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.

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).

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.

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.

Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. Although it has been theorized that sodium-glucose cotransporter 2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine whether sodium-glucose cotransporter 2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. METHODS: Between April 2021 and January 2022, 169 individuals, 40 to 80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomly assigned to empagliflozin (10 mg/d; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and LV end-systolic volumes indexed to baseline body surface area and LV ejection fraction. RESULTS: Among the 169 participants (141 men [83%]; mean age, 59.3±10.5 years), baseline LVMi was 63.2±17.9 g/m2 and 63.8±14.0 g/m2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group versus placebo group adjusted for baseline LVMi was -0.30 g/m2 (-2.1 to 1.5 g/m2; P=0.74). Median baseline (interquartile range) NT-proBNP (N-terminal-pro B-type natriuretic peptide) was 51 pg/mL (20-105 pg/mL) and 55 pg/mL (21-132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin versus placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mm Hg (-5.2 to 2.6 mm Hg; P=0.52), 0.69 mm Hg (-1.9 to 3.3 mm Hg; P=0.60), and -6.1 pg/mL (-37.0 to 24.8 pg/mL; P=0.70) for systolic blood pressure, diastolic blood pressure, and NT-proBNP, respectively. No clinically meaningful between-group differences in LV volumes (diastolic and systolic indexed to baseline body surface area) or ejection fraction were observed. No difference in adverse events was noted between the groups. CONCLUSIONS: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, sodium-glucose cotransporter 2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04461041.

Early developmental exposure to bisphenol A and bisphenol S disrupts socio-cognitive function, isotocin equilibrium, and excitation-inhibition balance in developing zebrafish.

Dysregulation of the oxytocinergic system and excitation/inhibition (E/I) balance in synaptic transmission and neural circuits are common hallmarks of various neurodevelopmental disorders. Several experimental and epidemiological studies have shown that perinatal exposure to endocrine-disrupting chemicals bisphenol A (BPA) and bisphenol S (BPS) may contribute to a range of childhood neurodevelopmental disorders. However, the effects of BPA and BPS on social-cognitive development and the associated mechanisms remain largely unknown. In this study, we explored the impacts of early developmental exposure (2hpf-5dpf) to environmentally relevant concentrations of BPA, and its analog BPS (0.001, 0.01, and 0.1 µM), on anxiety, social behaviors, and memory performance in 21 dpf zebrafish larvae. Our results revealed that early-life exposure to low concentrations of BPA and BPS elevated anxiety-like behavior, while fish exposed to higher concentrations of these chemicals displayed social deficits and impaired object recognition memory. Additionally, we found that co-exposure with an aromatase inhibitor antagonized BPA- and BPS-induced effects on anxiety levels and social behaviors, while the co-exposure to an estrogen receptor antagonist restored recognition memory in zebrafish larvae. These results indicate that BPA and BPS may affect social-cognitive function through distinct mechanisms. On the other hand, exposure to low BPA/BPS concentrations increased both the mRNA and protein levels of isotocin (zebrafish oxytocin) in the zebrafish brain, whereas a reduction in its mRNA level was observed at higher concentrations. Further, alterations in the transcript abundance of chloride transporters, and molecular markers of gamma-aminobutyric acid (GABA) and glutamatergic systems, were observed in the zebrafish brain, suggesting possible E/I imbalance following BPA or BPS exposure. Collectively, the results of this study demonstrate that early-life exposure to low concentrations of the environmental contaminants BPA and BPS can interfere with the isotocinergic signaling pathway and disrupts the establishment of E/I balance in the developing brain, subsequently leading to the onset of a suite of behavioral deficits and neurodevelopmental disorders.

Vascular repair and regeneration in cardiometabolic diseases.

Chronic cardiometabolic assaults during type 2 diabetes (T2D) and obesity induce a progenitor cell imbalance in the circulation characterized by overproduction and release of pro-inflammatory monocytes and granulocytes from the bone marrow alongside aberrant differentiation and mobilization of pro-vascular progenitor cells that generate downstream progeny for the coordination of blood vessel repair. This imbalance can be detected in the peripheral blood of individuals with established T2D and severe obesity using multiparametric flow cytometry analyses to discern pro-inflammatory vs. pro-angiogenic progenitor cell subsets identified by high aldehyde dehydrogenase activity, a conserved progenitor cell protective function, combined with lineage-restricted cell surface marker analyses. Recent evidence suggests that progenitor cell imbalance can be reversed by treatment with pharmacological agents or surgical interventions that reduce hyperglycaemia or excess adiposity. In this state-of-the-art review, we present current strategies to assess the progression of pro-vascular regenerative cell depletion in peripheral blood samples of individuals with T2D and obesity and we summarize novel clinical data that intervention using sodium-glucose co-transporter 2 inhibition or gastric bypass surgery can efficiently restore cell-mediated vascular repair mechanisms associated with profound cardiovascular benefits in recent outcome trials. Collectively, this thesis generates a compelling argument for early intervention using current pharmacological agents to prevent or restore imbalanced circulating progenitor content and maintain vascular regenerative cell trafficking to sites of ischaemic damage. This conceptual advancement may lead to the design of novel therapeutic approaches to prevent or reverse the devastating cardiovascular comorbidities currently associated with T2D and obesity.

