GLP-1 receptor agonists and atherosclerosis protection: the vascular endothelium takes center stage.

Atherosclerotic cardiovascular disease is a chronic condition that often copresents with type 2 diabetes and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin mimetics endorsed by major professional societies for improving glycemic status and reducing atherosclerotic risk in people living with type 2 diabetes. Although the cardioprotective efficacy of GLP-1RAs and their relationship with traditional risk factors are well established, there is a paucity of publications that have summarized the potentially direct mechanisms through which GLP-1RAs mitigate atherosclerosis. This review aims to narrow this gap by providing comprehensive and in-depth mechanistic insight into the antiatherosclerotic properties of GLP-1RAs demonstrated across large outcome trials. Herein, we describe the landmark cardiovascular outcome trials that triggered widespread excitement around GLP-1RAs as a modern class of cardioprotective agents, followed by a summary of the origins of GLP-1RAs and their mechanisms of action. The effects of GLP-1RAs at each major pathophysiological milestone of atherosclerosis, as observed across clinical trials, animal models, and cell culture studies, are described in detail. Specifically, this review provides recent preclinical and clinical evidence that suggest GLP-1RAs preserve vessel health in part by preventing endothelial dysfunction, achieved primarily through the promotion of angiogenesis and inhibition of oxidative stress. These protective effects are in addition to the broad range of atherosclerotic processes GLP-1RAs target downstream of endothelial dysfunction, which include systemic inflammation, monocyte recruitment, proinflammatory macrophage and foam cell formation, vascular smooth muscle cell proliferation, and plaque development.

Icosapent ethyl modulates circulating vascular regenerative cell content: The IPE-PREVENTION CardioLink-14 trial.

BACKGROUND: REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) showed that icosapent ethyl (IPE) reduced major adverse cardiovascular events by 25%. Since the underlying mechanisms for these benefits are not fully understood, the IPE-PREVENTION CardioLink-14 trial (ClinicalTrials.gov: NCT04562467) sought to determine if IPE regulates vascular regenerative (VR) cell content in people with mild to moderate hypertriglyceridemia. METHODS: Seventy statin-treated individuals with triglycerides ≥1.50 and <5.6 mmol/L and either atherosclerotic cardiovascular disease or type 2 diabetes with additional cardiovascular risk factors were randomized to IPE (4 g/day) or usual care. VR cells with high aldehyde dehydrogenase activity (ALDHhi) were isolated from blood collected at the baseline and 3-month visits and characterized with lineage-specific cell surface markers. The primary endpoint was the change in frequency of pro-vascular ALDHhiside scatter (SSC)lowCD133+ progenitor cells. Change in frequencies of ALDHhiSSCmid monocyte and ALDHhiSSChi granulocyte precursor subsets, reactive oxygen species production, serum biomarkers, and omega-3 levels were also evaluated. FINDINGS: Baseline characteristics, cardiovascular risk factors, and medications were balanced between the groups. Compared to usual care, IPE increased the mean frequency of ALDHhiSSClowCD133+ cells (-1.00% ± 2.45% vs. +7.79% ± 1.70%; p = 0.02), despite decreasing overall ALDHhiSSClow cell frequency. IPE assignment also reduced oxidative stress in ALDHhiSSClow progenitors and increased ALDHhiSSChi granulocyte precursor cell content. CONCLUSIONS: IPE-PREVENTION CardioLink-14 provides the first translational evidence that IPE can modulate VR cell content and suggests a novel mechanism that may underlie the cardioprotective effects observed with IPE in REDUCE-IT. FUNDING: HLS Therapeutics provided the IPE in kind and had no role in the study design, conduct, analyses, or interpretation.

Restoration of blood vessel regeneration in the era of combination SGLT2i and GLP-1RA therapy for diabetes and obesity.

