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.

Cardiovascular and renal outcomes in patients with atrial fibrillation and stage 4-5 chronic kidney disease receiving direct oral anticoagulants: a multicenter retrospective cohort study.

The role of direct oral anticoagulants (DOAC) in patients with atrial fibrillation (AF) and stage 4-5 chronic kidney disease (CKD) is controversial. Electronic medical records from 2012 to 2021 were retrieved for patients with AF and stage 4-5 CKD receiving oral anticoagulants. Patients were separated into those receiving DOACs (dabigatran, rivaroxaban, apixaban, or edoxaban) or vitamin K antagonists (VKA). Primary outcomes included ischemic stroke (IS), systemic thrombosis (SE), major bleeding, gastrointestinal bleeding, hemorrhagic stroke, acute myocardial infarction, cardiovascular death, and all-cause death. Renal outcomes included eGFR declines, creatinine doubling, progression to dialysis, and major adverse kidney events (MAKE). The primary analysis was until the end of follow up and the results at 1-year and 2-year of follow ups were also assessed. 2,382 patients (DOAC = 1,047, VKA = 1,335) between 2012 and 2021 with AF and stage 4-5 CKD were identified. The mean follow-up period was 2.3 ± 2.1 years in DOCAs and 2.6 ± 2.3 years in VKA respectively. At the end of follow up, the DOAC patients had significantly decreased SE (subdistribution hazard ratio [SHR] = 0.50, 95% confidence interval [CI] = 0.34-0.73), composite of IS/SE (SHR = 0.78, 95% CI = 0.62-0.98), major bleeding (HR = 0.77, 95% CI = 0.66-0.90), hemorrhagic stroke (HR = 0.52, 95% CI = 0.36-0.76), and composite of bleeding events (SHR = 0.80, 95% CI = 0.69-0.92) compared with VKA patients. The IS efficacy outcome revealed neutral between DOAC and VKA patients (HR = 1.05, 95% CI = 0.79-1.39). In addition, DOAC patients had significantly decreased rates of eGFR decline > 50% (SHR = 0.75, 95% CI = 0.64-0.87), creatinine doubling (SHR = 0.80, 95% CI = 0.67-0.95), and MAKE (SHR = 0.81, 95% CI = 0.71-0.93). In patients with AF and stage 4-5 CKD, use of DOAC was associated with decreased rates of a composite of ischemic stroke/systemic embolism, a composite of bleeding events, and renal events compared to VKA. Efficacy and safety benefits associated with apixaban at standard doses were consistent throughout follow-up.

The cardiovascular and renal effects of glucagon-like peptide 1 receptor agonists in patients with advanced diabetic kidney disease.

BACKGROUND: To determine whether glucagon-like peptide 1 receptor agonists (GLP-1RAs) have cardiovascular and renal protective effects in patients with advanced diabetic kidney disease (DKD) with an estimated glomerular filtration rate (eGFR) < 30 mL/min per 1.73 m2. METHODS: In this cohort study, patients with type 2 diabetes mellitus and eGFR < 30 mL/min per 1.73 m2 with a first prescription for GLP-1RAs or dipeptidyl peptidase 4 inhibitors (DPP-4is) from 2012 to 2021 (n = 125,392) were enrolled. A Cox proportional hazard model was used to assess the cardiorenal protective effects between the GLP-1RA and DDP-4i groups. RESULTS: A total of 8922 participants [mean (SD) age 68.4 (11.5) years; 4516 (50.6%) males; GLP-1RAs, n = 759; DPP-4is, n = 8163] were eligible for this study. During a mean follow-up of 2.1 years, 78 (13%) and 204 (13.8%) patients developed composite cardiovascular events in the GLP-1RA and DPP-4i groups, respectively [hazard ratio (HR) 0.88, 95% confidence interval CI 0.68-1.13]. Composite kidney events were reported in 134 (38.2%) and 393 (44.2%) patients in the GLP-1RA and DPP-4i groups, respectively (subdistribution HR 0.72, 95% CI 0.56-0.93). CONCLUSIONS: GLP-1RAs had a neutral effect on the composite cardiovascular outcomes but reduced composite kidney events in the patients with advanced DKD compared with DPP-4is.

