Sudden cardiac death due to ventricular arrhythmia in diabetes mellitus: A bench to bedside review.

Diabetes mellitus (DM) confers an increased risk of sudden cardiac death (SCD) independent of its associated cardiovascular comorbidities. Diabetes mellitus induces adverse structural, electrophysiological, and autonomic cardiac remodeling which can increase one's risk of ventricular arrhythmias and SCD. Although glycemic control and prevention of microvascular and macrovascular complications are cornerstones in the management of DM, they are not adequate for the prevention of SCD. In this narrative review, we describe the contribution of DM to the pathophysiology of SCD beyond its role in atherosclerotic cardiovascular disease and heart failure. Based on this pathophysiological framework, we outline potential preventive and therapeutic strategies to mitigate the risk of SCD in this high-risk patient population.

Extrarenal benefits of SGLT2 inhibitors in the treatment of cardiomyopathy.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as pivotal medications for heart failure, demonstrating remarkable cardiovascular benefits extending beyond their glucose-lowering effects. The unexpected cardiovascular advantages have intrigued and prompted the scientific community to delve into the mechanistic underpinnings of these novel actions. Pre-clinical studies have generated many mechanistic theories, ranging from their renal and extra-renal effects to potential direct actions on cardiac muscle cells, to elucidate the mechanisms linking these drugs to clinical cardiovascular outcomes. Despite the strengths and limitations of each theory, many await validation in human studies. Furthermore, whether SGLT2 inhibitors confer therapeutic benefits in specific subsets of cardiomyopathies akin to their efficacy in other heart failure populations remains unclear. By examining the shared pathological features between heart failure resulting from vascular diseases and other causes of cardiomyopathy, certain specific molecular actions of SGLT2 inhibitors (particularly those targeting cardiomyocytes) would support the concept that these medications will yield therapeutic benefits across a broad range of cardiomyopathies. This article aims to discuss important mechanisms of SGLT2 inhibitors and their implications in hypertrophic and dilated cardiomyopathies. Furthermore, we offer insights into future research directions for SGLT2 inhibitor studies, which hold the potential to further elucidate the proposed biological mechanisms in greater detail.

Sodium Zirconium Cyclosilicate in HFrEF and Hyperkalemia: REALIZE-K Design and Baseline Characteristics.

BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF). However, MRAs are often underused because of hyperkalemia concerns. OBJECTIVES: The purpose of this study was to assess whether sodium zirconium cyclosilicate (SZC), a nonabsorbed crystal that traps and rapidly lowers potassium, enables MRA use in patients with HFrEF and prevalent hyperkalemia (or at high risk). METHODS: REALIZE-K is a prospective, double-blind, placebo-controlled trial in patients with HFrEF (NYHA functional class II-IV; left ventricular ejection fraction ≤40%), optimal therapy (except MRA), and prevalent hyperkalemia (or at high risk). During the open-label run-in, all participants underwent protocol-mandated spironolactone titration (target: 50 mg daily); those with prevalent (cohort 1) or incident (cohort 2) hyperkalemia during titration started SZC. Participants achieving normokalemia while on spironolactone ≥25 mg daily were randomized to continuing SZC or matching placebo for 6 months. The primary composite endpoint was proportion of participants with optimal response (normokalemia, on spironolactone ≥25 mg daily, no rescue for hyperkalemia [months 1-6]). RESULTS: Of 365 patients (run-in), 202 were randomized. Baseline characteristics included mean age 70 years, prevalent comorbidities (78% estimated glomerular filtration rate <60 mL/min/1.73 m2, 38% atrial fibrillation/flutter), high N-terminal pro B-type natriuretic peptide (median 1,136 pg/mL), and high HFrEF therapy use (64% sacubitril/valsartan, 96% beta-blocker, 42% sodium glucose co-transporter 2 inhibitor). At randomization, 78% were receiving spironolactone 50 mg daily. CONCLUSIONS: REALIZE-K is the first trial to evaluate whether SZC can enable rapid and safe MRA optimization and long-term continuation in patients with HFrEF and prevalent/high risk of hyperkalemia. (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients with Symptomatic HFrEF Receiving Spironolactone; NCT04676646).

Regulation of the RhoA exchange factor GEF-H1 by pro-fibrotic stimuli through a positive feedback loop involving RhoA, MRTF and Sp1.

