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  • 1
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 146, No. Suppl_1 ( 2022-11-08)
    Abstract: Introduction: Evaluating the efficacy of newer medical therapies in black patients with heart failure with reduced ejection fraction (HFrEF) remains an important and unanswered question. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) in HFrEF to compare outcomes in black versus non-black patients with a specific focus on new therapies, namely ARNIs and SGLT2 inhibitors. Methods: Medline, Embase and Cochrane CENTRAL were searched from inception until May 2022. Pairs of reviewers independently identified RCTs that 1) compared either an SGLT2 inhibitor or an ARNI to placebo/standard of care in HFrEF patients and 2) reported outcomes stratified by race. Outcomes were pooled using the Generic Inverse Variance or Mantel-Haenszel models, and risk of bias was assessed using the Cochrane tool. Results: Four RCTs (n=17,797; 6.6% black) were identified, all of which were published in the past decade. In the placebo/control arm, black patients had a higher rate of heart failure hospitalization or cardiovascular death compared to non-black/white patients (OR: 1.52, 95% CI: 1.26, 1.84; absolute difference: 81, [95% CI: 43, 124] more events per 1,000 patients). In two RCTs, there was a trend towards a greater reduction in the composite of cardiovascular death or heart failure hospital ization with SGLT2 inhibitors in black patients (n=483; RR: 0.61, 95% CI: 0.45, 0.83) compared to white patients (n=6,445; RR: 0.84, 95% CI: 0.75, 0.95; p-interaction=0.06). In two RCTs, treatment with an ARNI was associated with reductions in the composite of cardiovascular death or heart failure hospitalization in both black patients (n=744; HR: 0.67, 95% CI: 0.40, 1.11) and non-black/white patients (n=6,109; HR: 0.80, 95% CI: 0.72, 0.89; p-interaction= p=0.49). Conclusions: Black patients are poorly represented in contemporary heart failure trials, and have worse outcomes compared with non-black patients. Newer therapies such as ARNIs and SGLT2 inhibitors are efficacious in black patients. SGLT2 inhibitors may afford greater risk reduction in black compared to non-black patients.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1466401-X
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  • 2
    In: European Heart Journal, Oxford University Press (OUP), Vol. 44, No. 37 ( 2023-10-01), p. 3640-3651
    Abstract: For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to reduce the composite of heart failure hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials. While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents. The SGLT2 inhibitors have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and autophagic flux in addition to altering iron homeostasis, which may contribute to improved cardiac energetics and function. These agents also reduce epicardial adipose tissue and alter adipokine signalling, which may play a role in the reductions in inflammation and oxidative stress observed with SGLT2 inhibition. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized. Finally, SGLT2 inhibitors have been shown to reduce myofilament stiffness as well as extracellular matrix remodelling/fibrosis in the heart, improving diastolic function. The SGLT2 inhibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will likely become foundational in the therapy of HFpEF.