Associations of Three-Dimensional Anthropometric Body Surface Scanning Measurements and Coronary Artery Disease.

Background and Objectives: The relationship between three-dimensional (3D) scanning-derived body surface measurements and biomarkers in patients with coronary artery disease (CAD) were assessed. Methods and Methods: The recruitment of 98 patients with CAD confirmed by cardiac catheterization and 98 non-CAD patients were performed between March 2016 and December 2017. A health questionnaire on basic information, life style variables, and past medical and family history was completed. 3D body surface measurements and biomarkers were obtained. Differences between the two groups were assessed and multivariable analysis performed. Results: It was found that chest width (odds ratio [OR] 0.761, 95% confidence interval [CI] = 0.586-0.987, p = 0.0399), right arm length (OR 0.743, 95% CI = 0.632-0.875, p = 0.0004), waist circumference (OR 1.119, 95% CI = 1.035-1.21, p = 0.0048), leptin (OR 1.443, 95% CI = 1.184-1.76, p = 0.0003), adiponectin (OR 0.978, 95% CI = 0.963-0.994, p = 0.006), and interleukin 6 (OR 1.181, 95% CI = 1.021-1.366, p = 0.0254) were significantly associated with CAD. The combination of biomarker scores and body measurement scores had the greatest area under the curve and best association with CAD (area under the curve of 0.8049 and 95% CI = 0.7440-0.8657). Conclusions: Our study suggests that 3D derived body surface measurements in combination with leptin, adiponectin, and interleukin 6 levels may direct us to those at risk of CAD, allowing a non-invasive approach to identifying high-risk patients.

Combination of Thigh Circumference and Indices of Central Obesity Helps Predict Incident Chronic Kidney Disease: A 14-Year Prospective Cohort Study Using a Three-Dimensional Body Laser Scanner.

OBJECTIVE: Obesity, high body mass index, and visceral fat accumulation are associated with renal diseases. However, the association between body measurements and chronic kidney disease (CKD) is still unclear. METHODS: A cohort of 7,825 participants scheduled for follow-up of CKD was recruited from 2000 to 2008 in Taiwan. A questionnaire was developed to collect the basic demographics, lifestyle variables, personal disease history, and family disease history of the participants. A 3-dimensional body surface scanning system was used to take their body measurements. The participants underwent an average follow-up of 14.3 years for evaluation of the incidence of CKD. A multiple Cox regression model was built. RESULTS: Three body measurements, namely chest width (hazard ratio [HR] 1.059, 95% confidence interval [CI] 1.011-1.110), waist circumference (HR 1.017, 95% CI 1.006-1.029), and thigh circumference (HR 0.941, 95% CI 0.922-0.961), were significantly associated with CKD. Two combinations of body measurements, namely the waist-to-thigh ratio and chest-to-thigh ratio, were derived to predict the occurrence of CKD. Participants with the highest quartile of waist-to-thigh ratio and chest-to-thigh ratio had a 2.175-fold and 2.182-fold risk of developing CKD, respectively. CONCLUSIONS: This study suggests that along with central obesity, body limb measurements can be used as an indicator to predict the occurrence of CKD. The effects of limb measurements on CKD could help provide an innovative perspective regarding the intervention to be developed for the treatment of CKD and a preventive medicine for high-risk individuals. The association of thigh circumference with CKD warrants further investigation.

Comparative risk evaluation for cardiovascular events associated with dapagliflozin vs. empagliflozin in real-world type 2 diabetes patients: a multi-institutional cohort study.