RhoA and its effectors, the transcriptional coactivators Myocardin-Related Transcription Factor (MRTF) and Serum Response Factor (SRF), control epithelial phenotype and are indispensable for profibrotic epithelial reprogramming during fibrogenesis. Context-dependent control of RhoA and fibrosis-associated changes in its regulators, however, remain incompletely characterized. We previously identified the guanine nucleotide exchange factor GEF-H1 as a central mediator of RhoA activation in renal tubular cells exposed to inflammatory or fibrotic stimuli. Here we found that GEF-H1 expression and phosphorylation were strongly elevated in two animal models of fibrosis. In the Unilateral Ureteral Obstruction mouse kidney fibrosis model, GEF-H1 was upregulated predominantly in the tubular compartment. GEF-H1 was also elevated and phosphorylated in a rat pulmonary artery banding model of right ventricular fibrosis. Prolonged stimulation of LLC-PK1 tubular cells with tumor necrosis factor-α or transforming growth factor ß1 increased GEF-H1 expression and activated a luciferase-coupled GEF-H1 promoter. Knockdown and overexpression studies revealed that these effects were mediated by RhoA, cytoskeleton remodeling and MRTF, indicative of a positive feed-back cycle. Indeed, silencing endogenous GEF-H1 attenuated activation of the GEF-H1 promoter. Importantly, inhibition of MRTF using CCG-1423 prevented GEF-H1 upregulation in both animal models. MRTF-dependent increase in GEF-H1 was prevented by inhibition of the transcription factor Sp1, and mutating putative Sp1 binding sites in the GEF-H1 promoter eliminated its MRTF-dependent activation. Since the GEF-H1/RhoA axis is key for fibrogenesis, this novel MRTF/Sp1-dependent regulation of GEF-H1 abundance represents a potential target for reducing renal and cardiac fibrosis.

Endothelial progenitor cells for diabetic cardiac and kidney disease.

The management of diabetes mellitus and its resultant end organ dysfunction represents a major challenge to global health-care systems. Diabetic cardiac and kidney disease commonly co-occur and are significant contributors to the morbidity and mortality of patients with diabetes, carrying a poor prognosis. The tight link of these parallel end organ manifestations suggests a deeper common underlying pathology. Here, we outline the mechanistic link between diabetic cardiac and kidney disease, providing evidence for the role of endothelial dysfunction in both processes and the potential for cellular therapy to correct these disorders. Specifically, we review the preclinical and clinical evidence for endothelial progenitor cell therapy in cardiac, kidney, and cardio-renal disease applications. Finally, we outline novel approaches to endothelial progenitor cell therapy through cell enhancement and the use of extracellular vesicles, discussing published and future work.

Prediction of Mortality and Heart Failure Hospitalization After Transcatheter Tricuspid Valve Interventions: Validation of TRISCORE.

BACKGROUND: Data on the prognostic role of the TRI-SCORE in patients undergoing transcatheter tricuspid valve intervention (TTVI) are limited. OBJECTIVES: The aim of this study was to evaluate the performance of the TRI-SCORE in predicting outcomes of patients undergoing TTVI. METHODS: TriValve (Transcatheter Tricuspid Valve Therapies) is a large multicenter multinational registry including patients undergoing TTVI. The TRI-SCORE is a risk model recently proposed to predict in-hospital mortality after tricuspid valve surgery. The TriValve population was stratified based on the TRI-SCORE tertiles. The outcomes of interest were all-cause death and all-cause death or heart failure hospitalization. Procedural complications and changes in NYHA functional class were also reported. RESULTS: Among the 634 patients included, 223 patients (35.2%) had a TRI-SCORE between 0 and 5, 221 (34.8%) had 6 or 7, and 190 (30%) had ≥8 points. Postprocedural blood transfusion, acute kidney injury, new atrial fibrillation, and in-hospital mortality were more frequent in the highest TRI-SCORE tertile. Postprocedure length of stay increased with a TRI-SCORE increase. A TRI-SCORE ≥8 was associated with an increased risk of 30-day all-cause mortality and all-cause mortality and the composite endpoint assessed at a median follow-up of 186 days (OR: 3.00; 95% CI: 1.38-6.55; HR: 2.17; 95% CI: 1.78-4.13; HR: 2.08, 95% CI: 1.57-2.74, respectively) even after adjustment for procedural success and EuroSCORE II or Society of Thoracic Surgeons Predicted Risk of Mortality. The NYHA functional class improved across all TRI-SCORE values. CONCLUSIONS: In the TriValve registry, the TRI-SCORE has a suboptimal performance in predicting clinical outcomes. However, a TRISCORE ≥8 is associated with an increased risk of clinical events and a lack of prognostic benefit after successful TTVI.