Ischaemic cardiovascular diseases, including peripheral and coronary artery disease, myocardial infarction, and stroke, remain major comorbidities for individuals with type 2 diabetes (T2D) and obesity. During cardiometabolic chronic disease (CMCD), hyperglycaemia and excess adiposity elevate oxidative stress and promote endothelial damage, alongside an imbalance in circulating pro-vascular progenitor cells that mediate vascular repair. Individuals with CMCD demonstrate pro-vascular 'regenerative cell exhaustion' (RCE) characterized by excess pro-inflammatory granulocyte precursor mobilization into the circulation, monocyte polarization towards pro-inflammatory vs. anti-inflammatory phenotype, and decreased pro-vascular progenitor cell content, impairing the capacity for vessel repair. Remarkably, targeted treatment with the sodium-glucose cotransporter-2 inhibitor (SGLT2i) empagliflozin in subjects with T2D and coronary artery disease, and gastric bypass surgery in subjects with severe obesity, has been shown to partially reverse these RCE phenotypes. SGLT2is and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped the management of individuals with T2D and comorbid obesity. In addition to glucose-lowering action, both drug classes have been shown to induce weight loss and reduce mortality and adverse cardiovascular outcomes in landmark clinical trials. Furthermore, both drug families also act to reduce systemic oxidative stress through altered activity of overlapping oxidase and antioxidant pathways, providing a putative mechanism to augment circulating pro-vascular progenitor cell content. As SGLT2i and GLP-1RA combination therapies are emerging as a novel therapeutic opportunity for individuals with poorly controlled hyperglycaemia, potential additive effects in the reduction of oxidative stress may also enhance vascular repair and further reduce the ischaemic cardiovascular comorbidities associated with T2D and obesity.

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).

Association of Cerebral Oximetry With Brain Ischemic Lesions and Functional Outcomes in Arch Repair.

BACKGROUND: This exploratory analysis of the randomized controlled Aortic Surgery Cerebral Protection Evaluation CardioLink-3 trial sought to determine if cerebral oximetry desaturation during elective proximal arch repair is associated with detrimental postoperative neuroradiologic and neurofunctional outcomes. METHODS: Cerebral oximetry and pre- and postoperative brain magnetic resonance imaging data from 101 participants were analyzed. Oximetry data from the trial allocation groups were compared; the relationships between cerebral oximetry indices and new ischemic cerebral lesions on magnetic resonance imaging and neurologic outcomes were also evaluated. RESULTS: Total cerebral desaturation events (>20% decrease from baseline) on the left (median [interquartile range], 1 [1-3] vs 1.5 [0.5-3] with innominate and axillary cannulation; P = .80) were comparable to those on the right (1 [1-3] vs 1 [0-3]; P = .75) as were the total area under the curve of desaturation (left, P = .61; right, P = .84). Seventy patients had new ischemic lesions, among whom 36 had new severe lesions. Total desaturation events and area under the curve of desaturation were similar in patients with and without new ischemic lesions or severe lesions. The nadir regional cerebral saturation was lower on the left (49% [41-56]) than the right (53% [44-59]); left desaturation episodes were associated with lower postoperative cognitive test scores (P = .004). CONCLUSIONS: The innominate and axillary cannulation techniques for elective proximal arch repair with unilateral antegrade cerebral perfusion were associated with similar occurrences of cerebral oximetry desaturation and neither were associated with new ischemic lesions.

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).

Glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor co-agonists for cardioprotection, type 2 diabetes and obesity: a review of mechanisms and clinical data.

PURPOSE OF REVIEW: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection. RECENT FINDINGS: Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D. SUMMARY: GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.

Empagliflozin improves circulating vascular regenerative cell content in people without diabetes with risk factors for adverse cardiac remodeling.

