Cardiovascular Death In Patients Research Articles

Pre-interventional renal artery calcification and survival after transcatheter aortic valve implantation.

The prognostic significance of renal artery calcification (RAC) is unknown in patients with severe aortic stenosis (AS) eligible for transcatheter aortic valve implantation (TAVI). RAC can be assessed by computed tomography (CT) performed during pre-interventional planning for TAVI. This study aimed at investigating the utility of RAC for predicting survival after TAVI. In this longitudinal cohort study, RAC volume was measured by CT in 268 consecutive patients with severe AS undergoing TAVI. Association of RAC with mortality was assessed using Cox regression analysis. RAC was evaluated as a binary parameter and in a supplementary analysis as a logarithmically transformed continuous variable. Over a median follow-up time of 9.6 years, 237 (88.4%) patients died, with 174 (73.4%) deaths attributable to a cardiovascular cause. RAC was highly prevalent (N = 150 (86.2%)) among patients suffering cardiovascular death. Competing risk cumulative incidence curves revealed a higher occurrence of cardiovascular death in patients with RAC (P-value = 0.008), while this was not the case for non-cardiovascular death (P-value = 0.71). RAC was independently associated with cardiovascular death (HR 1.61 [95% CI: 1.01-2.57]; P = 0.047) after adjustment for age, sex, cardiovascular risk factors, impaired renal function, and aortic valve calcification. The presence or absence of RAC rather than its volume was important in all the analyses. RAC is a strong and independent predictor of cardiovascular death in patients with severe AS undergoing TAVI. Given its favourable properties for event prediction, RAC may be considered valuable for prognostic assessment of TAVI patients.

Use of Aspirin and Initial Cardiovascular and Bleeding Risk in Patients with Chronic Kidney Disease

Background: Despite the high cardiovascular risk in patients with chronic kidney disease (CKD), the role of aspirin in primary prevention remains unclear. This study aimed to investigate the association between aspirin initiation in adults with CKD without prior cardiovascular disease (CVD) and the first cardiovascular and bleeding events using Korean nationwide cohort data. Methods: Among individuals aged 40–79 years with an estimated glomerular filtration rate between 15 and 59 mL/min/1.73 m2 who underwent routine health examinations between 2011 and 2016, 15,861 individuals who were newly prescribed aspirin at a dose of 100 mg/day were matched with 79,305 aspirin non-users by propensity score matching. The primary efficacy outcome was a composite of nonfatal atherosclerotic CVD or cardiovascular death. The primary safety outcome was hospitalization due to intracranial or gastrointestinal bleeding. Results: During a mean follow-up of 6.9±2.9 years, the incidence rates for the primary efficacy outcome in aspirin users and non-users were 8.0 and 9.0 per 1,000 person-years, respectively. Aspirin therapy initiation was not associated with the primary efficacy outcome (hazard ratio [HR], 0.93; 95% confidence intervals [CI], 0.86-1.04). However, the primary safety outcome of major bleeding was more frequent in aspirin users than in non-users (6.7 versus 4.7 per 1,000 person-years). The HR for this outcome in aspirin users versus non-users was 1.45 (95% CI, 1.32-1.59). Conclusions: No association was observed between aspirin use and the risk of nonfatal atherosclerotic CVD or cardiovascular death in patients with CKD stages G3 and G4 without prior CVD. Aspirin use was associated with higher risk of major bleeding.

Vericiguat Global Study in Participants with Chronic Heart Failure: Design of the VICTOR trial.

In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, the soluble guanylate cyclase stimulator vericiguat reduced the risk of hospitalization for heart failure (HHF) or cardiovascular death in patients with heart failure (HF) and reduced ejection fraction (HFrEF) with recent worsening HF. The effect of vericiguat in patients with HFrEF without recent worsening HF remains unknown. The VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial was designed to assess the efficacy and safety of vericiguat in patients with ejection fraction ≤40% without recent worsening HF on a background of current foundational HFrEF therapy. The primary endpoint for VICTOR is time to first event for the composite of HHF or cardiovascular death. The trial will also assess the effect of vericiguat on time to cardiovascular death, time to HHF, total HHF, and all-cause death. As an event-driven trial, at least 1080 primary events are expected, but follow-up will continue until the targeted number of at least 590 cardiovascular deaths has been reached. Approximately 6000 participants will be randomized to vericiguat or placebo. VICTOR is the first large event-driven HFrEF trial performed in the contemporary era of quadruple foundational guideline-directed medical therapy, in a compensated ambulatory HF population. VICTOR will add important information to the evidence of the effects of vericiguat across the spectrum of patients with HFrEF.

