Optimal Screening for Predicting and Preventing the Risk of Heart Failure Among Adults With Diabetes Without Atherosclerotic Cardiovascular Disease: A Pooled Cohort Analysis.

BACKGROUND: The optimal approach to identify individuals with diabetes who are at a high risk for developing heart failure (HF) to inform implementation of preventive therapies is unknown, especially in those without atherosclerotic cardiovascular disease (ASCVD). METHODS: Adults with diabetes and no HF at baseline from 7 community-based cohorts were included. Participants without ASCVD who were at high risk for developing HF were identified using 1-step screening strategies: risk score (WATCH-DM [Weight, Age, Hypertension, Creatinine, HDL-C, Diabetes Control, QRS Duration, MI, and CABG] ≥12), NT-proBNP (N-terminal pro-B-type natriuretic peptide ≥125 pg/mL), hs-cTn (high-sensitivity cardiac troponin T ≥14 ng/L; hs-cTnI ≥31 ng/L), and echocardiography-based diabetic cardiomyopathy (echo-DbCM; left atrial enlargement, left ventricular hypertrophy, or diastolic dysfunction). High-risk participants were also identified using 2-step screening strategies with a second test to identify residual risk among those deemed low risk by the first test: WATCH-DM/NT-proBNP, NT-proBNP/hs-cTn, NT-proBNP/echo-DbCM. Across screening strategies, the proportion of HF events identified, 5-year number needed to treat and number needed to screen to prevent 1 HF event with an SGLT2i (sodium-glucose cotransporter 2 inhibitor) among high-risk participants, and cost of screening were estimated. RESULTS: The initial study cohort included 6293 participants (48.2% women), of whom 77.7% without prevalent ASCVD were evaluated with different HF screening strategies. At 5-year follow-up, 6.2% of participants without ASCVD developed incident HF. The 5-year number needed to treat to prevent 1 HF event with an SGLT2i among participants without ASCVD was 43 (95% CI, 29-72). In the cohort without ASCVD, high-risk participants identified using 1-step screening strategies had a low 5-year number needed to treat (22 for NT-proBNP to 37 for echo-DbCM). However, a substantial proportion of HF events occurred among participants identified as low risk using 1-step screening approaches (29% for echo-DbCM to 47% for hs-cTn). Two-step screening strategies captured most HF events (75-89%) in the high-risk subgroup with a comparable 5-year number needed to treat as the 1-step screening approaches (30-32). The 5-year number needed to screen to prevent 1 HF event was similar across 2-step screening strategies (45-61). However, the number of tests and associated costs were lowest for WATCH-DM/NT-proBNP ($1061) compared with other 2-step screening strategies (NT-proBNP/hs-cTn: $2894; NT-proBNP/echo-DbCM: $16 358). CONCLUSIONS: Selective NT-proBNP testing based on the WATCH-DM score efficiently identified a high-risk primary prevention population with diabetes expected to derive marked absolute benefits from SGLT2i to prevent HF.

Effects of Sodium-Glucose Cotransporter-2 Inhibitors on Kidney Outcomes across Baseline Cardiovascular-Kidney-Metabolic Conditions: A Systematic Review and Meta-Analyses.

BACKGROUND: The effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on kidney outcomes in patients with varying combinations of heart failure, chronic kidney disease, and type 2 diabetes mellitus have not been quantified. METHODS: PubMed and Scopus were queried up to December 2023 for primary and secondary analysis of placebo-controlled trials of SGLT2i in patients with heart failure, chronic kidney disease, or type 2 diabetes mellitus. Outcomes of interest were composite kidney endpoint (combination of estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2, sustained doubling of serum creatinine, varying percent change in eGFR, and need for kidney replacement therapy), rate of eGFR slope decline and albuminuria progression. Hazard ratios (HR) and mean differences with their 95% confidence intervals (CI) were extracted onto an excel sheet, and the results were then pooled using a random-effect model through Review Manager (version 5.3, Cochrane Collaboration). RESULTS: Eleven trials (n=80,928 patients) were included. Compared with the placebo, SGLT2i reduced the risk of the composite kidney endpoint by 41% (hazard ratio 0.59; 95%CI 0.42-0.83) in heart failure with reduced ejection fraction, 36% (hazard ratio 0.64;95%CI 0.55-0.73) in chronic kidney disease, and 38% (hazard ratio 0.62;95%CI 0.56-0.69) in type 2 diabetes mellitus. A similar pattern of benefit was observed in combinations of these comorbidities, as well as patients without baseline heart failure, chronic kidney disease, or type 2 diabetes mellitus. SGLT2i slowed the rate of eGFR slope decline and reduced the risk of sustained doubling of serum creatinine by 36% (hazard ratio 0.64; 95%CI 0.56-0.72) in the overall population, and a consistent effect on kidney outcomes was observed in most subpopulations with available data. CONCLUSIONS: SGLT2i improved kidney outcomes in cohorts with heart failure, chronic kidney disease, and type 2 diabetes mellitus, and these effects were consistent across patients with different combinations of these comorbidities.

Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure.

BACKGROUND: It is not known whether the benefits of sodium-glucose cotransporter 2 inhibitors in heart failure persist after years of therapy. METHODS: In the EMPEROR-Reduced (Empagliflozin Outcome Trials in Chronic Heart Failure With Reduced Ejection Fraction) and EMPEROR-Preserved (Empagliflozin Outcome Trials in Chronic Heart Failure With Preserved Ejection Fraction) trials, patients with heart failure were randomly assigned (double-blind) to placebo or empagliflozin 10 mg/day for a median of 16 and 26 months, respectively. At the end of the trials, 6799 patients (placebo 3381, empagliflozin 3418) were prospectively withdrawn from treatment in a blinded manner, and, of these, 3981 patients (placebo 2020, empagliflozin 1961) underwent prespecified in-person assessments after ≈30 days off treatment. RESULTS: From 90 days from the start of closeout to the end of double-blind treatment, the annualized risk of cardiovascular death or hospitalization for heart failure was lower in empagliflozin-treated patients than in placebo-treated patients (10.7 [95% CI, 9.0-12.6] versus 13.5 [95% CI, 11.5-15.6] events per 100 patient-years, respectively; hazard ratio 0.76 [95% CI, 0.60-0.96]). When the study drugs were withdrawn for ≈30 days, the annualized risk of cardiovascular death or hospitalization for heart failure increased in patients withdrawn from empagliflozin but not in those withdrawn from placebo (17.0 [95% CI, 12.6-22.1] versus 14.1 [95% CI, 10.1-18.8] events per 100 patient-years for empagliflozin and placebo, respectively). The hazard ratio for the change in risk in the patients withdrawn from empagliflozin was 1.75 (95% CI, 1.20-2.54), P=0.0034, whereas the change in the risk in patients withdrawn from placebo was not significant (hazard ratio 1.12 [95% CI, 0.76-1.66]); time period-by-treatment interaction, P=0.068. After withdrawal, the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score declined by 1.6±0.4 in patients withdrawn from empagliflozin versus placebo (P<0.0001). Furthermore, withdrawal of empagliflozin was accompanied by increases in fasting glucose, body weight, systolic blood pressure, estimated glomerular filtration rate, N-terminal pro-hormone B-type natriuretic peptide, uric acid, and serum bicarbonate and decreases in hemoglobin and hematocrit (all P<0.01). These physiological and laboratory changes were the inverse of the effects of the drug seen at the start of the trials during the initiation of treatment (≈1-3 years earlier) in the same cohort of patients. CONCLUSIONS: These observations demonstrate a persistent effect of empagliflozin in patients with heart failure even after years of treatment, which dissipated rapidly after withdrawal of the drug. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT03057977 and NCT03057951.

The cardiovascular effects of novel weight loss therapies.

The prevalence of overweight and obesity has reached pandemic proportions. Obesity is known to increase the risk for Type 2 diabetes and hypertension, as well as the risk for overt cardiovascular (CV) disease, including myocardial infarction, heart failure, and stroke. The rising prevalence of obesity may counteract the recent advances in primary and secondary prevention of CV disease. Overweight and obesity are common in patients with CV disease; however, cardiologists face several challenges in managing body weight in this population. Many may not consider obesity as a therapeutic target probably because there were no previous highly effective and safe pharmacologic interventions to consider. In addition, they may not have the expertise or resources to implement lifestyle interventions and may have limited familiarity with obesity pharmacotherapy. Moreover, the long-term CV effects of obesity pharmacotherapy remain uncertain due to limited CV outcome data with weight loss as the primary intervention. Although current CV guidelines recognize the importance of weight loss, they primarily focus on lifestyle modifications, with fewer details on strategies to utilize obesity pharmacotherapy and surgery. However, the recent 2022 American Diabetes Association/European Association for the Study of Diabetes consensus on the management of Type 2 diabetes has moved up weight management to the front of the treatment algorithm, by prioritizing the use of pharmacologic interventions such as glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists, which have potent weight-lowering effects, in addition to glucose-lowering effects. This review appraises the current evidence regarding the CV effects of weight-loss interventions. Considering this evidence, practical guidance is provided to assist cardiologists in developing and implementing treatment plans, which may allow optimal weight management while maximizing CV benefits and minimizing side effects to improve the overall well-being of people with CV disease.