Sodium glucose-cotransporter 2 (SGLT2) inhibitors have been reported to reduce cardiovascular events and heart failure in people with and without diabetes. These medications have been shown to counter regenerative cell exhaustion in the context of prevalent diabetes. This study sought to determine if empagliflozin attenuates regenerative cell exhaustion in people without diabetes. Peripheral blood mononuclear cells were collected at the baseline and 6-mo visits from individuals randomized to receive empagliflozin (10 mg/day) or placebo who were participating in the EMPA-HEART 2 CardioLink-7 trial. Precursor cell phenotypes were characterized by flow cytometry for cell-surface markers combined with high aldehyde dehydrogenase activity to identify precursor cell subsets with progenitor (ALDHhi) versus mature effector (ALDHlow) cell attributes. Samples from individuals assigned to empagliflozin (n = 25) and placebo (n = 21) were analyzed. At baseline, overall frequencies of primitive progenitor cells (ALDHhiSSClow), monocyte (ALDHhiSSCmid), and granulocyte (ALDHhiSSChi) precursor cells in both groups were similar. At 6 mo, participants randomized to empagliflozin demonstrated increased ALDHhiSSClowCD133+CD34+ proangiogenic cells (P = 0.048), elevated ALDHhiSSCmidCD163+ regenerative monocyte precursors (P = 0.012), and decreased ALDHhiSSCmidCD86 + CD163- proinflammatory monocyte (P = 0.011) polarization compared with placebo. Empagliflozin promoted the recovery of multiple circulating provascular cell subsets in people without diabetes suggesting that the cardiovascular benefits of SGLT2 inhibitors may be attributed in part to the attenuation of vascular regenerative cell exhaustion that is independent of diabetes status.NEW & NOTEWORTHY Using an aldehyde dehydrogenase (ALDH) activity-based flow cytometry assay, we found that empagliflozin treatment for 6 mo was associated with parallel increases in circulating vascular regenerative ALDHhi-CD34/CD133-coexpressing progenitors and decreased proinflammatory ALDHhi-CD14/CD86-coexpressing monocyte precursors in individuals without diabetes but with cardiovascular risk factors. The rejuvenation of the vascular regenerative cell reservoir may represent a mechanism via which sodium glucose-cotransporter 2 (SGLT2) inhibitors limit maladaptive repair and delay the development and progression of cardiovascular diseases.

Wearable Cardiac Rhythm Monitoring Device for Detection of Postoperative Atrial Fibrillation.

PURPOSE: This study evaluated the use of a wearable, patch-based cardiac rhythm monitoring device in detecting postoperative atrial fibrillation (POAF) among cardiac surgical patients within 30 days after hospital discharge. DESCRIPTION: From the SEARCH-AF (The Post-Surgical Enhanced Monitoring for Cardiac Arrhythmias and Atrial Fibrillation) CardioLink-1 trial, this study examined rates of POAF according to surgery type and the incremental value of continuous cardiac rhythm monitoring among patients who underwent valve surgery. The primary outcome was cumulative atrial fibrillation or atrial flutter lasting for ≥6 minutes detected by continuous monitoring or atrial fibrillation or atrial flutter documented by a 12-lead electrocardiogram within 30 days of randomization. EVALUATION: The primary outcome occurred in 8.2%, 13.5%, and 21.2% of patients who underwent isolated coronary artery bypass grafting (CABG), isolated valve surgery, and combined CABG and valve surgery. Relative to patients who underwent isolated CABG, those patients who had valve surgery were more likely to experience POAF. A higher diagnostic yield was obtained when the patch-based cardiac rhythm monitor was applied in patients who underwent valve surgery. CONCLUSIONS: Use of a wearable, patch-based cardiac monitoring device was an effective detection strategy among patients undergoing valve surgery, given their higher risk of developing POAF.

Left ventricular mass predicts cardiac reverse remodelling in patients treated with empagliflozin.