BACKGROUND: To compare the cardiovascular event risk in type 2 diabetes patients newly receiving dapagliflozin vs. empagliflozin. METHODS: We conducted a retrospective cohort study by analyzing a multi-institutional electronic medical records database (Chang Gung Research Database) in Taiwan and included adult type 2 diabetes patients who were newly receiving sodium-glucose co-transporter 2 (SGLT2) inhibitors from 2016 to 2017. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischemic stroke and heart failure. We followed up patients from initiation of SGLT2 inhibitors until the occurrence of cardiovascular events before December 31, 2018. We performed multivariable Cox proportional hazard modeling, adjusting for patients' age, sex, laboratory data, co-morbidities, and concomitant medications. RESULTS: We identified 12,681 new SGLT2 inhibitor users with a mean age of 58.9 (SD 11.8) years, of whom 43.9% were female and 45.8% were new dapagliflozin users. A total of 10,442 person-years of dapagliflozin use and 12,096 person-years of empagliflozin use were included. Compared to empagliflozin users, new users of dapagliflozin were found to have similar risks for primary composite outcome (adjusted HR: 0.91; 95% CI 0.73-1.14), cardiovascular death (adjusted HR: 0.54; 95% CI 0.14-2.12), myocardial infarction (adjusted HR: 0.77, 95% CI 0.49-1.19) and ischemic stroke (adjusted HR: 1.15; 95% CI 0.80-1.65), but a lower risk of heart failure (adjusted HR: 0.68; 95% CI 0.49-0.95). CONCLUSION: The risk of cardiovascular events was similar between dapagliflozin and empagliflozin new users, but dapagliflozin may have a better outcome in the reduction of heart failure in type 2 diabetes patients. Future prospective studies are required to confirm the findings.

Understanding the Epidemiology of Heart Failure to Improve Management Practices: An Asia-Pacific Perspective.

Heart failure (HF) is a major global healthcare problem with an estimated prevalence of approximately 26 million. In Asia-Pacific regions, HF is associated with a significant socioeconomic burden and high rates of hospital admission. Epidemiological data that could help to improve management approaches to address this burden in Asia-Pacific regions are limited, but suggest patients with HF in the Asia-Pacific are younger and have more severe signs and symptoms of HF than those of Western countries. However, local guidelines are based largely on the European Society of Cardiology and American College of Cardiology Foundation/American Heart Association guidelines, which draw their evidence from studies where Western patients form the major demographic and patients from the Asia-Pacific region are underrepresented. Furthermore, regional differences in treatment practices likely affect patient outcomes. In the following review, we examine epidemiological data from existing regional registries, which indicate that these patients represent a distinct subpopulation of patients with HF. In addition, we highlight that patients with HF are under-treated in the region despite the existence of local guidelines. Finally, we provide suggestions on how data can be enriched throughout the region, which may positively affect local guidelines and improve management practices.

One-Year Outcomes of Acute Decompensated Systolic Heart Failure in Taiwan: Lessons from TSOC-HFrEF Registry.

BACKGROUND: Heart failure (HF) is a global health problem. The Taiwan Society of Cardiology-Heart Failure with reduced Ejection Fraction (TSOC-HFrEF) registry was a multicenter, observational survey of patients admitted with HFrEF in Taiwan. The aim of this study was to report the one-year outcome in this large-cohort of hospitalized patients presenting with acute decompensated HFrEF. METHODS: Patients hospitalized for acute HFrEF were recruited in 21 hospitals in Taiwan. A total of 1509 patients were enrolled into the registry by the end of October 2014. Clinical status, readmission rates and dispensed medications were collected and analyzed 1 year after patient index hospitalization. RESULTS: Our study indicated that re-hospitalization rates after HFrEF were 31.9% and 38.5% at 6 and 12 months after index hospitalization, respectively. Of these patients, 9.7% of them were readmitted more than once. At 6 and 12 months after hospital discharge, all-cause mortality rates were 9.5% and 15.9%, respectively, and cardiovascular mortality rates were 6.8% and 10.5%, respectively. Twenty-three patients (1.5%) underwent heart transplantation. During a follow-up period of 1 year, 46.4% of patients were free from mortality, HF re-hospitalization, left ventricular assist device use and heart transplantation. At the conclusion of follow-up, 57.5% of patients were prescribed either with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers; also, 66.3% were prescribed with beta-blockers and 40.8% were prescribed with mineralocorticoid receptor antagonists. CONCLUSIONS: The TSOC-HFrEF registry showed evidence of suboptimal practice of guideline-directed medical therapy and high HF re-hospitalization rate in Taiwan. The one-year mortality rate of the TSOC-HFrEF registry remained high. Ultimately, our data indicated a need for further improvement in HF care.