Measures of left atrial structure and function predict cardiovascular death in patients with heart failure with reduced ejection fraction

Abstract Background The role of the left atrium (LA) is increasingly recognized as a predictor of cardiovascular health outcomes. This study aimed to investigate the prognostic value of LA strain in relation to cardiovascular (CV) death in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Methods In this retrospective cohort analysis, patients diagnosed with stable HFrEF and free from atrial fibrillation at baseline were included. All patients had a Left Ventricular Ejection Fraction (LVEF) of 45% or below at the time of referral. Baseline clinical and echocardiographic parameters were collected from the database of the HF outpatient clinic, and data on CV death was gathered through the Danish National Patient Registry. LA function was assessed by means of LA emptying fraction (LAEF), peak atrial longitudinal strain (PALS), peak atrial contraction strain (PACS), and LA conduit strain (LACS). Uni- and multivariable Cox regression models adjusted for clinical and echocardiographic baseline characteristics were used to determine the association between LA parameters and CV death. Cubic splines were used to identify cutoff values for LA parameters corresponding to a HR of 1. Results The study population consisted of 495 patients (mean age 66 ±11.5 years, 71% males). During a follow-up of 10.9 years [IQR: 6.2; 13.4], 134 (27%) patients reached the outcome of CV death. At baseline, patients who died of CV death were generally older (70.7±9.7 years vs. 64.2±11.7, p<0.001), had a higher prevalence of diabetes (25.4% vs. 13.9%, p=0.004), and a higher prevalence of moderate or severe valve disease (11.2% vs. 3.9%, p=0.004), as well as a lower LVEF (25.1%±8.5 vs. 29.4±8.9, p<0.001). Among LA parameters, the patients who met the outcome had a significantly lower LAEF (30.5% [IQR: 18.0; 42.0] vs. 38.9% [IQR: 29.0; 49.3], p<0.001), PALS (18.2% [IQR: 12.7; 24.4] vs. 23.0% [IQR: 18.3; 29.9], p<0.001), PACS (7.7% [IQR: 2.9; 13.6] vs. 11.7% [IQR: 7.9; 16.4], p<0.001), and LACS (9.4% [IQR: 7.2 ; 12.4] vs. 11.9% [IQR: 8.8; 15.0], p<0.001). Lower levels of all LA parameters were associated with an increased risk of CV death in univariable analysis (p<0.0001 for all parameters). However, in multivariable analysis, only LAEF (HR 0.99 per 1% increase, 95% CI 0.973-0.999, p=0.039), PALS (HR 0.96 per 1% increase, 95% CI 0.931–0.991, p=0.011), and PACS (HR 0.94 per 1% increase, 95% CI 0.90–0.98, p=0.002) remained significant. Splines for LAEF, PALS, and PACS were constructed with identified cutoff points for higher CV death risk (Figure 1), which were utilized to generate Kaplan-Meier curves (Figure 2). Conclusion Lower LA parameters, including LAEF, PALS, and PACS, are associated with increased risk of CV death in patients with HFrEF.Spline curves for LAEF, PALS, and PACS.Kaplan-Meier survival estimates for CVD

Higher product of right ventricle to left ventricle diameter ratio and septal wall thickness is associated with increased risk of cardiovascular death in patients post TAVI

Abstract Background Right ventricular (RV) dilatation is a significant predictor for mortality in various cardiovascular diseases. Hypertrophy is common in patients undergoing transcatheter aortic valve implantation (TAVI). We tested the hypothesis that the product of right ventricle to left ventricle diameter (RV/LV) ratio and septal wall thickness (SWT) might be a determinant of cardiovascular death in TAVI patients. Methods This retrospective study enrolled 1123 patients undergoing TAVI in our department between 2009 and 2021 (mean age 81.4±5.6 year, male 51.2%). We assessed standard echocardiographic measures prior to the TAVI procedure. End-diastolic basal biventricular dimensions were measured from a standard apical 4-chamber view, and the ratio of RV dimension (RVD) to LV dimension (LVD) was calculated as the RV/LV ratio. We tested the prognostic performance of the product of RV/LV ratio and septal wall thickness (RV/LV ratio*SWT). The primary endpoint was cardiovascular (CV) death up to 2 years after TAVI. Results CV mortality was 11.8% (132/1123) at 2 years after TAVI. SWT was similar between the groups with and without CV death (11.9±1.9 vs. 11.6±1.8 mm, P=0.188). However, the RV/LV ratio (0.84±0.15 vs. 0.80±0.13, P=0.002) and RV/LV ratio*SWT (10.0±2.7 vs. 9.3±3.1 mm, P=0.005) were notably higher in the CV-death group compared to the no CV-death group. Higher RV/LV ratio*SWT remained independently associated with elevated 2-year CV mortality after TAVI (HR=1.09, 95% CI 1.01-1.17, P=0.024), while the RV/LV ratio was no longer significantly linked with CV mortality (HR=2.83, 95% CI 0.87-9.19, P=0.082) after adjusting for potential confounding factors including age, sex, and atrial fibrillation. RV/LV ratio*SWT >12.7 mm was associated with a twofold increased risk of 2-year CV mortality compared to patients with RV/LV ratio*SWT ≤12.7 mm (2-year mortality 14.4% vs. 6.0%, P<0.001; HR=2.04, 95% CI 1.25-3.32, P=0.004), regardless of age, sex, and atrial fibrillation. Conclusions Combined assessment of biventricular remodelling and left ventricular hypertrophy by calculating RV/LV ratio*SWT is of clinical importance for risk stratification of cardiovascular death among TAVI patients.