BACKGROUND: The cardiovascular (CV) benefits of sodium-glucose transport protein 2 inhibitors have been attributed, in part, to cardiac reverse remodelling. The EMPA-HEART CardioLink-6 study reported that sodium-glucose cotransporter-2 inhibition for 6 months with empagliflozin was associated with a significant reduction in left ventricular mass indexed to body surface area (LVMi). In this sub-analysis, we evaluated whether baseline LVMi may influence how empagliflozin affects cardiac reverse remodelling. METHODS: A total of 97 patients with type 2 diabetes and coronary artery disease were randomized to empagliflozin (10 mg/d) or matching placebo for 6 months. The study cohort was divided into those whose baseline LVMi was ≤ 60 g/m2 and those who had a baseline LVMi > 60 g/m2. Subgroup comparisons were conducted using a linear regression model adjusted for baseline values (ANCOVA) that included an interaction term between LVMi subgroup and treatment. RESULTS: Baseline LVMi was 53.3 g/m2 (49.2-57.2) and 69.7 g/m2 (64.2-76.1) for those with baseline ≤ 60 g/m2 (n = 54) and LVMi > 60 g/m2 (n = 43) respectively. The adjusted difference of LVMi regression between those randomized to empagliflozin and placebo were - 0.46 g/m2 (95% CI: -3.44, 2.52, p = 0.76) in the baseline LVMi ≤ 60 g/m2 subgroup and - 7.26 g/m2 (95% CI: -11.40, -3.12, p = 0.0011) in the baseline LVMi > 60 g/m2 subgroup (p-for-interaction = 0.007). No significant associations were found between baseline LVMi and 6-month change in LV end systolic volume-indexed (p-for-interaction = 0.086), LV end diastolic volume-indexed (p-for-interaction = 0.34), or LV ejection fraction (p-for-interaction = 0.15). CONCLUSIONS: Patients with higher LVMi at baseline experienced greater LVM regression with empagliflozin.

The Impact of Statins on Postdischarge Atrial Fibrillation After Cardiac Surgery: Secondary Analysis from a Randomized Trial.

Background: Whether statins reliably reduce the risk of postoperative atrial fibrillation (POAF) in patients undergoing cardiac surgery remains controversial. We sought to determine the impact of statin use on new-onset postdischarge POAF in the Post-Surgical Enhanced Monitoring for Cardiac Arrhythmias and Atrial Fibrillation (SEARCH-AF) CardioLink-1 randomized controlled trial. Methods: We randomized 336 patients with risk factors for stroke (CHA2DS2-VASc score ≥ 2) and no history of preoperative atrial fibrillation (AF) to 30-day continuous cardiac rhythm monitoring after discharge from cardiac surgery with a wearable, patched-based device or to usual care. The primary endpoint was the occurrence of cumulative AF and/or atrial flutter lasting for ≥ 6 minutes detected by continuous monitoring, or AF and/or atrial flutter documented by a 12-lead electrocardiogram within 30 days of randomization. Results: The 260 patients (77.4%) discharged on statins were more likely to be male (P = 0.018) and to have lower CHA2DS2-VASc scores (P = 0.011). Patients treated with statins at discharge had a 2-fold lower rate of POAF than those who were not treated with statins in the entire cohort (18.4% vs 8.1%, log-rank P = 0.0076). On multivariable Cox regression including the CHA2DS2-VASc score adjustment, statin use was associated with a lower risk of POAF (hazard ratio 0.43, 95% confidence interval: 0.25-0.98, P = 0.043). Use of statins at a higher intensity was associated with lower risk of POAF, suggestive of a dose-response effect (log-rank P trend = 0.0082). Conclusions: The use of statins was associated with a reduction in postdischarge POAF risk among patients undergoing cardiac surgery. The routine use of high-intensity statin to prevent subacute POAF after discharge deserves further study.