    Type of Medium: Online Resource
    ISSN: 0195-668X , 1522-9645
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2001908-7
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  • 3
    In: European Journal of Heart Failure, Wiley, Vol. 25, No. 4 ( 2023-04), p. 591-593
    Type of Medium: Online Resource
    ISSN: 1388-9842 , 1879-0844
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 1500332-2
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  • 4
    Online Resource
    Online Resource
    American Physiological Society ; 2024
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 326, No. 3 ( 2024-03-01), p. H670-H688
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 326, No. 3 ( 2024-03-01), p. H670-H688
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    RVK:
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2024
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2022
    In:  European Heart Journal Vol. 43, No. 31 ( 2022-08-14), p. 2931-2945
    In: European Heart Journal, Oxford University Press (OUP), Vol. 43, No. 31 ( 2022-08-14), p. 2931-2945
    Abstract: Despite existing treatments, patients with heart failure and chronic kidney disease (CKD) remain at high risk for adverse outcomes and progression to end-stage disease. Steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone reduce mortality but remain under-prescribed due to the perceived risk of hyperkalaemia and hormonal side effects. The discovery of non-steroidal MRAs represents a major new dimension in cardiorenal disease therapy. Non-steroidal MRAs have high affinity and specificity for the mineralocorticoid receptor (MR) and differ from both steroidal agents and each other with respect to important physiochemical, pharmacodynamic, and pharmacokinetic parameters. Similar to their steroidal counterparts, they have beneficial anti-inflammatory, anti-remodelling, and anti-fibrotic properties in the kidneys, heart, and vasculature. There are several non-steroidal MRAs under development and clinical assessment; of these, only esaxerenone and finerenone are approved for treatment globally. In Japan, esaxerenone is approved for essential hypertension and has been studied in diabetic nephropathy. Compared with steroidal MRAs, finerenone more potently inhibits MR co-regulator recruitment and fibrosis and distributes more evenly between the heart and kidneys. The landmark Phase III trials FIGARO-DKD and FIDELIO-DKD demonstrated that finerenone-reduced major kidney and cardiovascular events on top of maximally tolerated renin–angiotensin–aldosterone system inhibition in patients with CKD associated with Type 2 diabetes. Non-steroidal MRAs are currently under evaluation in heart failure and for synergistic treatment with sodium–glucose contransporter 2 inhibitors. These ground-breaking agents could become an important therapy across the spectrum of cardiorenal disease.
    Type of Medium: Online Resource
    ISSN: 0195-668X , 1522-9645
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2001908-7
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  • 6
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 323, No. 3 ( 2022-09-01), p. E254-E266
    Abstract: Sex differences in the prevalence and development of diabetes and associated cardiometabolic complications are well established. The objective of this study was to analyze the effects of estrogen on the maintenance of β-cell health/function and atherosclerosis progression, using a mouse model of hyperglycemia-induced atherosclerosis, the ApoE −/− : Ins2 +/Akita mouse. ApoE −/− : Ins2 +/Akita mice exhibit sexual dimorphism in the control of blood glucose levels. Male ApoE −/− : Ins2 +/Akita mice are chronically hyperglycemic due to a significant reduction in pancreatic β-cell mass. Female mice are only transiently hyperglycemic, maintain β-cell mass, and blood glucose levels normalize at 35 ± 1 days of age. To determine the effects of estrogen on pancreatic β-cell health and function, ovariectomies and estrogen supplementation experiments were performed, and pancreatic health and atherosclerosis were assessed at various time points. Ovariectomized ApoE −/− : Ins2 +/Akita mice developed chronic hyperglycemia with significantly reduced β-cell mass. To determine whether the observed effects on ovariectomized ApoE −/− : Ins2 +/Akita mice were due to a lack of estrogens, slow-releasing estradiol pellets were inserted subcutaneously. Ovariectomized ApoE −/− : Ins2 +/Akita mice treated with exogenous estradiol showed normalized blood glucose levels and maintained β-cell mass. Exogenous estradiol significantly reduced atherosclerosis in both ovariectomized female and male ApoE −/− : Ins2 +/Akita mice relative to