Atrial fibrillation in middle-aged athletes: Impact on left atrial, ventricular and exercise performance.

High volume endurance training may increase the risk of paroxysmal atrial fibrillation (AF) in middle-aged athletes. Limited data are available describing the cardiovascular phenotype of middle-aged endurance athletes, or the impact of AF on atrial function and exercise performance performed in sinus rhythm. The purpose of this study was to characterize LA phasic function at rest and during exercise in athletes with paroxysmal AF, and to determine its impact on exercise performance. Fifteen endurance trained males (EA) (56 ± 5 years) without AF and 14 endurance trained males with paroxysmal AF (EA-AF) (55 ± 8 years) underwent echocardiography during cycle-ergometry at light and moderate intensities. Resting LA maximal volumes were similar between EA and EA-AF (30 ± 4 vs. 29 ± 8 ml/m2, p = 0.50), and there were no differences in atrial electromechanical delay (AEMD). During moderate intensity exercise, EA-AF had reduced LA conduit (30 ± 6 vs. 40 ± 5 ml/m2, p = 0.002) LA booster volumes (17 ± 5 vs. 21 ± 4 ml/m2, p = 0.021), and reduced LV stroke volumes (100 ± 12 vs. 117 ± 16 ml, p = 0.007). These results demonstrate that exercise testing in athletes with AF unmasks evidence of adverse functional cardiac remodelling that may contribute to impaired exercise performance. It is unclear whether these functional alterations are the consequence of AF. Reductions in LA conduit volume, LA booster volume, and LV stroke volume during exercise may be helpful in clinical management and distinguishing pathologic from physiologic remodelling.

Exercise-Dependent Modulation of Immunological Response Pathways in Endurance Athletes With and Without Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia characterized by uncoordinated atrial electrical activity. Lone AF occurs in the absence of traditional risk factors and is frequently observed in male endurance athletes, who face a 2- to 5-fold higher risk of AF compared with healthy, moderately active males. Our understanding of how endurance exercise contributes to the pathophysiology of lone AF remains limited. This study aimed to characterize the circulating protein fluctuations during high-intensity exercise as well as explore potential biomarkers of exercise-associated AF. METHODS AND RESULTS: A prospective cohort of 12 male endurance cyclists between the ages of 40 and 65 years, 6 of whom had a history of exercise-associated AF, were recruited to participate using a convenience sampling method. The circulating proteome was subsequently analyzed using multiplex immunoassays and aptamer-based proteomics before, during, and after an acute high-intensity endurance exercise bout to assess temporality and identify potential markers of AF. The endurance exercise bout resulted in significant alterations to proteins involved in immune modulation (eg, growth/differentiation factor 15), skeletal muscle metabolism (eg, α-actinin-2), cell death (eg, histones), and inflammation (eg, interleukin-6). Subjects with AF differed from those without, displaying modulation of proteins previously known to have associations with incident AF (eg, C-reactive protein, insulin-like growth factor-1, and angiopoietin-2), and also with proteins having no previous association (eg, tapasin-related protein and α2-Heremans-Schmid glycoprotein). CONCLUSIONS: These findings provide insights into the proteomic response to acute intense exercise, provide mechanistic insights into the pathophysiology behind AF in athletes, and identify targets for future study and validation.

Effects of tricuspid transcatheter edge-to-edge repair on tricuspid annulus diameter - Data from the TriValve registry.