TSOC-HFrEF Registry: A Registry of Hospitalized Patients with Decompensated Systolic Heart Failure: Description of Population and Management.

INTRODUCTION: Heart failure (HF) is a medical condition with a rapidly increasing incidence both in Taiwan and worldwide. The objective of the TSOC-HFrEF registry was to assess epidemiology, etiology, clinical management, and outcomes in a large sample of hospitalized patients presenting with acute decompensated systolic HF. METHODS: The TSOC-HFrEF registry was a prospective, multicenter, observational survey of patients presenting to 21 medical centers or teaching hospitals in Taiwan. Hospitalized patients with either acute new-onset HF or acute decompensation of chronic HFrEF were enrolled. Data including demographic characteristics, medical history, primary etiology of HF, precipitating factors for HF hospitalization, presenting symptoms and signs, diagnostic and treatment procedures, in-hospital mortality, length of stay, and discharge medications, were collected and analyzed. RESULTS: A total of 1509 patients were enrolled into the registry by the end of October 2014, with a mean age of 64 years (72% were male). Ischemic cardiomyopathy and dilated cardiomyopathy were diagnosed in 44% and 33% of patients, respectively. Coronary artery disease, hypertension, diabetes, and chronic renal insufficiency were the common comorbid conditions. Acute coronary syndrome, non-compliant to treatment, and concurrent infection were the major precipitating factors for acute decompensation. The median length of hospital stay was 8 days, and the in-hospital mortality rate was 2.4%. At discharge, 62% of patients were prescribed either angiotensin-converting enzyme-inhibitors or angiotensin receptor blockers, 60% were prescribed beta-blockers, and 49% were prescribed mineralocorticoid receptor antagonists. CONCLUSIONS: The TSOC-HFrEF registry provided important insights into the current clinical characteristics and management of hospitalized decompensated systolic HF patients in Taiwan. One important observation was that adherence to guideline-directed medical therapy was suboptimal.

Evaluating the applicability of ivabradine in acute heart failure.

BACKGROUND: While ivabradine has demonstrated benefits in heart rate control and prognosis for chronic heart failure patients, its application in acute decompensated heart failure remains underexplored. HYPOTHESIS: For patients with acute decompensated heart failure with reduced ejection fraction (HFrEF) who are intolerant to ß-blockers or unable to further titrate their dosage, the use of ivabradine is hypothesized to be effective and safe is improving outcomes. METHODS: This retrospective, multicenter database analysis included patients with hospitalized decompensated heart failure with a left ventricular ejection fraction of ≤40% from June 1, 2015 to December 31, 2020. The exclusion criteria were a baseline heart rate of <70 bpm, previous use of ivabradine, mortality during admission, existing atrial fibrillation, or atrial flutter. The primary outcome was the composite of cardiovascular death and hospitalization for heart failure. RESULTS: Of the 4163 HFrEF patients analyzed, 684 (16.4%) were administered ivabradine during their index admission. After matching, there were 617 patients in either group. The results indicated that ivabradine use was not significantly associated with the risk of the primary composite outcome (hazard ratio: 1.10; 95% confidence interval: 0.94-1.29). Similarly, the risk of secondary outcomes and adverse renal events did not significantly differ between the ivabradine and non-ivabradine cohorts (all p > .05). CONCLUSION: For hospitalized acute decompensated heart failure patients who are intolerant to ß-blockers or cannot further titrate them, ivabradine offers a consistent therapeutic effect. No significant disparities were noted between the ivabradine and non-ivabradine groups in heart failure hospitalization and cardiovascular death.