Surgical Treatment for Gerbode Defect Caused by Infective Endocarditis.

In this case illustration, a Gerbode defect in a 52-year-old woman caused by infective endocarditis was closed with autologous pericardium. Postoperative echocardiographic findings were satisfactory without residual shunt flow or perivalvular leak. Her postoperative recovery was uneventful without infection recurrence. Gerbode defect is a rare complication of infective endocarditis and careful preoperative echocardiographic work-up is imperative for successful repair.

SGLT2 inhibitors and cardiac remodelling: a systematic review and meta-analysis of randomized cardiac magnetic resonance imaging trials.

AIMS: Recent large randomized controlled trials (RCTs) have demonstrated efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in both preventing and treating heart failure (HF). SGLT2i-induced reversal of left ventricular remodelling has been proposed as a mechanism contributing to this effect. METHODS AND RESULTS: We performed a systematic review and meta-analysis of RCTs to compare SGLT2i versus placebo (treatment duration >3 months) on cardiac remodelling parameters as measured by cardiac magnetic resonance imaging (cMRI) in patients with HF and/or diabetes. The PubMed and ClinicalTrials.gov databases were searched until 15 June 2021. Our primary outcome was change in absolute left ventricular mass (LVM) from baseline to study endpoint. Secondary outcomes included changes in LVM indexed to body surface area, left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and left ventricular ejection fraction (LVEF) from baseline to study endpoint. The Cochrane Collaboration's tool was used to assess risk of bias. Five studies representing 408 patients were included. SGLT2i was associated with greater LVM regression compared to placebo (MD, -5.76 g; 95% CI, -10.87 g to -0.64 g, I2  = 73%; overall effect, P < 0.03; four RCTs). Statistical subgroup differences were not observed in our sensitivity analysis focusing on HF with reduced ejection fraction (P = 0.37) and were observed in our sensitivity analysis focusing on diabetes (P < 0.001). SGLT2i was not associated with statistical changes in LV mass indexed to body surface area (I2  = 75%; P = 0.16; five RCTs), LVESV (I2  = 87%; P = 0.07; five RCTs), LVEDV (I2  = 81%; P = 0.20; five RCTs), nor LVEF (I2  = 85%; P = 0.19; five RCTs) versus placebo. Sixty per cent of RCTs had low risk of bias. CONCLUSIONS: Sodium-glucose cotransporter-2 inhibitors treatment was associated with a reduction in left ventricular mass as assessed by cMRI.

Using zebrafish as a model to assess the individual and combined effects of sub-lethal waterborne and dietary zinc exposure during development.

The present research used zebrafish (5-28 days post-fertilization; dpf) as a model organism to investigate the effects of chronic exposure to environmentally relevant sub-lethal concentrations of waterborne (261 µg/L) and dietary zinc (Zn) (1500 mg Zn/kg dw), either independently or simultaneously, during development. The results showed that whole body contents of Zn were increased in all Zn treatment groups, with the highest accumulation of Zn observed in larvae simultaneously exposed to elevated waterborne and dietary Zn. In addition, exposure to elevated levels of Zn, either through the water or the diet, led to a decrease in whole body calcium (Ca) contents at 28 dpf. The findings also suggested that exposure to elevated levels of Zn resulted in a significant reduction in whole body manganese (Mn) contents. More importantly, the magnitude of decrease in Mn contents by Zn exposure was markedly higher than that in Ca and appeared to mirror the increases in whole body Zn accumulation. These results indicate that Mn regulation is more sensitive than Ca to disruption by Zn exposure in developing fish. Further examination of the Zrt-Irt-Like Protein (ZIP) family of transporters using droplet digital PCR technologies revealed that several zip transporters exhibited temporal and exposure route-specific changes following Zn exposure. In particular, the level of zip4 was influenced by Zn exposure regardless of the exposure routes, while changes in zip7 and zip8 levels were predominantly driven by waterborne exposure. Overall, our findings demonstrated that zebrafish during the developmental periods are sensitive to elevated levels of Zn seen in the environment, particularly following co-exposures to waterborne and dietary Zn. Future toxicological assessment of elevated Zn exposure should consider both the exposure routes and the life stages of fish.