AIMS: T-TEER is an effective therapy for the treatment of tricuspid regurgitation (TR). However, the effects of leaflets clipping on tricuspid valve annulus (TA) have not been investigated in detail. The aim of this study is to investigate the effects of tricuspid transcatheter edge-to-edge repair (T-TEER) on TA diameter. METHODS AND RESULTS: The TriValve registry (Transcatheter Tricuspid Valve Therapies, NCT03416166) collected 556 patients from 22 European and North American centres undergoing transcatheter tricuspid valve interventions from 2016 to 2022. Patients undergoing T-TEER with available pre- and post-procedural data on TA diameter measured in the apical 4-chamber view on transthoracic echocardiography were selected for this study. Primary end-point was the reduction of TA diameter after T-TEER. A total of 186 patients were included in the study. In 115 patients (62%) TA diameter was reduced by at least 1 mm as compared to baseline. A significant reduction of TA dimension was observed following T-TEER (mean 2.3 mm [from pre-procedural diameter 46.7 mm to post-procedural diameter 44.4 mm], p < 0.001). In particular, the greatest reduction was observed in those with T-TEER in antero-septal commissure (mean 2.7 mm [from 47.1 mm to 44.4 mm], p < 0.001) as compared to those combining both antero-septal and postero-septal commissures (mean 1.4, from 46.0 mm to 44.6 mm, P = 0.06). A significant reduction of TA dimension was recorded in patients with 1 or 2 clips implanted but not in those patients with ≥3 clips implanted. CONCLUSIONS: In almost two third of patients T-TEER reduces TA diameter in addition to leaflet approximation. CONDENSED ABSTRACT: The effects of tricuspid transcatheter edge-to-edge repair (T-TEER) on tricuspid valve annulus (TA) have not been studied in details. This study investigates TA diameter as measured in apical 4-chamber view on transthoracic echocardiography before and after T-TEER. A total of 186 patients from the TriValve registry were included in the study. The study results show that 62% of patients have a TA reduction after T-TEER, especially in those receiving 1 or 2 clips in the antero-septal commissure. These suggest that T-TEER reduces tricuspid regurgitation not only by approximation of leaflets, but also by TA diameter reduction.

Tissue mapping by cardiac magnetic resonance imaging for the prognostication of cardiac amyloidosis: A systematic review and meta-analysis.

BACKGROUND: Cardiac amyloidosis is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality. With the emergence of novel therapies, there is a growing interest in prognostication of patients with cardiac amyloidosis using cardiac magnetic resonance imaging (CMR). In this systematic review and meta-analysis, we aimed to examine the prognostic significance of myocardial native T1 and T2, and extracellular volume (ECV). METHODS: Observational cohort studies or single arms of clinical trials were eligible. MEDLINE, EMBASE and CENTRAL were systematically searched from their respective dates of inception to January 2023. No exclusions were made based on date of publication, study outcomes, or study language. The study populations composed of adult patients (≥18 years old) with amyloid cardiomyopathy. All studies included the use of CMR with and without intravenous gadolinium contrast administration to assess myocardial native T1 mapping, T2 mapping, and ECV in association with the pre-specified primary outcome of all-cause mortality. Data were extracted from eligible primary studies by two independent reviewers and pooled via the inverse variance method using random effects models for meta-analysis. RESULTS: A total of 3852 citations were reviewed. A final nine studies including a total of 955 patients (mean age 65 ± 10 years old, 32% female, mean left ventricular ejection fraction (LVEF) 59 ± 12% and 24% had NYHA class III or IV symptoms) with cardiac amyloidosis [light chain amyloidosis (AL) 50%, transthyretin amyloidosis (ATTR) 49%, other 1%] were eligible for inclusion and suitable for data extraction. All included studies were single centered (seven with 1.5 T MRI scanners, two with 3.0 T MRI scanners) and non-randomized in design, with follow-up spanning from 8 to 64 months (median follow-up = 25 months); 320 patients died during follow-up, rendering a weighted mortality rate of 33% across studies. Compared with patients with AL amyloid, patients with ATTR amyloid had significantly higher mean left ventricular mass index (LVMi) (102 ± 34 g/m2 vs 127 ± 37 g/m2, p = 0.02). N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin T levels, mean native T1 values, ECV and T2 values did not differ between patients with ATTR amyloid and AL amyloid (all p > 0.25). Overall, the hazard ratios for mortality were 1.33 (95% CI = [1.10, 1.60]; p = 0.003; I2 = 29%) for every 60 ms higher T1 time, 1.16 (95% CI = [1.09, 1.23], p < 0.0001; I2 = 76%) for every 3% higher ECV, and 5.23 (95% CI = [2.27, 12.02]; p < 0.0001; I2 = 0%) for myocardial-to-skeletal T2 ratio below the mean (vs above the mean). CONCLUSION: Higher native T1 time and ECV, and lower myocardial to skeletal T2 ratio, on CMR are associated with worse mortality in patients with cardiac amyloidosis. Therefore, tissue mapping using CMR may offer a useful non-invasive technique to monitor disease progression and determine prognosis in patients with cardiac amyloidosis.