Socioeconomic disparity in utilization of transcatheter aortic valve replacement

Abstract Introduction Transcatheter aortic valve replacement (TAVR) is a major therapeutic option, rapidly replacing surgical aortic valve replacement (SAVR) in patients with aortic stenosis (AS) in recent years. However, the use of TAVR may vary with the socioeconomic status (SES) since new technologies are more likely to have the lower accessibility in some medico-social environments. In South Korean patients with AS, we investigated the difference in the use of TAVR based on SES and whether the difference influences clinical outcomes of patients with AS. Methods Between 2010 and 2020, 30,142 patients newly diagnosed with AS in a tertiary or regional center were investigated through the Korean National Health Insurance System (KNHIS). Patients were received either medical, SAVR or TAVR therapy for AS. The patients were categorized into 3 groups based on the insurance premium level (IPL) of the KNHIS (IPL1, <100 KW; IPL2, 100-249 KW; IPL3, ≥250KW). AS-related death was defined as death by AS, heart failure or ventricular arrhythmia. Cardiovascular (CV) death was defined as AS-related death or death by myocardial infarction or stroke. The study period was divided at year 2015, when the partial coverage for TAVR was implemented by the KNHIS. Results The numbers of patients referred to the tertiary/regional centers have continuously grown for the 11 years but the referring rate has grown even faster since 2015. The proportions of TAVR has increased while that of SAVR has decreased since 2015. TAVR was more frequently chosen by patients with a higher IPL (5.5%, 8.0% and 12.5%, respectively in the IPL1, IPL2 and IPL3, p<0.001), whereas the medical therapy appeared not affected by the IP levels. The patients in the IPL2 (odd ratio [OR] 1.33 [1.20-1.47]) and IPL3 (OR 1.65 [1.45-1.86]) had a higher chance to undergo TAVR than those in the IPL1 whereas the patients in the IPL3 was a lower chance to undergo SAVR than those in the IPL1 (OR 0.86 [0.78-0.94]). In patients with severe AS, the disparities between the IPL1 and IPL3 exaggerated (OR 1.99 [1.70-2.33]) (Figure 1). Higher IPLs were associated with lower risks of CV death and AS-related death. Time-varying Cox proportional hazard models showed that TAVR was associated with a lower risk of CV death than both medical therapy and SAVR in the entire study period and in year 2015 or later, whereas TAVR was associated with a lower risk of AS-related death than the both only in year 2015 or later, after adjustment of relevant covariates including the IPL (Figure 2). The choice of TAVR significantly medicated the associations between IPLs and the risk of CV death (responsible for 3.0% in the IPL2 and 4.1% in the IPL3). Conclusion The SES based on the IPL is independently associated with the choice of TAVR in patients with AS and the association has become stronger since 2015. The disparity in use of TAVR could mediate more frequent CV deaths in patients with the lower IPL.Figure 1Figure 2

Changes in the Treatment and Prevention of Heart Failure Based on the 2023 Focused Update of the 2021 European Society of Cardiology Guidelines

Introduction and Objective:The 2023 update to the 2021 ESC Guidelines for diagnosing and treating acute and chronic heart failure introduces significant changes in pharmacotherapy and prevention. Staying informed about these updates is crucial given the evolving landscape of heart failure management. This review provides an overview of the latest recommendations and supporting evidence. Review Methods:A comprehensive review of scientific publications and guidelines from PubMed, Google Scholar, Clinical Key, Via Medica Journals, and relevant clinical guidelines was conducted to ensure the most recent evidence is considered. Brief Description of the State of Knowledge:Heart failure is a growing global concern. The 2023 update highlights key management changes. Recent trials, including EMPEROR-Preserved and DELIVER, show empagliflozin and dapagliflozin reduce heart failure hospitalization and cardiovascular death in patients with mildly reduced and preserved ejection fraction. The guidelines now recommend intravenous iron for patients with reduced or mildly reduced ejection fraction and iron deficiency. For those with type 2 diabetes and chronic kidney disease, SGLT2 inhibitors and finerenone, a non-steroidal mineralocorticoid antagonist, are recommended to reduce heart failure hospitalization and prevent renal function decline. Summary:The 2023 ESC Guidelines update offers revised recommendations for heart failure management and prevention, integrating the latest clinical trial data and meta-analyses. Key areas include the use of SGLT2 inhibitors, iron deficiency management, and preventive strategies for high-risk populations. Implementing these guidelines can significantly improve preventive and therapeutic outcomes for heart failure patients.

Prognostic Value of Transthoracic Impedance Cardiography, Amino-Terminal Pro-B-Type Natriuretic Peptide Levels, The Six-Minute Walk Test, and Chest X-Ray in Elderly Patients with Chronic Heart Failure: A Comparative Study in Lithuania.