Endpoint adjudication in cardiovascular clinical trials.

Endpoint adjudication (EA) is a common feature of contemporary randomized controlled trials (RCTs) in cardiovascular medicine. Endpoint adjudication refers to a process wherein a group of expert reviewers, known as the clinical endpoint committee (CEC), verify potential endpoints identified by site investigators. Events that are determined by the CEC to meet pre-specified trial definitions are then utilized for analysis. The rationale behind the use of EA is that it may lessen the potential misclassification of clinical events, thereby reducing statistical noise and bias. However, it has been questioned whether this is universally true, especially given that EA significantly increases the time, effort, and resources required to conduct a trial. Herein, we compare the summary estimates obtained using adjudicated vs. non-adjudicated site designated endpoints in major cardiovascular RCTs in which both were reported. Based on these data, we lay out a framework to determine which trials may warrant EA and where it may be redundant. The value of EA is likely greater when cardiovascular trials have nuanced primary endpoints, endpoint definitions that align poorly with practice, sub-optimal data completeness, greater operator variability, and lack of blinding. EA may not be needed if the primary endpoint is all-cause death or all-cause hospitalization. In contrast, EA is likely merited for more nuanced endpoints such as myocardial infarction, bleeding, worsening heart failure as an outpatient, unstable angina, or transient ischaemic attack. A risk-based approach to adjudication can potentially allow compromise between costs and accuracy. This would involve adjudication of a small proportion of events, with further adjudication done if inconsistencies are detected.

Leveraging electronic health records to streamline the conduct of cardiovascular clinical trials.

Conventional randomized controlled trials (RCTs) can be expensive, time intensive, and complex to conduct. Trial recruitment, participation, and data collection can burden participants and research personnel. In the past two decades, there have been rapid technological advances and an exponential growth in digitized healthcare data. Embedding RCTs, including cardiovascular outcome trials, into electronic health record systems or registries may streamline screening, consent, randomization, follow-up visits, and outcome adjudication. Moreover, wearable sensors (i.e. health and fitness trackers) provide an opportunity to collect data on cardiovascular health and risk factors in unprecedented detail and scale, while growing internet connectivity supports the collection of patient-reported outcomes. There is a pressing need to develop robust mechanisms that facilitate data capture from diverse databases and guidance to standardize data definitions. Importantly, the data collection infrastructure should be reusable to support multiple cardiovascular RCTs over time. Systems, processes, and policies will need to have sufficient flexibility to allow interoperability between different sources of data acquisition. Clinical research guidelines, ethics oversight, and regulatory requirements also need to evolve. This review highlights recent progress towards the use of routinely generated data to conduct RCTs and discusses potential solutions for ongoing barriers. There is a particular focus on methods to utilize routinely generated data for trials while complying with regional data protection laws. The discussion is supported with examples of cardiovascular outcome trials that have successfully leveraged the electronic health record, web-enabled devices or administrative databases to conduct randomized trials.

Visual Hallucinations After a Russell's Viper Bite.

Visual hallucinations (VHs) are extremely rare in snakebites. We report a case of Russell's viper bite in an otherwise healthy 55-y-old woman who presented to a hospital in south India with established clinical features of systemic and local envenomation, including coagulation failure, without any neurologic manifestations on admission. She reported simple VH on the third day, which abruptly stopped on the fifth day without any specific medications. Clinical, laboratory, imaging, and electrophysiological studies did not reveal any neuropsychiatric disorders. Including this case, only 5 cases of VH are documented in the literature, 2 following cobra and viper bites and 1 after a sea snake bite. Two cases were reported from Australia and 1 each from the United States, Iran, and India.