Evaluating a novel accelerated free-breathing late gadolinium enhancement imaging sequence for assessment of myocardial injury.

INTRODUCTION: Cardiac magnetic resonance imaging (MRI), including late gadolinium enhancement (LGE), plays an important role in the diagnosis and prognostication of ischemic and non-ischemic myocardial injury. Conventional LGE sequences require patients to perform multiple breath-holds and require long acquisition times. In this study, we compare image quality and assessment of myocardial LGE using an accelerated free-breathing sequence to the conventional standard-of-care sequence. METHODS: In this prospective cohort study, a total of 41 patients post Coronavirus 2019 (COVID-19) infection were included. Studies were performed on a 1.5 Tesla scanner with LGE imaging acquired using a conventional inversion recovery rapid gradient echo (conventional LGE) sequence followed by the novel accelerated free-breathing (FB-LGE) sequence. Image quality was visually scored (ordinal scale from 1 to 5) and compared between conventional and free-breathing sequences using the Wilcoxon rank sum test. Presence of per-segment LGE was identified according to the American Heart Association 16-segment myocardial model and compared across both conventional LGE and FB-LGE sequences using a two-sided chi-square test. The perpatient LGE extent was also evaluated using both sequences and compared using the Wilcoxon rank sum test. Interobserver variability in detection of per-segment LGE and per-patient LGE extent was evaluated using Cohen's kappa statistic and interclass correlation (ICC), respectively. RESULTS: The mean acquisition time for the FB-LGE sequence was 17 s compared to 413 s for the conventional LGE sequence (P < 0.001). Assessment of image quality was similar between both sequences (P = 0.19). There were no statistically significant differences in LGE assessed using the FB-LGE versus conventional LGE on a per-segment (P = 0.42) and per-patient (P = 0.06) basis. Interobserver variability in LGE assessment for FB-LGE was good for per-segment (= 0.71) and per-patient extent (ICC = 0.92) analyses. CONCLUSIONS: The accelerated FB-LGE sequence performed comparably to the conventional standard-of-care LGE sequence in a cohort of patients post COVID-19 infection in a fraction of the time and without the need for breath-holding. Such a sequence could impact clinical practice by increasing cardiac MRI throughput and accessibility for frail or acutely ill patients unable to perform breath-holding.

Vascular Regenerative Cell Deficiencies in South Asian Adults.

BACKGROUND: South Asian individuals shoulder a disproportionate burden of cardiometabolic diseases. OBJECTIVES: The purpose of this study was to determine if vascular regenerative cell content varies significantly between South Asian and White European people. METHODS: Between January 2022 and January 2023, 60 South Asian and 60 White European adults with either documented cardiovascular disease or established diabetes with ≥1 other cardiovascular risk factor were prospectively enrolled. Vascular regenerative cell content in venous blood was enumerated using a flow cytometry assay that is based on high aldehyde dehydrogenase (ALDHhi) activity and cell surface marker phenotyping. The primary outcome was the difference in frequency of circulating ALDHhi progenitor cells, monocytes, and granulocytes between the 2 groups. RESULTS: Compared with White European participants, those of South Asian ethnicity were younger (69 ± 10 years vs 66 ± 9 years; P < 0.05), had lower weight (88 ± 19 kg vs 75 ± 13 kg; P < 0.001), and exhibited a greater prevalence of type 2 diabetes (62% vs 92%). South Asian individuals had markedly lower circulating frequencies of pro-angiogenic ALDHhiSSClowCD133+ progenitor cells (P < 0.001) and ALDHhiSSCmidCD14+CD163+ monocytes with vessel-reparative capacity (P < 0.001), as well as proportionally more ALDHhi progenitor cells with high reactive oxygen species content (P < 0.05). After correction for sex, age, body mass index, and glycated hemoglobin, South Asian ethnicity was independently associated with lower ALDHhiSSClowCD133+ cell count. CONCLUSIONS: South Asian people with cardiometabolic disease had less vascular regenerative and reparative cells suggesting compromised vessel repair capabilities that may contribute to the excess vascular risk in this population. (The Role of South Asian vs European Origins on Circulating Regenerative Cell Exhaustion [ORIGINS-RCE]; NCT05253521).