Ticagrelor versus Adjusted-Dose Prasugrel in Acute Coronary Syndrome with Percutaneous Coronary Intervention.

Dual antiplatelet therapy (DAPT) with ticagrelor or adjusted-dose prasugrel has been used for acute coronary syndrome (ACS). However, few studies have directly compared these two drugs. In this study, we compared the real-world applications and outcomes of these two drugs in patients with ACS who had undergone percutaneous coronary intervention (PCI). This retrospective cohort study was conducted using the data of eligible patients with ACS who had undergone PCI at Chang Gung Memorial Hospital System between June 2019 and December 2021. The primary efficacy-related outcome was the occurrence of major adverse cardiovascular events (MACEs), and the primary safety-related outcome was major bleeding. Inverse probability of treatment weighting based on propensity score was performed to reduce confounding effects. The study included 2,636 patients; of them, 429 received prasugrel and 2,207 received ticagrelor. No significant between-group difference was observed in the risk of MACE (13.1 vs. 13.1 events per 100 person-years, respectively, hazard ratio (HR): 1.01, 95% confidence interval (CI): 0.71-1.43). Both groups exhibited similar rates of major bleeding (3.9 vs. 4.1 events per 100 person-years, respectively, subdistribution HR: 0.96, 95% CI: 0.68-1.35). In real-world settings, adjusted-dose prasugrel and ticagrelor exhibit comparable safety and efficacy profiles in East Asian patients with ACS after PCI. Our findings offer valuable insights for future clinical decision making and patient management strategies.

Bone marrow rejuvenation accelerates re-endothelialization and attenuates intimal hyperplasia after vascular injury in aging mice.

BACKGROUND: Aging-associated functional impairment of endothelial progenitor cells (EPCs) contributes to delayed re-endothelialization after vascular injury and exaggerated intimal hyperplasia (IH). This study tested if bone marrow (BM) rejuvenation accelerates post-injury re-endothelialization in aging mice. METHODS AND RESULTS: Using BM transplantation (BMT(Gfp→Wild)), young(Gfp) to young(Wild) (YTY), old(Gfp) to old(Wild) (OTO), young(Gfp) to old(Wild) (YTO), and old(Gfp) to young(Wild) (OTY) groups were created. After vascular injury, IH was significantly greater in the old group than the young group (P<0.001). BM rejuvenation (YTO) significantly accelerated re-endothelialization and attenuated IH. Compared with the OTO group, the YTY and YTO groups had earlier and greater EPC-derived re-endothelialization (P<0.001). The number of Sca-1(+)KDR(+) EPCs mobilized in the circulation induced by vascular injury was higher in young, YTO, and YTY mice than in old mice (P<0.05). Sca-1(+) BM cells from the young, YTO, and YTY groups had better migration and adhesion capacities than those from the old group (P<0.05). The increase in blood vascular endothelial growth factor (VEGF) levels after vascular injury was higher in young than in old mice. PI3K, Akt, and FAK pathways played a pivotal role in VEGF-associated EPC migration. Specifically, EPCs from young and YTO mice, compared with old mice, demonstrated stronger FAK phosphorylation after VEGF stimulation. CONCLUSIONS: EPCs play a critical role in vascular repair in aging mice. BM rejuvenation accelerates re-endothelialization by improving EPC function.

Differences of left ventricular systolic deformation in hypertensive patients with and without apical hypertrophic cardiomyopathy.