BACKGROUND Chronic heart failure (CHF) is a complex clinical syndrome associated with frequent, recurrent, and long-term hospitalizations. This study from a single center in Lithuania aimed to evaluate outcomes in 87 elderly patients hospitalized with CHF. The methods used included comparing transthoracic impedance cardiography (ICG), amino-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, the six-minute walk test (6MWT), and dilatation of the right pulmonary artery on chest X-ray (dRPAcXR). MATERIAL AND METHODS The study sample consisted of 87 patients (49 men and 38 women). All subjects underwent 6MWT and ICG in addition to the standard CHF tests. The median duration of the follow-up was 23 months. Data about patient outcomes were gathered from the National Medical Record Database. RESULTS By multivariate Cox proportional analysis, thoracic fluid content (TFC) ≥41.1 1/kΩ (hazard ratio [HR] 32.354, 95% confidence interval [CI] 2.758-379.488), NT-proBNP ≥332.0 pmol/L (HR 4.739, 95% CI 1.656-13.559), 6-minute walk distance (6MWD) ≤203.5 m (HR 3.975, 95% CI 1.002-15.770), and dRPAcXR (HR 5.555, 95% CI 1.714-18.005) were associated with a poor prognosis in CHF patients (all P<0.05). The correlations between ICG and 6MWD and other non-invasive diagnostic tests examined in this study were weak to moderate. CONCLUSIONS TFC ≥41.1 1/kΩ, NT-proBNP ≥332.0 pmol/L, 6MWD ≤203.5 m, and dRPAcXR had a combined prognostic value in predicting cardiovascular death in patients with CHF. Therefore, these parameters may be of value in the assessment of the diagnosis and prognosis in this patient cohort.

Long-Term Risk of Cardiovascular Death in Patients With Mildly Reduced Ejection Fraction After Acute Myocardial Infarction: A Multicenter, Prospective Registry Study.

The prognostic implication of mildly reduced ejection fraction (mrEF) after acute myocardial infarction has not been clearly demonstrated. We investigated the long-term risk of cardiovascular death and its predictors in patients with mrEF following acute myocardial infarction. A total of 18 668 patients who presented with acute myocardial infarction were included in 2 prospective, multicenter registries. The incidence of adverse cardiovascular events according to the left ventricular ejection fraction (EF) strata at index admission were evaluated. A score system consisting of clinical variables were developed to predict long-term cardiovascular death in the mrEF group. There were 2548 patients with reduced EF (EF ≤40%), 4266 patients with mrEF (EF 41%-49%), and 11 854 patients with preserved EF (EF ≥50%). During a median follow-up period of 37.9 months, the cardiovascular death rate was 22.3% in the reduced EF group, 10.3% in the mrEF group, and 7.3% in the preserved EF group (P<0.001). In the mrEF group, age>65 years, hypertension, stroke, severe renal insufficiency, and Killip class ≥3 were independent predictors for cardiovascular death. Presence of >2 predictors best discriminated the high-risk patients for cardiovascular death with an area under the curve of 0.746. Incidence of cardiovascular death in the high-risk mrEF group was comparable with the rEF group, while it was lower in the low-risk mrEF group than in the pEF group. Patients with mrEF after acute myocardial infarction had a modest risk of cardiovascular death. Clinical predictors could help discriminate a high-risk subpopulation with cardiovascular death risks comparable with those in the reduced EF group.

High Resting Heart Rate Is Associated with Cardiovascular Death in Patients with Stroke, Independent of Sex

Introduction: High resting heart rate (HRHR) is a surrogate marker of increased sympathetic outflow. In acute stroke patients, HRHR is more commonly observed in women than in men. We analyzed whether HRHR (>86 bpm) adds incremental prognostic value for stroke outcomes in women. Methods: We analyzed data of 6,024 patients (2,568 women, mean age 68.98 years) with acute ischemic stroke from the Virtual International Stroke Trials Archive (VISTA). Results: Patients with HRHR were more often female (45.3 vs. 41.8%, p = 0.017), younger (66.0 ± 13.2 vs. 67.8 ± 12.6 years, p < 0.001), had higher baseline systolic blood pressure and more often diabetes. The primary composite endpoint of recurrent ischemic stroke, transient ischemic attack, myocardial infarction, or cardiovascular death within 90 days occurred more often in patients with HRHR (19.3 vs. 14.6%, p < 0.001). HRHR was associated with worse functional outcome at 90 days as assessed by modified Rankin Scale (mRS90: 3.03 ± 1.98 vs. 2.82 ± 1.94, p = 0.001). As exclusion of deceased patients (mRS90 of 6) resulted in a loss of association of HRHR with mRS90, it can be assumed that HRHR is mainly associated with poststroke vascular mortality, but not disability. Female sex was not associated with the primary endpoint but with adverse functional outcome measured by mRS90. Conclusion: HRHR was associated with adverse events and mortality after stroke. Despite a higher prevalence of HRHR in women, they did not reach the primary endpoint more often. However, women had a worse functional outcome (mRS) 3 months after stroke, independent of HRHR.