Comparison of revascularization strategies in patients with acute coronary syndrome and multivessel coronary disease: A systematic review and network meta-analysis.

BACKGROUND: Whether revascularization should be performed as multivessel intervention at the time of index procedure (MV-index), staged procedure (MV-staged), or culprit only intervention (COI) in patients with multivessel disease (MVD) presenting with acute coronary syndrome (ACS) is unclear. We performed a systematic review and network meta-analysis of randomized controlled trials to assess the optimal revascularization strategy in this patient population. METHODS: PubMed, Embase, and Cochrane Central databases were systematically searched to identify all relevant studies. The outcomes assessed were major cardiac adverse events (MACE), all-cause mortality, cardiovascular mortality, myocardial infarction (MI), and revascularization. A Bayesian random-effects network meta-analysis was used to calculate odds ratio (OR) with credible interval (CrI). RESULTS: Thirteen studies with 8,066 patients were included in the analysis. There was a decreased risk of MACE (MV-index vs. COI: OR, 0.35; 95% CrI, 0.23-0.55; MV-staged vs COI: OR, 0.52; 95% CrI, 0.31-0.81) and revascularization (MV-index vs. COI: OR, 0.27; 95% CrI, 0.15-0.49; MV-staged vs. COI: OR, 0.38; 95% CrI, 0.19-0.70) with MV-index intervention and MV-staged intervention compared with COI. However, MV-index intervention and not MV-staged intervention was associated with a decreased risk of MI (MV-index vs. COI: OR, 0.35; 95% CrI, 0.12-0.93; MV-staged vs. COI: OR, 0.65; 95% CrI, 0.24-1.59) compared with COI. CONCLUSIONS: Our analysis suggests that multivessel intervention either at index procedure or as staged intervention may be more efficacious compared to COI in patients with MVD presenting with ACS.

Safety and efficacy of transcatheter aortic valve replacement for native aortic valve regurgitation: A systematic review and meta-analysis.

OBJECTIVE: The objective of this study was to analyze the available literature on using transcatheter aortic valve replacement (TAVR) for native aortic regurgitation (AR). BACKGROUND: Surgical aortic valve replacement is the gold standard therapy for native AR. TAVR has emerged as an alternative approach in high-risk patients. METHODS: MEDLINE, Scopus, and Cochrane CENTRAL were searched for reports of at least 5 patients undergoing TAVR for native AR. Outcomes included 30-day mortality, myocardial infarction, stroke, major bleeding, postprocedural moderate to severe AR, and device success. Pooled estimates were calculated using a random-effects model. Subgroup analysis and a meta-regression were performed to study the effects of study level covariates on outcomes. RESULTS: Nineteen studies (n =998 patients) were included. The rate of procedural success per Valve Academic Research Consortium - 2 (VARC-2) criteria was 86.2% (78.8%-92.2%]. Thirty-day mortality was 11.9% (9.4%-14.7%). Subgroup analysis showed the use of new generation valves was associated with lower 30-day mortality (P = 0.02) and higher device success (P = 0.009) compared with early generation valves. There was no significant difference (P = 0.13) in the rate of 30-day mortality between patients receiving purpose-specific [8.2% (4.3%-13.1%); I2 = 0%] and nonpurpose specific valves [13.0% (8.2%-18.6%); I2 = 25%]. However, device success was higher (P = 0.02) in patients who received purpose-specific valves [96.3% (92.2%-98.9%); I2 = 0%] compared with nonpurpose specific valves [84.4% (75%-91.9%); I2 =46%]. CONCLUSION: TAVR for native AR is associated with acceptable procedural success but increased early mortality. However, the safety and the efficacy of the procedure increased with newer valves.

Percutaneous Mitral Valve Repair versus Optimal Medical Therapy in Patients with Functional Mitral Regurgitation: A Systematic Review and Meta-Analysis.