Contexte: L'efficacité des statines dans la réduction du risque de fibrillation auriculaire postopératoire (FAPO) chez les patients ayant subi une chirurgie cardiaque ne fait pas l'unanimité. Nous avons tenté de déterminer l'effet de l'utilisation des statines sur la survenue d'une FAPO inaugurale consécutive au congé de l'hôpital dans l'essai SEARCH-AF CardioLink-1, un essai contrôlé à répartition aléatoire sur le suivi étroit en postopératoire des arythmies cardiaques et de la fibrillation auriculaire. Méthodologie: Nous avons réparti aléatoirement 336 patients présentant des facteurs de risque d'AVC (score CHA2DS2-VASc ≥ 2) sans antécédents de fibrillation auriculaire (FA) préopératoire dans deux groupes : les patients du premier groupe étaient équipés d'un dispositif portable sous forme de timbre pour la surveillance continue du rythme cardiaque pendant 30 jours après la sortie de l'hôpital suivant une chirurgie cardiaque; les patients du second groupe étaient suivis de façon conventionnelle. Le critère d'évaluation principal était la survenue cumulative de FA et/ou de flutter auriculaire durant ≥ 6 minutes détecté par la surveillance continue, ou la FA et/ou le flutter auriculaire confirmé par un électrocardiogramme à 12 dérivations dans les 30 jours suivant la répartition aléatoire. Résultats: Les 260 patients (77,4 %) prenant des statines à leur congé de l'hôpital étaient plus susceptibles d'être des hommes (p = 0,018) et d'avoir un score CHA2DS2-VASc plus faible (p = 0,011). Les patients traités par des statines à leur congé de l'hôpital avaient deux fois moins de risques de présenter une FAPO que les patients ne recevant pas de statines dans l'ensemble de la cohorte (18,4 % contre 8,1 %, valeur de p calculée selon le test de Mantel-Haenszel = 0,0076). Dans une régression de Cox multivariable incluant l'ajustement du score CHA2DS2-VASc, l'utilisation des statines a été associée à un risque moindre de FAPO (rapport des risques instantanés : 0,43, intervalle de confiance à 95 % de 0,25 à 0,98; p = 0,043). L'utilisation de statines à plus fortes doses a été associée à un risque moindre de FAPO, ce qui laisse croire à un effet dose-réponse (valeur de p de tendance selon le test de Mantel-Haenszel = 0,0082). Conclusions: L'utilisation de statines est associée à une réduction du risque de FAPO après le congé de l'hôpital chez les patients ayant subi une chirurgie cardiaque. L'utilisation systématique de statines à fortes doses pour prévenir la FAPO subaiguë après le congé d'hôpital mérite une étude plus approfondie.

Impact of diabetes duration on left ventricular mass regression with empagliflozin.

AIMS: The duration of type 2 diabetes mellitus (T2DM) is an important determinant of diabetes severity. The EMPA-HEART CardioLink-6 trial reported significant left ventricular (LV) mass indexed to body surface area (LVMi) regression in patients treated with the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin for 6 months. This exploratory sub-analysis of the same trial investigated the association between T2DM duration and LVMi regression. METHODS AND RESULTS: A total of 97 individuals with T2DM and coronary artery disease (CAD) were randomly assigned to receive empagliflozin 10 mg daily or placebo. LVMi was measured at the baseline and 6 month visit using cardiac magnetic resonance imaging. The study population was divided into those with a baseline T2DM duration <10 years (n = 40) or ≥10 years (n = 57). A linear model adjusting for baseline values in each of the subgroups (ANCOVA) was used to assess the treatment effect of 6 month change in LVMi, LV end systolic volume indexed to body surface area, LV end diastolic volume indexed to body surface area and LV ejection fraction. Patients in the T2DM duration <10 years group (38 males [95.0%], median age 63 [IQR: 55 years to 70 years]) had a median T2DM duration of 4 years (IQR: 2.0 years to 7.0 years). Those in the T2DM duration ≥10 years group (52 males [91.2%], median age 65 [IQR: 57 years to 71 years]) had a median duration of 15 years (IQR: 12 years to 20 years). There was no significant difference in baseline LVMi according to T2DM duration (median 62 g/m2 [IQR: 53.1 g/m2 to 70.0 g/m2 ] for T2DM duration <10 years; median 57.5 g/m2 [IQR: 52.1 g/m2 to 66.2 g/m2 ] for T2DM duration ≥10 years; P = 0.11). Empagliflozin was associated with reductions in LVMi irrespective of duration of T2DM above and below 10 years (T2DM duration <10 years group, mean adjusted difference -2.90 g/m2 [95% CI: -6.64 g/m2 to 0.84 g/m2 ]; T2DM duration ≥10 years group, mean adjusted difference -3.69 g/m2 [95% CI: -0.14 g/m2 to -7.24 g/m2 ]; Pinteraction  = 0.07). CONCLUSIONS: In the EMPA-HEART CardioLink-6 trial, empagliflozin treatment was associated with reductions in LVMi in people with T2DM and CAD irrespective of the duration of diabetes assessed categorically above and below 10 years.