SGLT2 inhibitors for patients with type 2 diabetes mellitus after myocardial infarction: a nationwide observation registry study from SWEDEHEART

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce rates of heart failure hospitalisations and cardiovascular death in patients with type 2 diabetes and prior cardiovascular disease. We hypothesised that SGLT2 inhibitors could provide cardiovascular benefits in the post-myocardial infarction setting. We aimed to investigate cardiovascular outcomes of SGLT2 inhibitor therapy in patients with type 2 diabetes mellitus after myocardial infarction in a Swedish nationwide registry. We included all patients with type 2 diabetes surviving a type 1 acute myocardial infarction from January 1, 2018 to December 31, 2021. Patients were included if they were discharged with an estimated glomerular filtration rate (eGFR)>30mL/min/1.73 m2 in the nationwide Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) registry. We identified all patients discharged with or without an SGLT2 inhibitor prescription 120 days before or within three days after discharge from the cardiac care unit. The primary outcome measure was a composite of death and first hospitalisation for heart failure after one year analysed using an adjusted Cox regression. A total of 11,271 patients were included. Of these, 2498 (22.2%) received SGLT2 inhibitor treatment. Patients who were prescribed SGLT2 inhibitors were younger, more often presented with a STEMI and had worse left ventricular ejection fraction at index hospitalisation. SGLT2 inhibitor use was associated with lower rates of the composite outcome (hazard ratio (HR) of 0.70 (95% confidence interval (CI) 0.59-0.82). Treatment with SGLT2 inhibitors after myocardial infarction in patients with type 2 diabetes was associated with a lower rate of cardiovascular events. This work was supported by Hjärt-Lungfonden, Vetenskapsrådet, Knut and Alice Wallenberg Foundation, ALF, the Bundy Academy, and Skåne University Hospital funds.

Renin-Angiotensin System Inhibition in Patients With Myocardial Injury Complicating Transcatheter Aortic Valve Replacement

BackgroundPeriprocedural myocardial injury impacts clinical outcome after transcatheter aortic valve replacement (TAVR). The optimal medical management strategy for TAVR-related periprocedural myocardial injury has not been established. ObjectivesThe authors aimed to investigate the prognostic association of renin-angiotensin system (RAS) inhibitors in patients with periprocedural myocardial injury after TAVR. MethodsIn a prospective TAVR registry, patients were retrospectively stratified according to Valve Academic Research Consortium (VARC)-3 periprocedural myocardial injury and RAS inhibitor prescription after TAVR. The main outcomes of interest were prevalence of myocardial injury and cardiovascular death. Logistic and Cox proportional hazards regression were used to analyze outcomes of interest. ResultsAmong 2,083 eligible patients undergoing TAVR between August 2007 and June 2023, 283 patients (13.8%) developed VARC-3 periprocedural myocardial injury. RAS inhibitors were prescribed in 197 patients (70%) with periprocedural myocardial injury and in 1,251 patients (71.2%) without injury. Compared with patients without periprocedural myocardial injury, patients with myocardial injury had an increased risk of cardiovascular death at 1 year (HRadjusted: 2.08; 95% CI: 1.39-3.11). The use of RAS inhibitors after TAVR was associated with a reduced risk of cardiovascular death in patients with and without periprocedural myocardial injury (HRadjusted: 0.46; 95% CI: 0.22-0.95, and HRadjusted: 0.44; 95% CI: 0.30-0.65, respectively). ConclusionsOne out of 7 patients undergoing TAVR experienced periprocedural myocardial injury. VARC-3 periprocedural myocardial injury was associated with a 2-fold increased risk of cardiovascular death at 1 year after TAVR. The favorable association of RAS inhibitor prescription was consistent in patients with and without periprocedural myocardial injury. (SwissTAVI Registry; NCT01368250)

Influencing and prognostic factors of end-stage hypertrophic cardiomyopathy.

End-stage hypertrophic cardiomyopathy (ES-HCM) is a disease with severe complications and a poor prognosis. This study aimed to explore the influencing and prognostic factors of ES-HCM. A total of 1282 patients with HCM who were hospitalized for the first time at Fujian Medical University Union Hospital between 1 January 2013 and 30 September 2021 were recorded. The patients with HCM and left ventricular ejection fraction (LVEF)<50% were defined as having ES-HCM, and a control group (LVEF≥50%) was generated from the collected medical records of HCM. The patients were matched in a ratio of 4:1 based on age and sex. Logistic regression analysis was used to determine the influencing factors of ES-HCM. Kaplan-Meier survival analysis was performed to analyse the clinical outcomes of ES-HCM patients. A total of 250 inpatients with HCM were enrolled in the study; 50 patients had ES-HCM, and 200 had HCM with LVEF≥50%. The mean age of the patients at enrolment was 62.5±10.3years, and 215 patients (215/250, 86.0%) were male. The median follow-up time of the patients was 2.8 (1.4-5.4) years. The incidence of all-cause death and cardiovascular death in patients with ES-HCM was higher than those in patients with HCM and LVEF≥50% (22/50 [44.0%] vs. 13/200 [6.5%]; 12/50 [24.0%] vs. 4/200 [2.0%], all P<0.001). Multivariate logistic regression analysis showed that the influencing factors associated with ES-HCM included age at first symptom onset (odds ratio [OR]=0.95, 95% CI [0.90, 1.00], P=0.042), New York Heart Association (NYHA) class (OR=7.73, 95% CI [2.93, 20.41], P<0.001), heart rate (OR=1.07, 95% CI [1.02, 1.12], P=0.003), QRS duration (OR=1.03, 95% CI [1.00, 1.05], P=0.020), left ventricular end-diastolic diameter (LVEDD) (OR=1.15, 95% CI [1.04, 1.28], P=0.006), left atrial anteroposterior diameter (LAD) (OR=1.13, 95% CI [1.03, 1.24], P=0.012), and maximum left ventricular wall thickness (MLVWT) (OR=0.80, 95% CI [0.68, 0.93], P=0.005). Among the 50 patients with ES-HCM, NYHA class (P<0.001) and heart rate (P=0.017) were each associated with a higher likelihood and earlier occurrence of heart transplantation or all-cause mortality in univariate analyses. The influencing factors for ES-HCM included the age at first symptom onset, NYHA class, heart rate, QRS duration, LVEDD, LAD, and MLVWT. Both NYHA class and heart rate were related to the prognosis of ES-HCM.

