but had little impact on the occurrence of major adverse cardiac events. Ongoing clinical trials and subanalyses of the trials that have been reported should shed further light on the clinical benefits and utility of SGLT2 inhibitors.

Pathophysiological background and prognostic implication of systolic aortic root motion in non-ischemic dilated cardiomyopathy

Recordings of aortic root movement represent one of the first accomplishments of ultrasound in medicine and mark the beginning of functional cardiac imaging. However, the underlying mechanism is not completely understood. Since the aortic root is directly connected to the cardiac skeleton we hypothesize, that the amplitude of systolic aortic root motion (SARM) may be mainly caused by displacement of the cardiac base towards the apex and might therefore be used as measure of left ventricular longitudinal function (LV-LF). One hundred and eighty patients with dilated cardiomyopathy and 180 healthy controls were prospectively included into this study. SARM was lower in patients compared to controls (9 ± 3 mm vs. 12 ± 2 mm, p < 0.001) and lowest in patients with cardiovascular events (9 ± 3 mm vs. 7 ± 3 mm, p < 0.001). During a median follow-up time of 38 months, the combined end-point of cardiovascular death or hospitalization for heart failure was reached by 25 patients (13.9%). Reduced SARM had significant prognostic impact on outcome (hazard ratio 0.74, 95% confidence interval 0.63–0.88, p < 0.001) and remained an independent predictor in the multivariate analysis. Compared to parameters with potential influence on its mechanism, SARM correlated best (r = 0.75, p < 0.001) with global longitudinal strain (GLS). SARM may therefore represent an alternative echocardiographic parameter for the assessment of LV-LF, particularly when GLS is not feasible or apical views are not available.

Cardiovascular and mortality events in type 2 diabetes cardiovascular outcomes trials: a systematic review with trend analysis

AimsTo investigate cardiovascular disease and mortality trends in control arm participants of diabetes cardiovascular outcome trials (CVOTs).MethodsWe electronically searched CVOTs published before October 2017. Data on all-cause mortality, cardiovascular mortality and events, and baseline characteristics were collected, along with study calendar years. Trends were estimated using negative binomial regressions and reported as rate ratio (RR) per 5-year intervals.Results26 CVOTs, conducted from 1961 to 2015, included 86788 participants with 6543 all-cause deaths, 3265 cardiovascular deaths, and 7657 3-point major adverse cardiovascular events (3-P MACE; combined endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke). In unadjusted analysis, there was an increasing trend for 3-P MACE rates over time (5-year RR 1.57; 95% CI 1.34, 1.84); a small increasing trend for cardiovascular disease mortality rates (1.13; 1.01, 1.26); and stable rates for all-cause death. Adjusting for age, sex, previous myocardial infarction, and diabetes duration, there was no evidence of trends for 3-P MACE or cardiovascular disease mortality rates, while reducing rates were observed for nonfatal myocardial infarction (5-year RR: 0.72; 0.54, 0.96), total stroke (0.76; 0.66, 0.88), and nonfatal stroke (0.60; 0.43, 0.82).ConclusionsIn contrast to real-world data, there was no evidence of an improvement in all-cause and cardiovascular mortality in type 2 diabetes participants included in control arms of randomised clinical trials across 5 decades. Further studies should investigate whether and how dissimilarities in populations, procedures, and assessments of exposures and outcomes explain the differences between real-world setting and clinical trials.

Abstract 16953: Prospective Negative Microvolt T-Wave Alternans Testing is a Marker for Lower Risk of Cardiovascular Death and Appropriate Shock Therapy

Introduction: Microvolt T-wave alternans (MTWA) refers to a pattern of beat-to-beat oscillations in T-wave morphology. Hypothesis: We hypothesized that patients with negative MTWA testing were at decreased risk for cardiovascular death and appropriate shock therapy. Methods: We studied 913 patients from a prospective international registry from Europe, Asia and USA (9 centers total). All recruited patients qualified for primary prevention of sudden cardiac death with ICD or CRT-D. Beta-blockers were discontinued prior to MTWA testing. We used best-subsets analysis of our study population to identify predictors of all-cause mortality. Ten clinical and demographic variables were included in the analysis. We then used these predictors to evaluate the predictive capacity of MTWA in a multivariate model. Results: The mean follow-up was 4.0 ± 3.0 years, mean age was 69.5 ± 12.5 years, 84% were male, and 63% had ischemic cardiomyopathy. 52% and 11% of patients received ICD and CRT-D, respectively. LVEF &lt;25% (HR 2.17, p&lt;0.001), NYHA class&gt;II (HR 1.75, p=0.01) and use of diuretics (HR 2.64, p&lt;0.001) were significantly associated with all-cause mortality in a multivariate model. Using this multivariate model, a negative MTWA outcome was not associated with all-cause mortality (HR 0.95, p=0.80), however a negative MTWA outcome was associated with the risk of cardiovascular death (HR 0.40, p=0.01) and the combined endpoint of cardiovascular death and ICD-rendered shock therapy (HR 0.28, p&lt;0.001). This was consistent in both ischemic and nonischemic cardiomyopathy (p value for interaction=0.999). Conclusions: These findings suggest that non-negative MTWA testing is indicative of an underlying arrhythmogenic substrate, manifested as cardiovascular death and appropriate shock therapy. MTWA testing can provide further information for patient selection for ICD placement. Figure 1 . Kaplan-Meier Curve demonstrating the time-dependent endpoint of cardiovascular death. The follow-up time displayed on this graph is measured in days.