OBJECTIVES: To compare percutaneous mitral valve repair (PMVR) with optimal medical therapy (OMT) in patients with heart failure (HF) and severe functional mitral regurgitation (FMR). BACKGROUND: Many patients with HF and FMR are not suitable for surgical valve replacement and remain symptomatic despite maximal OMT. PMVR has recently emerged as an alternative solution. METHODS: We performed a systematic review and a meta-analysis to address this question. Cochrane CENTRAL, MEDLINE, and Scopus were searched for randomized (RCT) and nonrandomized studies comparing PMVR with OMT in patients with HF and FMR. Primary endpoint was all-cause midterm mortality (at 1 and 2 years). Secondary endpoints were 30-day mortality and cardiovascular mortality and HF hospitalizations, at maximum follow-up. Studies including mixed cohort of degenerative and functional MR were allowed initially but were excluded in a secondary sensitivity analysis for each of the study's end points. This meta-analysis was performed following the publication of two RCTs (MITRA-FR and COAPT). RESULTS: Eight studies (six observational, two RCTs) comprising 3,009 patients were included in the meta-analysis. In comparison with OMT, PMVR significantly reduced 1-year mortality (RR: 0.70 [0.56, 0.87]; p=0.002; I2=47.6%), 2-year mortality (RR: 0.63 [0.55, 0.73]; p<0.001; I2=0%), and cardiovascular mortality (RR: 0.32 [0.23, 0.44]; p<0.001; I2=0%). No significant difference between PMVR+OMT and OMT was noted in HF hospitalization (HR: 0.69 [0.40, 1.20]; p=0.19; I2=85%) and 30-day mortality (RR: 1.13 [0.68, 1.87]; p=0.16; I2=0%). CONCLUSIONS: In comparison with OMT, PMVR significantly reduces 1-year mortality, 2-year mortality, and cardiovascular mortality in patients with HF and severe MR.

Differential Use of Glycoprotein IIb/IIIa Inhibitors with Bivalirudin in Patients with STEMI Undergoing PCI: A Systematic Review and Meta-Analysis.

AIM: The efficacy and safety of bivalirudin when used concurrently with glycoprotein IIb/IIIa inhibitors (GPI) is uncertain. In this systematic review and meta-analysis, we aimed to evaluate the efficacy and safety of bivalirudin versus heparin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) and to explore the impact of differential use (greater and balanced) of GPI. METHODS: Online databases were queried from inception to March 2023 to identify eight randomized controlled trials (n = 22,483) for inclusion. The primary outcomes included all-cause mortality, major bleeding, major adverse cardiovascular events (MACE), and net adverse clinical events (NACE). Secondary efficacy endpoints included cardiac death, reinfarction, stent thrombosis (ST), and stroke. Data were pooled using a random-effects model to derive risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: When compared to heparin, bivalirudin was associated with a significant reduction in all-cause mortality (RR 0.83; 95% CI 0.72-0.97; P = 0.02), major bleeding (RR 0.73; 95% CI 0.57-0.93; P = 0.01), cardiac death (RR 0.79; 95% CI 0.66-0.94; P = 0.01), and NACE (RR 0.80; 95% CI 0.72-0.89; P < 0.0001). However, while the bivalirudin arm showed an increased likelihood of ST in the greater GPI subgroup (RR 1.70; 95% CI 1.13-2.56; P = 0.01), it was associated with a decreased likelihood of ST in the balanced GPI subgroup (RR 0.40; 95% CI 0.24-0.65; P = 0.0003). CONCLUSION: Overall, our findings suggest that bivalirudin may be a more efficacious intervention than heparin for reducing certain adverse events in patients with STEMI undergoing primary PCI.

Association of low diastolic blood pressure with cardiovascular outcomes and all-cause mortality: A meta-analysis.

BACKGROUND: Reduction of diastolic blood pressure (DBP) below 70 mmHg may decrease perfusion to the heart and worsen cardiovascular (CV) outcomes. AIMS: Explore the association between low DBP and CV outcomes. METHODS: We searched the online databases until August 2023 for studies reporting the risk of all-cause mortality (ACM) or CV outcomes in patients with low versus normal DBP (70-80mm Hg). RESULTS: Inclusion of 10 studies (n = 1,998,223 patients) found that a mean achieved DBP < 60 mmHg was associated with an increased risk of all-cause mortality (HR 1.48; 95 % CI [1.26-1.74]), especially in patients with pre-existing CV disease. It was also associated to a higher risk of major adverse cardiovascular events (HR 1.84; [1.28-2.65]) and myocardial infarction (HR 1.49; [1.13-1.97]). A DBP of 60-69 mmHg was associated with an increased risk of all-cause mortality (HR 1.11; [1.03-1.20]). CONCLUSION: Reduction of DBP, particularly below 60 mmHg, is associated with increased risk of ACM.