Effect of sex on sodium-glucose co-transporter-2 antagonists and glucagon-like peptide-1 agonists in heart failure.

Recent evidence suggests that medications not primarily targeting the cardiovascular (CV) system may have cardioprotective effects in patients with heart failure (HF), in particular the anti-diabetic therapies sodium-glucose co-transporter-2 (SGLT-2) antagonists and glucagon-like peptide-1 (GLP-1) agonists. We conducted a systematic review to assess the pooled evidence for the use of SGLT-2 antagonists and GLP-1 agonists in patients with HF and the effect of biological sex on the results. MEDLINE, Embase, Cochrane Library and clinical trial databases were searched until February 2023. Randomized controlled trials (RCTs) published in English that included adult participants with HF who were randomized to an SGLT-2 antagonist or GLP-1 agonist with a primary or secondary outcome of HF hospitalization (HFH) or CV death were eligible for inclusion. Data pooling was undertaken using a random effects model and odds ratios (ORs) to determine the association between drug and outcome. Sub-group analyses to investigate sex differences were conducted. Six RCTs were included (24781 patients). Four studies investigated SGLT-2 antagonists, and two studies examined GLP-1 agonists. SGLT-2 antagonists improved HFH {OR [95% confidence interval (CI)]: 0.69 [0.63, 0.77], P<0.001} and CV death [0.87 (0.78, 0.97), P=0.01] independent of diabetes status, with excellent homogeneity across all four studies. No beneficial effects were found for GLP-1 agonists. The effects of SGLT-2 antagonists on HFH and CV death were similar in men and women [OR (95% CI): HFH, 0.70 (0.64, 0.76), P<0.001 and 0.58 (0.46, 0.74), P<0.001, respectively; CV death, 0.86 (0.78, 0.95), P=0.003 and 0.84 (0.73, 0.96), P=0.01, respectively], and the neutral effect of GLP-1 agonists on HFH and CV death was similar in men and women (all P>0.05). SGLT-2 antagonists but not GLP-1 agonists beneficially affect HFH and CV death in patients with HF with or without diabetes. We show for the first time that GLP-1 agonists have a neutral effect on HFH and CV death in both male and female HF patients and a reduction in HFH and CV death in male and female HF patients taking SGLT-2 antagonists.

Aptamer Proteomics for Biomarker Discovery in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Proteomic Substudy.

Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity-Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (β-2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein-outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or high-sensitivity cardiac troponin. Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON-HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

Cost-effectiveness of add-on empagliflozin versus standard of care in management of CKD in Malaysia, Thailand and Vietnam – findings from a modelling study assessing an EMPA-KIDNEY eligible population, using CKD progression model

Background and objectives Nearly one in ten individuals in South-East Asia are estimated to be affected by chronic kidney disease (CKD). The burden of end-stage kidney disease is significant and can be heavy on the healthcare system. The recent EMPA-KIDNEY trial demonstrated a significant reduction in the risk of kidney disease progression or cardiovascular death in patients with CKD with a broad range of kidney function using add-on empagliflozin versus standard of care (SoC) alone. The objective of this study was to estimate the economic benefit of empagliflozin for patients with CKD in Malaysia, Thailand and Vietnam. Methods An individual patient level simulation model with an annual cycle that estimates the progression of kidney function and associated risk-factors was employed. Local costs and mortality rates were estimated from a wide range of published literature. A healthcare perspective was used over a 50-year time horizon. Results The use of add-on empagliflozin versus SoC alone was found to be cost-saving in Malaysia and Thailand and cost-effective (ICER: 77,838,407 Vietnam Dong/QALY vs. a willingness to pay threshold of 96,890,026/QALY) in Vietnam. The bulk of the costs avoided over a lifetime is derived from the prevention or delay of dialysis initiation or kidney transplant – the cost offsets were nearly twice the additional treatment cost. The results were similar in patients with and without diabetes and across broad range of albuminuria. Conclusions The use of add-on empagliflozin in a broad population of patients with CKD is expected to be cost-saving in Malaysia and Thailand and cost-effective in Vietnam and will help alleviate the increasing burden of CKD in the region.