BACKGROUND: We tested the hypothesis that the apical myocardial mechanics differ from those of other ventricular segments in hypertensive patients with and without apical hypertrophic cardiomyopathy (ApHCM). METHODS: We retrospectively studied hypertensive patients with and without ApHCM. Left ventricular longitudinal, circumferential, and radial strains were examined by two-dimensional speckle-tracking echocardiography at the basal, middle, and apical walls of the parasternal short-axis and apical 2-, 3- and 4-chamber views. RESULTS: Fourteen consecutive patients with hypertension and ApHCM and 14 patients with hypertension without ApHCM were studied. Lower mitral annular peak systolic velocity and greater diastolic dysfunction were present in hypertensive patients with ApHCM than in hypertensive patients without ApHCM. Compared with hypertensive patients without ApHCM, hypertensive patients with ApHCM had significantly lower apical longitudinal (-13.9% vs -21.9%, p = 0.010) and radial strains (4.4% vs 11.5%, p = 0.017) without the base-to-apex gradient. The global longitudinal (-15.6% vs -18.8%, p = 0.027) and circumferential strains (-16.1% vs -19.2%, p = 0.019) were significantly lower in hypertensive patients with ApHCM than in hypertensive patients without ApHCM. Among systolic parameters, the global longitudinal strain was independently associated with hypertension with ApHCM (odds ratio, 1.457; 95% confidence interval, 1.002-2.119; p = 0.049). CONCLUSIONS: Reduced apical longitudinal and radial strains without a base-to-apex gradient were present in hypertensive patients with ApHCM. The global longitudinal strain was independently associated with ApHCM in hypertensive patients.

Direct Renin Inhibitor Attenuates Left Ventricular Remodeling in Post-Myocardial Infarction Heart Failure Mice.

BACKGROUND: The role of direct renin inhibitors in myocardial ischemia-induced heart failure is controversial. We hypothesized that direct renin inhibitors play a positive role, affecting in vivo myocardial function as well as in vitro extracellular matrix change. METHODS: Ten-week-old C57BL/6J male mice with 2-kidney 1-clip (2K1C) model were enrolled in this study. The mice were divided into 3 groups each with 18 mice; group 1 sham-operated, group 2 coronary artery ligation- induced heart failure, and group 3 coronary artery ligation-induced heart failure receiving aliskiren minipump infusion. These mice were assessed for systemic hemodynamics and left ventricular function by 2-dimensional echocardiography (iE33, Philips). Myocardial tissue was stained and crude protein was isolated from the non- ischemic viable left ventricle. Myocardial tissue contents of anti-angiotensin II type 1 (AT1) receptor, matrix metalloproteinase (MMP)-2 and MMP-9 were examined. RESULTS: There were 54 mice that received 2K1C and were followed up for three weeks. Baseline characteristics showed no difference. At follow-up, the heart failure-only group had greater left ventricular mass and worse systolic function as compared to the sham group. Whereas the heart failure-aliskiren group had lower left ventricle mass and better systolic function as compared to the heart failure-only group. AT1 receptor, MMP-2 and MMP-9 levels were increased in the heart failure-only model while direct renin inhibitor attenuated this significantly. CONCLUSIONS: Direct renin inhibitors improved myocardial function in a myocardial ischemia-induced heart failure mouse model. The improvement seen is present in myocardial mass, left ventricular systolic function and also in myocardial interstitial tissue. KEY WORDS: Direct renin inhibitor; Echocardiography; Heart failure.

Clinical Application of Endothelial Progenitor Cell: Are We Ready?

UNLABELLED: The discovery of circulating endothelial progenitor cells (EPCs) opened up a new era of EPC-based therapies for cardiovascular diseases. While researchers are enthusiastic about applying EPCs to clinical therapy, progress has been substantially limited due to the lack of a thorough characterization and understanding of early and late outgrowth EPCs (also called endothelial colony-forming cell, ECFCs) biology. As a means of facilitating the understanding of how late EPCs can most effectively be applied to clinical therapeutics, this article reviews the recent progress covering 5 important issues: (1) The best passages of ex vivo-cultivated EPCs for cell therapy; (2) inflammatory activation of late EPCs: a real world consideration; (3) late EPC is not an endothelial cell: an issue of cell contamination; (4) ways to improve EPC function and differentiation; and (5) how to separate and delete smooth muscle progenitor cells (SPCs). KEY WORDS: Cardiovascular disease; Cell therapy; Endothelial progenitor cell; Smooth muscle progenitor cell.