Bilateral nephrectomy impairs cardiovascular function and cerebral perfusion in a rat model of acute hemodilutional anemia.

Anemia and renal failure are independent risk factors for perioperative stroke, prompting us to assess the combined impact of acute hemodilutional anemia and bilateral nephrectomy (2Nx) on microvascular brain Po2 (PBro2) in a rat model. Changes in PBro2 (phosphorescence quenching) and cardiac output (CO, echocardiography) were measured in different groups of anesthetized Sprague-Dawley rats (1.5% isoflurane, n = 5-8/group) randomized to Sham 2Nx or 2Nx and subsequently exposed to acute hemodilutional anemia (50% estimated blood volume exchange with 6% hydroxyethyl starch) or time-based controls (no hemodilution). Outcomes were assessed by ANOVA with significance assigned at P < 0.05. At baseline, 2Nx rats demonstrated reduced CO (49.9 ± 9.4 vs. 66.3 ± 19.3 mL/min; P = 0.014) and PBro2 (21.1 ± 2.9 vs. 32.4 ± 3.1 mmHg; P < 0.001) relative to Sham 2Nx rats. Following hemodilution, 2Nx rats demonstrated a further decrease in PBro2 (15.0 ± 6.3 mmHg, P = 0.022). Hemodiluted 2Nx rats did not demonstrate a comparable increase in CO after hemodilution compared with Sham 2Nx (74.8 ± 22.4 vs. 108.9 ± 18.8 mL/min, P = 0.003) that likely contributed to the observed reduction in PBro2. This impaired CO response was associated with reduced fractional shortening (33 ± 9 vs. 51 ± 5%) and increased left ventricular end-systolic volume (156 ± 51 vs. 72 ± 15 µL, P < 0.001) suggestive of systolic dysfunction. By contrast, hemodiluted Sham 2Nx animals demonstrated a robust increase in CO and preserved PBro2. These data support the hypothesis that the kidney plays a central role in maintaining cerebral perfusion and initiating the adaptive increase in CO required to optimize PBro2 during acute anemia.NEW & NOTEWORTHY This study has demonstrated that bilateral nephrectomy acutely impaired cardiac output (CO) and microvascular brain Po2 (PBro2), at baseline. Following acute hemodilution, nephrectomy prevented the adaptive increase in CO associated with acute hemodilution leading to a further reduction in PBro2, accentuating the degree of cerebral tissue hypoxia. These data support a role for the kidney in maintaining PBro2 and initiating the increase in CO that optimized brain perfusion during acute anemia.

The effectiveness of sodium-glucose co-transporter 2 inhibitors on cardiorenal outcomes: an updated systematic review and meta-analysis.

BACKGROUND: The 2022 Canadian Cardiovascular Society (CCS) cardiorenal guideline provided clinical recommendations on sodium-glucose co-transport 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) use. Since then, additional trials of relevance for SGLT2i have been published. This update re-evaluates the clinical recommendations for using SGLTi and their indirect comparison with existing evidence on GLP-1RA as compared to the standard of care to reduce cardiorenal morbidity and mortality. METHODS: We updated our existing search and screening of the literature from September 2021 to April 2023 for randomized controlled trials of SGLT2i and GLP-1RA with placebo control. We conducted risk of bias assessment, data extraction and updated our meta-analysis of studies with similar interventions and components. The certainty of the evidence was determined using GRADE. RESULTS: Evidence from three new trials and additional results from an updated existing trial on SGLT2i met our inclusion criteria after an updated search. Across all the included studies, the total sample size was 151,023 adults, with 90,943 in SGLT2i trials and 60,080 in GLP-1 RA trials. The mean age ranged from 59.9 to 68.4 years. Compared with standard care, the use of SGLT2i and GLP-1 RA showed significant reductions in the outcomes of cardiovascular (CV) mortality (14% & 13%), any-cause mortality (12% & 12%), major adverse CV events (MACE) (11% & 14%), heart failure (HF) hospitalization (30% & 9%), CV death or HF hospitalization (23% & 11%), and kidney composite outcome (32% & 22%). In participants with T2D, both classes demonstrated significant cardiorenal protection. But, only GLP-1RA showed a reduction in non-fatal stroke (16%) and only SGLT2i showed a reduction in HF hospitalization (30%) in this population of people living with T2D. CONCLUSIONS: This updated and comprehensive meta-analysis substantiates and strengthens the clinical recommendations of the CCS cardiorenal guidelines.