Empagliflozin Improves Diastolic Function in HFpEF by Restabilizing the Mitochondrial Respiratory Chain.

Clinical studies demonstrated beneficial effects of sodium-glucose-transporter 2 inhibitors on the risk of cardiovascular death in patients with heart failure with preserved ejection fraction (HFpEF). However, underlying processes for cardioprotection remain unclear. The present study focused on the impact of empagliflozin (Empa) on myocardial function in a rat model with established HFpEF and analyzed underlying molecular mechanisms. Obese ZSF1 (Zucker fatty and spontaneously hypertensive) rats were randomized to standard care (HFpEF, n=18) or Empa (HFpEF/Empa, n=18). ZSF1 lean rats (con, n=18) served as healthy controls. Echocardiography was performed at baseline and after 4 and 8 weeks, respectively. After 8 weeks of treatment, hemodynamics were measured invasively, mitochondrial function was assessed and myocardial tissue was collected for either molecular and histological analyses or transmission electron microscopy. In HFpEF Empa significantly improved diastolic function (E/é: con: 17.5±2.8; HFpEF: 24.4±4.6; P<0.001 versus con; HFpEF/Empa: 19.4±3.2; P<0.001 versus HFpEF). This was accompanied by improved hemodynamics and calcium handling and by reduced inflammation, hypertrophy, and fibrosis. Proteomic analysis demonstrated major changes in proteins involved in mitochondrial oxidative phosphorylation. Cardiac mitochondrial respiration was significantly impaired in HFpEF but restored by Empa (Vmax complex IV: con: 0.18±0.07 mmol O2/s/mg; HFpEF: 0.13±0.05 mmol O2/s/mg; P<0.041 versus con; HFpEF/Empa: 0.21±0.05 mmol O2/s/mg; P=0.012 versus HFpEF) without alterations of mitochondrial content. The expression of cardiolipin, an essential stability/functionality-mediating phospholipid of the respiratory chain, was significantly decreased in HFpEF but reverted by Empa (con: 15.9±1.7 nmol/mg protein; HFpEF: 12.5±1.8 nmol/mg protein; P=0.002 versus con; HFpEF/Empa: 14.5±1.8 nmol/mg protein; P=0.03 versus HFpEF). Transmission electron microscopy revealed a reduced size of mitochondria in HFpEF, which was restored by Empa. The study demonstrates beneficial effects of Empa on diastolic function, hemodynamics, inflammation, and cardiac remodeling in a rat model of HFpEF. These effects were mediated by improved mitochondrial respiratory capacity due to modulated cardiolipin and improved calcium handling.

Safety of Empagliflozin: An Individual Participant-Level Data Meta-Analysis from Four Large Trials.

Empagliflozin is a sodium-glucose co-transporter-2 inhibitor used to treat type 2 diabetes (T2D) to improve glycemic control, reduce risk of cardiovascular death in patients with T2D, and treat patients with symptomatic chronic heart failure (HF) and chronic kidney disease (CKD). The safety profile of empagliflozin is well documented, although adverse events (AEs) remain of interest to clinicians. This study provides an up-to-date safety evaluation of empagliflozin. Data were pooled from four long-term trials which included: patients with T2D and established cardiovascular disease (EMPA-REG OUTCOME), patients with HF, with/without diabetes (EMPEROR-Reduced and EMPEROR-Preserved), and patients with CKD, with/without diabetes (EMPA-KIDNEY). Since three of the four trials evaluated empagliflozin 10mg, the meta-analysis was restricted to this dose. Total trial medication exposure was 19,727 patient-years for patients who received empagliflozin (n = 10,472) and 19,447 patient-years for placebo (n = 10,461). The percentages of patients with serious AEs, fatal AEs, and AEs leading to discontinuation were similar for both groups. The incidences of serious urinary tract infection and serious pyelonephritis or urosepsis were similar for both groups but higher for women taking empagliflozin versus placebo. Serious genital infections were not increased with empagliflozin versus placebo. There was a slight increase in ketoacidosis and serious volume depletion in patients who received empagliflozin versus placebo. The occurrence of serious acute kidney injury was lower with empagliflozin versus placebo. Empagliflozin was not associated with an increased incidence of severe hypoglycemia, bone fractures, or lower limb amputations. Empagliflozin is therefore considered safe in people without diabetes, the elderly, patients with very low estimated glomerular filtration rate, low body mass index, and HF. Safety is unaltered by blood pressure, concomitant medication for hypertension, HF, and immunosuppression. This meta-analysis of long-term safety data extends current knowledge and confirms the safety and tolerability of empagliflozin.