Baseline neutrophil-to-lymphocyte ratio and efficacy of SGLT2 inhibition with empagliflozin on cardiac remodelling.

AIMS: The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation and plays a critical role in the assessment and prognosis in patients with heart failure. The EMPA-HEART CardioLink-6 trial demonstrated that patients with type 2 diabetes (T2D) and coronary artery disease (CAD) treated with a sodium-glucose transport protein 2 inhibitor for 6 months experienced regression in left ventricular mass. Given this, we evaluated the relationship of baseline NLR and cardiac reverse remodelling in the entire cohort of this trial. METHODS AND RESULTS: A total of 97 individuals were randomized to receive empagliflozin (10 mg/day) or placebo for 6 months. The primary outcome of the trial was change in left ventricular mass indexed to body surface area (LVMi) from baseline to 6 months as measured by cardiac magnetic resonance imaging. In our analysis, the cohort was stratified above and below an NLR level of 2. To assess the treatment effect on the 6 month change in NLR, we used a linear model adjusting for baseline differences in NLR [analysis of covariance (ANCOVA)] that included an interaction term between the baseline NLR and treatment. To assess the treatment effect on the 6 month change in LVMi in each of the subgroups divided by baseline NLR, we used an ANCOVA adjusting for baseline differences in LVMi that included an interaction term between the subgroups and treatment. The results of the regression models were summarized as adjusted differences with two-sided 95% confidence intervals (CIs). Patients who exhibited an elevated baseline NLR demonstrated higher LVMi and left ventricular end-diastolic volume indexed to body surface area than those with a lower NLR. In patients with an NLR < 2 and NLR ≥ 2, the adjusted difference in LVMi between the empagliflozin- and placebo-treated patients was -2.98 g/m2 (95% CI: -6.18 to 0.22 g/m2 ) (P value = 0.067) and -4.43 g/m2 (95% CI: -8.50 to -1.11 g/m2 ), respectively (Pinteraction  = 0.60). CONCLUSIONS: Empagliflozin treatment is associated with consistent reductions in LVMi in patients with T2D and CAD independent of baseline NLR.

IGFBP7 and left ventricular mass regression: a sub-analysis of the EMPA-HEART CardioLink-6 randomized clinical trial.