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

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: None.

Development and validation of a machine learning-based approach to identify high-risk diabetic cardiomyopathy phenotype.

AIMS: Abnormalities in specific echocardiographic parameters and cardiac biomarkers have been reported among individuals with diabetes. However, a comprehensive characterization of diabetic cardiomyopathy (DbCM), a subclinical stage of myocardial abnormalities that precede the development of clinical heart failure (HF), is lacking. In this study, we developed and validated a machine learning-based clustering approach to identify the high-risk DbCM phenotype based on echocardiographic and cardiac biomarker parameters. METHODS AND RESULTS: Among individuals with diabetes from the Atherosclerosis Risk in Communities (ARIC) cohort who were free of cardiovascular disease and other potential aetiologies of cardiomyopathy (training, n = 1199), unsupervised hierarchical clustering was performed using echocardiographic parameters and cardiac biomarkers of neurohormonal stress and chronic myocardial injury (total 25 variables). The high-risk DbCM phenotype was identified based on the incidence of HF on follow-up. A deep neural network (DeepNN) classifier was developed to predict DbCM in the ARIC training cohort and validated in an external community-based cohort (Cardiovascular Health Study [CHS]; n = 802) and an electronic health record (EHR) cohort (n = 5071). Clustering identified three phenogroups in the derivation cohort. Phenogroup-3 (n = 324, 27% of the cohort) had significantly higher 5-year HF incidence than other phenogroups (12.1% vs. 4.6% [phenogroup 2] vs. 3.1% [phenogroup 1]) and was identified as the high-risk DbCM phenotype. The key echocardiographic predictors of high-risk DbCM phenotype were higher NT-proBNP levels, increased left ventricular mass and left atrial size, and worse diastolic function. In the CHS and University of Texas (UT) Southwestern EHR validation cohorts, the DeepNN classifier identified 16% and 29% of participants with DbCM, respectively. Participants with (vs. without) high-risk DbCM phenotype in the external validation cohorts had a significantly higher incidence of HF (hazard ratio [95% confidence interval] 1.61 [1.18-2.19] in CHS and 1.34 [1.08-1.65] in the UT Southwestern EHR cohort). CONCLUSION: Machine learning-based techniques may identify 16% to 29% of individuals with diabetes as having a high-risk DbCM phenotype who may benefit from more aggressive implementation of HF preventive strategies.

The effect of sodium-glucose cotransporter 2 inhibitors on left cardiac remodelling in heart failure with reduced ejection fraction: Systematic review and meta-analysis.

AIMS: The therapeutic mechanism of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on left cardiac remodelling in patients with heart failure with reduced ejection fraction (HFrEF) is not well-established. This study meta-analysed the impact of SGLT2i on left cardiac structure and function in patients with HFrEF. METHODS AND RESULTS: Online databases were queried up to April 2023 for trials reporting indicators of left cardiac structure and function in patients with HFrEF treated with SGLT2i. Data from studies were pooled using a random-effects model to derive weighted mean differences (WMDs) and 95% confidence intervals (CIs). Six trials were included (n = 555). Compared with control, SGLT2i significantly improved left ventricular end-diastolic volume (LVEDV; WMD: -17.07 ml [-23.84, -10.31]; p < 0.001), LVEDV index (WMD: -5.62 ml/m2 [-10.28, -0.97]; p = 0.02), left ventricular end-systolic volume (LVESV; WMD: -15.63 ml [-26.15, -5.12]; p = 0.004), LVESV index (WMD: -6.90 ml/m2 [-10.68, -3.11]; p = 0.001), left ventricular ejection fraction (WMD: 2.71% [0.70, 4.72]; p = 0.008), and left atrial volume index (WMD: -2.19 ml/m2 [-4.26, -0.11]; p = 0.04) in patients with HFrEF. SGLT2i use was associated with a non-significant trend towards a reduction in left ventricular mass index (WMD: -6.25 g/m2 [-12.79, 0.28]; p = 0.06). No significant impact on left ventricular global longitudinal strain was noted (WMD: 0.21% [-0.25, 0.67]; p = 0.38). CONCLUSIONS: Sodium-glucose cotransporter 2 inhibitors improve cardiac structure and function in patients with HFrEF.