Comparing angiotensin receptor-neprilysin inhibitors with sodium-glucose cotransporter 2 inhibitors for heart failure with diabetes mellitus.

BACKGROUND AND AIMS: Clinical comparisons of angiotensin receptor-neprilysin inhibitors (ARNI) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) treatment in patients with HFrEF and T2DM are limited. This study evaluated the clinical outcomes and treatment benefits of SGLT2i versus ARNI treatment in patients with HFrEF and T2DM in a large real-world data set. METHODS: We identified 1487 patients with HFrEF and T2DM who were undergoing ARNI or SGLT2i treatment for the first time (n = 647 and 840, respectively) between January 1, 2016, and December 31, 2021, and with clinical outcomes of CV death, hospitalization for heart failure (HHF), composite CV outcomes, or renal outcomes. RESULTS: The HHF risk reduction conferred by SGLT2i treatment was more significant than that conferred by ARNI treatment (37.7% vs. 30.4%; 95% confidence interval [CI] 1.06-1.41). SGLT2i use conferred significantly greater renal protection against the doubling of serum creatinine (13.1% vs. 9.3%; 95% CI 1.05-1.75), an estimated glomerular filtration rate decline of > 50% (24.9% vs. 20.0%; 95% CI 1.02-1.45), and progression to end-stage renal disease (3.1% vs. 1.5%; 95% CI 1.62-5.23). The improvements in echocardiographic parameters were comparable between the groups. CONCLUSIONS: Compared with ARNI treatment, SGLT2i treatment was associated with a more significant HHF risk reduction and greater preservation of renal function in patients with HFrEF and T2DM. This study also supports the prioritization of SGLT2i use in these patients when patients' conditions or economic resources need to be considered.

Edema index-guided disease management improves 6-month outcomes of patients with acute heart failure.

The efficacy of heart failure (HF) management programs is compromised by the challenge of early identification of patients at imminent risk. Segmental multifrequency bioelectrical impedance analysis can generate an "edema index" (EI) as a surrogate for the body fluid status. In this study, we tested whether integration of EI-guided management improved the 6-month outcomes of HF patients under multidisciplinary care. In total, 159 patients with acute HF were randomized into control, case management (CM), and EI-guided CM (EI) groups (n = 53 in each group). In the EI group, a management algorithm was designed based on the measured EI. The analyzed endpoints included HF-related and all cause-related events during the 6-month follow-up period. In the 6 months, there were 11 (6.9%) deaths, 19 (11.9%) HF-related rehospitalizations, and 45 (28.3%) all-cause-related rehospitalizations. Compared to the control (26.4%) and CM groups (15.1%), the EI group had a lower rate of HF-related death and rehospitalization (3.8%, P = 0.004). Multivariate analysis revealed that EI-guided management was an independent predictor of a lower HF-related event rate (hazard ratio = 0.15, 95%CI = 0.03~0.66, P = 0.012). Patients with a higher pre-discharge EI were older, had lower blood albumin and hemoglobin levels, and had a higher functional class and incidences of diabetes mellitus and chronic kidney disease. An increase in the pre-discharge EI by 0.001 increased the HF-related event rate by 6% (P = 0.002). Use of EI-guided management lowered this risk (P = 0.03). In conclusion, an EI-based HF management program demonstrated an event-lowering effect superior to traditional nurse-led multidisciplinary care in 6 months after an acute HF episode.

Genetic Disruption of KLF1 K74 SUMOylation in Hematopoietic System Promotes Healthy Longevity in Mice.