AIMS: Given recent suggestions that serum levels of insulin-like growth factor-binding protein 7 (IGFBP7) may identify patients who derive greater cardiorenal benefits from treatment with sodium-glucose transport 2 inhibitors (SGLT2i), this exploratory sub-analysis of the EMPA-HEART CardioLink-6 randomized controlled trial evaluated the association between serum levels of IGFBP7 and empagliflozin-mediated left ventricular mass regression. METHODS AND RESULTS: The EMPA-HEART CardioLink-6 trial used gold-standard cardiac magnetic resonance imaging to detect change in left ventricular mass indexed to body surface area (LVMi) following 6 months of treatment with empagliflozin or matching placebo in 97 patients with type 2 diabetes and coronary artery disease. Serum samples were collected at baseline and analysed for IGFBP7 using an enzyme-linked immunosorbent assay. A multivariate linear regression model was used to assess the association between IGFBP7 and baseline LVMi. A linear model adjusting for baseline differences in LVMi was used to test the relationship between baseline IGFBP7 level, change in LVMi over 6 months, and treatment arm. Of the 97 patients enrolled, 74 had complete covariate data and were included in our analysis. No association between baseline IGFBP7 and baseline LVMi was found [baseline LVMi: 0.14 g/m2 (95% CI: -0.29 g/m2 to 0.57 g/m2 ) per 1 ng/mL higher baseline IGFBP7]. In addition, no difference between patients treated with empagliflozin versus matching placebo was found when evaluating the association between serum IGFBP7, 6 month change in LVMi, and treatment arm [empagliflozin 6 month change in LVMi: 0.25 g/m2 (95% CI: -0.17 g/m2 to 0.67 g/m2 ) per 1 ng/mL higher IGFBP7 vs. matching placebo 6 month change in LVMi: 0.07 g/m2 (95% CI: -0.21 g/m2 to 0.35 g/m2 ) per 1 ng/mL higher IGFBP7; Pinteraction  = 0.49]. Additional sensitivity analysis assessing IGFBP7 as a categorical variable (above/below the median) showed no significant association between IGFBP7, 6 month change in LVMi, and treatment arm. CONCLUSIONS: Our study provides insight into the generalizability of IGFBP7 as a surrogate marker of cardiac remodelling in patients with type 2 diabetes and coronary artery disease. Our results suggest that SGLT2i-mediated reverse cardiac remodelling may be independent of IGFBP7 levels. Further investigations evaluating the association between IGFBP7 and SGLT2i are suggested to understand if and how IGFBP7 levels may modulate benefits received from SLGT2i.

Predictors of mitral valve haemodynamics after mitral valve repair for degenerative mitral regurgitation.

OBJECTIVE: Intraoperative predictors of functional mitral valve (MV) stenosis after surgical repair of mitral regurgitation (MR) caused by prolapse remain poorly characterised. This study evaluated the effect of annuloplasty size on postoperative MV haemodynamics during exercise and evaluated predictors of MV hemodynamics. METHODS: 104 patients were randomly assigned to leaflet resection or preservation for surgical repair of MR in the Canadian Mitral Research Alliance CardioLink-2 study. In this post hoc analysis, we compared MV haemodynamics between the two surgical groups and examined the relationship between annuloplasty size and MV haemodynamics 1 year after repair in the combined groups. Echocardiograms were performed at baseline and intraoperatively. Exercise transthoracic echocardiography was performed 1 year postoperatively. Multivariable linear regression analysis was used to identify predictors of exercise MV gradients at follow-up. RESULTS: Mean age of participants was 65±10 years, and 83% were male. Median annuloplasty size was 34 (IQR 32-36). Dividing by the median, 48 (46%) had annuloplasty size of <34 mm and 56 (54%) had ≥34 mm. Mean and peak exercise gradients at 1 year were 11±5 mm Hg and 22±9 mm Hg in <34, and 6±3 mm Hg and 14±5 mm Hg in ≥34 (p<0.001). Rate of residual MR was similar in both groups. In multivariable analyses, annuloplasty size of ≥34 mm was associated with lower mean and peak exercise gradients at 12 months, after adjustment for repair type, age, sex, heart rate and body surface area (ß -4.1, 95% CI -6 to -3, p<0.001, and ß -7 95% CI -10 to -4, p<0.001, respectively). Intraoperative mean and peak MV gradients by transesophageal echocardiography independently predicted mean and peak resting and exercise gradients at follow-up (p<0.001). Similar results were obtained in both leaflet resection and preservation. CONCLUSION: Annuloplasty size of ≥34 mm is associated with a 4 and 7 mm Hg reduction in mean and peak exercise MV gradients, respectively, 1 year post MV repair regardless of the repair strategy used. Intraoperative TEE MV gradients predict exercise MV gradients 1 year post repair. TRIAL REGISTRATION NUMBER: NCT02552771.

Generalizability of the REDUCE-IT trial to South Asians with cardiovascular disease.