Obesity/cardiometabolic phenotype of heart failure with preserved ejection fraction: mechanisms to recent trials.

PURPOSE OF REVIEW: Heart failure with preserved ejection fraction (HFpEF) is a leading and growing cause of morbidity and mortality globally. Of the various phenotypes identified, the obesity (or cardiometabolic) phenotype appears to be most common. The purpose of this review is to provide the clinician with an abridged understanding of recent developments that have elucidated obesity/visceral adiposity as a central mechanism linking inflammation/immune dysregulation to the development of the HFpEF syndrome. Recent clinical trials examining the efficacy of pharmacological treatments that target obesity in HFpEF will also be discussed. RECENT FINDINGS: Recent data indicate that visceral adiposity and insulin resistance in HFpEF serve as key mechanisms driving inflammation and immune dysregulation, which play a critical role in the development of cardiac stiffness, diastolic dysfunction and fibrosis in HFpEF. In obesity, alterations in macrophage polarization, changes in innate and adaptive immune systems and altered myocardial energetics promote metabolic inflammation in HFpEF. Finally, emerging data suggest that inflammatory biomarkers, specifically, IL-6, may provide useful information about HFpEF severity and symptom burden in obesity. SUMMARY: The obesity phenotype of HFpEF is seen in upward of 80% with HFpEF. Obesity is not just a bystander, but plays an essential role in the pathobiology and clinical course of HFpEF. Targeting overweight/obesity in HFpEF with GLP-1 receptor agonists holds promise in these patients.

The Canadian Cardiovascular Society Classification of Acute Atherothrombotic Myocardial Infarction Based on Stages of Tissue Injury Severity: An Expert Consensus Statement.

Myocardial infarction (MI) remains a leading cause of morbidity and mortality. In atherothrombotic MI (ST-elevation MI and type 1 non-ST-elevation MI), coronary artery occlusion leads to ischemia. Subsequent cardiomyocyte necrosis evolves over time as a wavefront within the territory at risk. The spectrum of ischemia and reperfusion injury is wide: it can be minimal in aborted MI or myocardial necrosis can be large and complicated by microvascular obstruction and reperfusion hemorrhage. Established risk scores and infarct classifications help with patient management but do not consider tissue injury characteristics. This document outlines the Canadian Cardiovascular Society classification of acute MI. It is an expert consensus formed on the basis of decades of data on atherothrombotic MI with reperfusion therapy. Four stages of progressively worsening myocardial tissue injury are identified: (1) aborted MI (no/minimal myocardial necrosis); (2) MI with significant cardiomyocyte necrosis, but without microvascular injury; (3) cardiomyocyte necrosis and microvascular dysfunction leading to microvascular obstruction (ie, "no-reflow"); and (4) cardiomyocyte and microvascular necrosis leading to reperfusion hemorrhage. Each stage reflects progression of tissue pathology of myocardial ischemia and reperfusion injury from the previous stage. Clinical studies have shown worse remodeling and increase in adverse clinical outcomes with progressive injury. Notably, microvascular injury is of particular importance, with the most severe form (hemorrhagic MI) leading to infarct expansion and risk of mechanical complications. This classification has the potential to stratify risk in MI patients and lay the groundwork for development of new, injury stage-specific and tissue pathology-based therapies for MI.

Relationship between saxagliptin use and left ventricular diastolic function assessed by cardiac MRI.