The quest for rejuvenation and prolonged lifespan through transfusion of young blood has been studied for decades with the hope of unlocking the mystery of the key substance(s) that exists in the circulating blood of juvenile organisms. However, a pivotal mediator has yet been identified. Here, atypical findings are presented that are observed in a knockin mouse model carrying a lysine to arginine substitution at residue 74 of Krüppel-like factor 1 (KLF1/EKLF), the SUMOylation-deficient Klf1K74R/K74R mouse, that displayed significant improvement in geriatric disorders and lifespan extension. Klf1K74R/K74R mice exhibit a marked delay in age-related physical performance decline and disease progression as evidenced by physiological and pathological examinations. Furthermore, the KLF1(K74R) knockin affects a subset of lymphoid lineage cells; the abundance of tumor infiltrating effector CD8+ T cells and NKT cells is increased resulting in antitumor immune enhancement in response to tumor cell administration. Significantly, infusion of hematopoietic stem cells (HSCs) from Klf1K74R/K74R mice extends the lifespan of the wild-type mice. The Klf1K74R/K74R mice appear to be an ideal animal model system for further understanding of the molecular/cellular basis of aging and development of new strategies for antiaging and prevention/treatment of age-related diseases thus extending the healthspan as well as lifespan.

Correlation of clinical changes with regard to thyroxine replacement therapy in hypothyroid patients: focusing on the change of renal function.

Thyroid dysfunction has an important role in renal insufficiency. The aim of the study was to correlate the change of renal function with other clinical factors after thyroxine therapy in hypothyroid patients. A prospective study was designed and 30 hypothyroid patients were included. All study subjects received 0.15-0.2 mg/day thyroxine for 12 weeks. Diastolic blood pressure and serum levels of creatine phosphokinase (CPK) and myoglobulin decreased significantly after thyroxine therapy. Serum creatinine decreased (0.87 ± 0.22 vs. 0.70 ± 0.17 mg/dl, p < 0.001) and estimated glomerular filtration rate (eGFR) increased significantly (82.06 ± 31.08 vs. 100.31 ± 31.79 ml/min/1.73 m(2); p < 0.001) after thyroxine replacement. Left ventricular ejection fraction (LVEF) was significantly increased after thyroxine replacement (64.47 ± 11.94 vs. 72.40 ± 13.89%, p = 0.026). No significant vascular functional changes of peripheral (pulse wave velocity) and renal interlobar arteries (pulsatility index and resistance index) were noted. The change of eGFR significantly correlated with the changes of serum-free T(4) (fT(4)), CPK, myoglobulin and LVEF. The correlation between the change of eGFR and thyroid-stimulating hormone (TSH) level was not significant. In conclusion, the GFR of hypothyroid patients increased significantly after thyroxine replacement. The change of GFR was significantly correlated with the changes of fT(4), CPK, myoglobulin and LVEF, but not with TSH.

Adverse body measurements are superior to sarcopenia-associated measurements in predicting chronic diseases.

Few studies have demonstrated an association of sarcopenia-associated body measurements with chronic diseases through a comprehensive methodology. This study aims to examine the relationship between sarcopenia-associated body measurements and chronic diseases. This is a cohort study. We recruited 316 community dwellers, including 76 patients with sarcopenia and 240 controls, and obtained their body measurements associated with sarcopenia. We collected three-dimensional anthropometric body-surface measurements from 11,158 participants during 2000-2008 and followed up this cohort for 15 years to examine the association of these measurements with the risk of chronic diseases such as hypertension, type 2 diabetes mellitus (T2DM), heart disease, and nephrotic syndrome. Univariate analysis, canonical correlation, and Cox regression analysis were performed to explore the associations. Decreased waist width, upper left arm circumference, and left thigh circumference were significantly associated with sarcopenia. The adverse body measure score (ABMS) was derived by combining significant measurements, namely left upper arm circumference, waist width, and left thigh circumference, and used to predict the risk of hypertension, T2DM, heart diseases, and nephrotic syndrome. A positive association was observed between the ABMS and chronic diseases. Considering the first quartile of the ABMS as a reference, we determined hazard ratios of 2.259, 2.495, 1.332, and 1.595 for hypertension, T2DM, heart disease, and nephrotic syndrome, respectively, in the fourth quartile. Chronic diseases were more strongly associated with the ABMS than with sarcopenia-related body measurements alone. A high ABMS, which includes higher upper arm circumference, higher waist width, and lower thigh circumference, can significantly predict chronic diseases.