Effect of SGLT2 inhibitors on heart failure outcomes and cardiovascular death across the cardiometabolic disease spectrum: a systematic review and meta-analysis

Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been studied in patients with heart failure, type 2 diabetes, chronic kidney disease, atherosclerotic cardiovascular disease, and acute myocardial infarction. Individual trials were powered to study composite outcomes in one disease state. We aimed to evaluate the treatment effect of SGLT2 inhibitors on specific clinical endpoints across multiple demographic and disease subgroups. In this systematic review and meta-analysis, we queried online databases (PubMed, Cochrane CENTRAL, and SCOPUS) up to Feb 10, 2024, for primary and secondary analyses of large trials (n>1000) of SGLT2 inhibitors in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease (including acute myocardial infarction). Outcomes studied included composite of first hospitalisation for heart failure or cardiovascular death, first hospitalisation for heart failure, cardiovascular death, total (first and recurrent) hospitalisation for heart failure, and all-cause mortality. Effect sizes were pooled using random-effects models. This study is registered with PROSPERO, CRD42024513836. We included 15 trials (N=100 952). Compared with placebo, SGLT2 inhibitors reduced the risk of first hospitalisation for heart failure by 29% in patients with heart failure (hazard ratio [HR] 0·71 [95% CI 0·67-0·77]), 28% in patients with type 2 diabetes (0·72 [0·67-0·77]), 32% in patients with chronic kidney disease (0·68 [0·61-0·77]), and 28% in patients with atherosclerotic cardiovascular disease (0·72 [0·66-0·79]). SGLT2 inhibitors reduced cardiovascular death by 14% in patients with heart failure (HR 0·86 [95% CI 0·79-0·93]), 15% in patients with type 2 diabetes (0·85 [0·79-0·91]), 11% in patients with chronic kidney disease (0·89 [0·82-0·96]), and 13% in patients with atherosclerotic cardiovascular disease (0·87 [0·78-0·97]). The benefit of SGLT2 inhibitors on both first hospitalisation for heart failure and cardiovascular death was consistent across the majority of the 51 subgroups studied. Notable exceptions included acute myocardial infarction (22% reduction in first hospitalisation for heart failure; no effect on cardiovascular death) and heart failure with preserved ejection fraction (26% reduction in first hospitalisation for heart failure; no effect on cardiovascular death). SGLT2 inhibitors reduced heart failure events and cardiovascular death in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease. These effects were consistent across a wide range of subgroups within these populations. This supports the eligibility of a large population with cardiorenal-metabolic diseases for treatment with SGLT2 inhibitors. None.

Synergistic effect of lipoprotein(a) and high-sensitivity C-reactive protein on the risk of all-cause and cardiovascular death in patients with acute myocardial infarction: a large prospective cohort study.

Although lipoprotein(a) [Lp(a)] and high-sensitivity C-reactive protein (Hs-CRP) are closely associated with the mortality of acute myocardial infarction (AMI), their synergistic effect on the risk of death remains unknown. Therefore, this study aimed to explore the combined effect of Lp(a) and Hs-CRP on the incidence of all-cause and cardiovascular death in AMI patients. A comprehensive cohort study enrolled 912 AMI patients, categorizing them into four groups based on Lp(a) and Hs-CRP levels: Group 1 [Lp(a) < 30 mg/dL & Hs-CRP < 2 mg/L], Group 2 [Lp(a) < 30 mg/dL & Hs-CRP ≥ 2 mg/L], Group 3 [Lp(a) ≥ 30 mg/dL & Hs-CRP < 2 mg/L], and Group 4 [Lp(a) ≥ 30 mg/dL & Hs-CRP ≥ 2 mg/L]. Cox regression analysis, Kaplan-Meier survival analysis and sensitivity analysis were employed to determine the combined effects of Lp(a) and Hs-CRP on the risk of all-cause and cardiovascular death. Over a median observation period of 38.98 months, 217 patients passed away, with 137 deaths attributed to cardiovascular causes. The multivariate Cox regression analysis revealed that in the comprehensively adjusted Model 3, only Lp(a) and the combination of Lp(a) and Hs-CRP exhibited a strong association with cardiovascular death risk. Specifically, for Lp(a) levels ≥ 30 mg/dL compared to < 30 mg/dL, the hazard ratio (HR) was 2.434 with a 95% confidence interval (CI) of 1.653-3.583 (P < 0.001); for log10(Lp(a)), the HR was 2.630 with a 95% CI of 1.530-4.523 (P < 0.001); for Group 4 versus Group 1, the HR was 2.346 with a 95% CI of 1.054-5.220 (P = 0.037); and for Group 4 versus Groups 1 + 2 + 3, the HR was 1.878 with a 95% CI of 1.284-2.748 (P = 0.001). Sensitivity analysis indicated that the synergy between Lp(a) and Hs-CRP continued to be independently associated with the risk of cardiovascular death. For Group 3 versus Group 1, the HR was 3.353 with a 95% CI of 1.133-9.917 (P = 0.029); for Group 4 versus Group 1, the HR was 3.710 with a 95% CI of 1.466-9.392 (P = 0.006); and for Group 4 versus Groups 1 + 2 + 3, the HR was 2.433 with a 95% CI of 1.620-3.656 (P < 0.001). Compared to elevated levels of either Lp(a) or Hs-CRP alone, the concurrent high levels of both significantly increased the risk of cardiovascular death in patients with AMI, underscoring the importance of considering their combined effects in the prognostic management of AMI patients.