BACKGROUND: South Asians (SAs) represent ∼25% of the world's population and account for >50% of global cardiovascular (CV) deaths, yet they continue to be underrepresented in contemporary clinical trials. The REDUCE-IT study demonstrated in a high-risk and predominantly White population that icosapent ethyl (IPE) lowered major adverse cardiovascular events by 25%. We sought to determine the generalizability of these results to a high-risk population of SAs with established CV disease living in Canada. METHODS: This was a cross-sectional observational study of 200 statin-treated SAs (≥45 years) with atherosclerotic CV disease (ASCVD) (NCT05271591). SA ethnicity was self-identified as being of Anglo-Indian, Bangladeshi, Bengali, Bhutanese, Goan, Gujarati, Indian, Jatt, Kashmiri, Maharashtrian, Malayali, Nepali, Pakistani, Punjabi, Sindhi, Sinhalese, Sri Lankan, Tamil, Telugu, or other SA. ASCVD was defined as the presence of coronary, carotid, or peripheral atherosclerosis. FINDINGS: Mean age of the cohort was 67 years, where 82% were men and 57% had diabetes. The predominant ASCVD phenotype was coronary artery disease (94%). Mean (SD) baseline LDL-C and triglycerides were 1.70 (0.8) mmol/L and 1.42 (1.0) mmol/L, respectively. Three-quarters were on high-intensity statin therapy. According to the Health Canada/Canadian Cardiovascular Society Guidelines and FDA-approved indication, 33% and 25% of the participants were, respectively, eligible for IPE. CONCLUSIONS: A large proportion of high-intensity, statin-treated, high-risk patients with ASCVD and of self-reported SA ethnicity are eligible for IPE. These data have important translational implications for SAs who are at a disproportionately higher risk of CV morbidity and mortality. FUNDING: This study was funded by an unrestricted grant provided by HLS Therapeutics Inc, Canada.

Acute Infarcts on Brain MRI Following Aortic Arch Repair With Circulatory Arrest: Insights From the ACE CardioLink-3 Randomized Trial.

BACKGROUND: to investigate the frequency and distribution of new ischemic brain lesions detected by diffusion-weighted imaging on brain magnetic resonance imaging after aortic arch surgery. METHODS: This preplanned secondary analysis of the randomized, controlled ACE (Aortic Surgery Cerebral Protection Evaluation) CardioLink-3 trial compared the safety and efficacy of innominate versus axillary artery cannulation during elective proximal aortic arch surgery. Participants underwent pre and postoperative magnetic resonance imaging. New ischemic lesions were defined as lesions visible on postoperative, but not preoperative diffusion weighted imaging. RESULTS: Of the 111 trial participants, 102 had complete magnetic resonance imaging data. A total of 391 new ischemic lesions were observed on diffusion-weighted imaging in 71 (70%) patients. The average number of lesions in patients with ischemic lesion were 5.5±4.9 with comparable numbers in the right (2.9±2.0) and left (3.0±2.3) hemispheres (P=0.49). Half the new lesions were in the middle cerebral artery territory; 63% of the cohort had ischemic lesions in the anterior circulation, 49% in the posterior circulation, 42% in both, and 20% in watershed areas. A probability mask of all diffusion-weighted imaging lesions revealed that the cerebellum was commonly involved. More severe white matter hyperintensity on preoperative magnetic resonance imaging (odds ratio, 1.80 [95% CI, 1.10-2.95]; P=0.02) and lower nadir nasopharyngeal temperature during surgery (odds ratio per 1°C decrease, 1.15 [95% CI, 1.00-1.32]; P=0.05) were associated with the presentation of new ischemic lesion; older age (risk ratio per 1-year increase, 1.02 [95% CI, 1.00-1.04]; P=0.03) and lower nadir temperature (risk ratio per 1°C decrease, 1.06 [95% CI, 1.00-1.14]; P=0.06) were associated with greater number of lesions. CONCLUSIONS: In patients who underwent elective proximal aortic arch surgery, new ischemic brain lesions were common, and predominantly involved the middle cerebral artery territory or cerebellum. Underlying small vessel disease, lower temperature nadir during surgery, and advanced age were risk factors for perioperative ischemic lesions. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02554032.