AIMS: Type 2 diabetes mellitus (T2DM) increases the risk of major cardiovascular events. In SAVOR-TIMI53 trial, the excess heart failure (HF) hospitalization among patients with T2DM in the saxagliptin group remains poorly understood. Our aim was to evaluate left ventricular (LV) diastolic function after 6 months of saxagliptin treatment using cardiac magnetic resonance imaging (CMR) in patients with T2DM. METHODS: In this prospective study, 16 T2DM patients without HF were prescribed saxagliptin as part of routine guideline-directed management. CMR performed at baseline and 6 months after initiation of saxagliptin treatment were evaluated in a blinded fashion. We assessed LV diastolic function by measuring LV peak filling rate with correction for end-diastolic volume (PFR/LVEDV), time to peak filling rate with correction for cardiac cycle (TPF/RR), and early diastolic strain rate parameters [global longitudinal diastolic strain rate (GLSR-E), global circumferential diastolic strain rate (GCSR-E)] by feature tracking (FT-CMR). RESULTS: Among the 16 patients (mean age of 59.9, 69% males, mean hemoglobin A1c 8.3%, mean left ventricular ejection fraction 57%), mean PFR was 314 ± 108 ml/s at baseline and did not change over 6 months (- 2.7, 95% CI - 35.6, 30.2, p = 0.86). There were also no significant changes in other diastolic parameters including PFR/EDV, TPF, TPF/RR, and GLSR-E and GCSR-E (all p > 0.50). CONCLUSION: In T2DM patients without HF receiving saxagliptin over 6 months, there were no significant subclinical changes in LV diastolic function as assessed by CMR.

The effect of chronic exercise training and acute exercise on power spectral analysis of heart rate variability.

Moderate to vigorous physical activity performed regularly is cardioprotective and reduces all-cause mortality, concomitant with increased resting heart rate variability (HRV). However, there are contradictory reports regarding the effects of chronic and acute exercise on nocturnal HRV in those performing exercise well-beyond physical activity guidelines. Therefore, the purpose of this study was to compare the power spectral analysis components of HRV in middle-aged endurance athletes (EA) and recreationally active individuals (REC) and explore acute exercise effects in EA. A total of 119 EA (52, 49-57 years) and 32 REC (56, 52-60 years) were recruited to complete 24 h Holter monitoring (GE SEER 1000) in the absence of exercise. Fifty one EA (52, 49-57 years) then underwent 24 h Holter monitoring following an intense bout of endurance exercise. Power spectral HRV analysis was completed hourly and averaged to quantify morning (1000-1200 h), evening (1900-2100 h), and nocturnal (0200-0400 h) HRV. EA had greater very low frequency (VLF) and low frequency (LF) (both p < 0.001) compared to REC. LF/high frequency (HF) was greater in EA at 0200-0400 h (p = 0.04). Among all participants, the change in HR and HF from 1000-1200 to 0200-0400 h was negatively correlated (r = -0.47, p < 0.001). Following acute exercise in EA, only nocturnal HRV was assessed. VLF (p < 0.001) and HF (p = 0.008) decreased, while LF/HF increased (p = 0.02). These results suggest that in EA, both long-term and acute exercises increase nocturnal sympathovagal activity through an increase in LF and decrease in HF, respectively. Further work is required to understand the mechanism underlying reduced nocturnal HRV in middle-aged EA and the long-term health implications.

Aldosterone and aldosterone synthase inhibitors in cardiorenal disease.

Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance.

Effect of empagliflozin on cardiac remodelling in South Asian and non-South Asian individuals: insights from the EMPA-HEART CardioLink-6 randomised clinical trial.

BACKGROUND: This exploratory sub-analysis of the EMPA-HEART CardioLink-6 trial examined whether the previously reported benefit of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin on left ventricular (LV) mass (LVM) regression differs between individuals of South Asian and non-South Asian ethnicity. METHODS: EMPA-HEART CardioLink-6 was a double-blind, placebo-controlled clinical trial that randomised 97 individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) to either empagliflozin 10 mg daily or placebo for 6 months. LV parameters and function were assessed using cardiac magnetic resonance imaging. The 6-month changes in LVM and LV volumes, all indexed to baseline body surface area, for South Asian participants were compared to those for non-South Asian individuals. RESULTS: Compared to the non-South Asian group, the South Asian sub-cohort comprised more males, was younger and had a lower median body mass index. The adjusted difference for LVMi change over 6 months was -4.3 g/m2 (95% confidence interval [CI], -7.5, -1.0; P = 0.042) for the South Asian group and -2.3 g/m2 (95% CI, -6.4, 1.9; P = 0.28) for the non-South Asian group (Pinteraction = 0.45). There was no between-group difference for the adjusted differences in baseline body surface area-indexed LV volumes and LV ejection fraction. CONCLUSIONS: There was no meaningful difference in empagliflozin-associated LVM regression between South Asian and non-South Asian individuals living with T2DM and CAD in the EMPA-HEART CardioLink-6 trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02998970 (First posted on 21/12/ 2016).