controls. Together, these findings suggest that estradiol confers significant protection to pancreatic β-cell health and can directly and indirectly slow the progression of atherosclerosis. NEW & NOTEWORTHY This study examines the effect(s) of estrogen on β cell and cardiometabolic health/function in a novel mouse model of hyperglycemia-induced atherosclerosis ( ApoE −/− : Ins2 +/Akita ). Using a combination of estrogen deprivation (ovariectomy) and supplementation strategies, we quantify effects on glucose homeostasis and atherogenesis. Our results clearly show a protective role for estrogen on pancreatic β-cell health and function and glucose homeostasis. Furthermore, estrogen supplementation dramatically reduces atherosclerosis progression in both male and female mice.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2022
    detail.hit.zdb_id: 1477331-4
    SSG: 12
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  • 7
    In: ESC Heart Failure, Wiley, Vol. 9, No. 2 ( 2022-04), p. 942-946
    Abstract: Sodium‐glucose cotransporter 2 (SGLT2) inhibitors have been shown to be an effective therapy in improving heart failure outcomes. We conducted a meta‐analysis of randomized controlled trials to evaluate the efficacy of SGLT2 inhibitors in heart failure patients with either a reduced or preserved ejection fraction. Methods and results We searched MEDLINE and EMBASE for large (≥1000 patients) randomized controlled trials evaluating the effects of SGLT2 inhibitors compared with placebo in the setting of heart failure until September 2021. Our primary outcome was the composite of heart failure hospitalization and cardiovascular death, and secondary outcomes included all‐cause mortality and total heart failure hospitalizations. We pooled hazard ratios and risk ratios and evaluated risk of bias with the Cochrane Collaboration tool. Four randomized controlled trials (DAPA HF, EMPEROR‐Preserved, EMPEROR‐Reduced, and SOLOIST‐WHF) were included ( n  = 15 684); two of which evaluated patients with a reduced LVEF, one of which evaluated patients with a preserved LVEF, and one of which included both. Treatment with SGLT2 inhibitors resulted in a significant reduction in the composite of CV death and heart failure hospitalization (HR: 0.76, 95% CI: 0.70, 0.82, I 2 : 0%, P   〈  0.00001). This was consistent in sub‐groups of patients with LVEF ≤40% ( n  = 9199, HR: 0.74, 95% CI: 0.68, 0.81, I 2 : 0%) and LVEF 〉 40% ( n  = 6482, HR: 0.78, 95% CI: 0.68, 0.89, I 2 : 0%, P ‐for‐interaction: 0.57), as well as in sub‐groups of patients with and without diabetes mellitus at baseline ( P ‐for‐interaction: 0.81). SGLT2 inhibitors were associated with a significant reduction in cardiovascular death (HR: 0.87, 95% CI: 0.79, 0.97, I 2 : 0%, P   〈  0.00001) and total heart failure hospitalization (RR: 0.71, 95% CI: 0.67, 0.76, I 2 : 0%, P   〈  0.00001); although a potential trend towards reduced all‐cause mortality was noted with SGLT2 inhibitors, no statistically significant difference was observed (HR: 0.91, 95% CI: 0.83, 1.00, I 2 : 14%, P  = 0.05). Conclusions Sodium‐glucose cotransporter 2 inhibitors reduce cardiovascular death and heart failure hospitalization among patients with heart failure, regardless of LVEF status.
    Type of Medium: Online Resource
    ISSN: 2055-5822 , 2055-5822
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2814355-3
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  • 8
    In: The Annals of Thoracic Surgery, Elsevier BV, Vol. 115, No. 2 ( 2023-02), p. 437-443
    Type of Medium: Online Resource
    ISSN: 0003-4975
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 1499869-5
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  • 9
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2022
    In:  European Heart Journal Vol. 43, No. 31 ( 2022-08-14), p. 2994-2996
    In: European Heart Journal, Oxford University Press (OUP), Vol. 43, No. 31 ( 2022-08-14), p. 2994-2996
    Type of Medium: Online Resource
    ISSN: 0195-668X , 1522-9645
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2001908-7
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  • 10
    In: Cardiovascular Diabetology, Springer Science and Business Media LLC, Vol. 22, No. 1 ( 2023-06-28)
    Abstract: 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/m 2 and those who had a baseline LVMi  〉  60 g/m 2 . 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/m 2 (49.2–57.2) and 69.7 g/m 2 (64.2–76.1) for those with baseline ≤ 60 g/m 2 (n = 54) and LVMi  〉  60 g/m 2 (n = 43) respectively. The adjusted difference of LVMi regression between those randomized to empagliflozin and placebo were − 0.46 g/m 2 (95% CI: −3.44, 2.52, p  = 0.76) in the baseline LVMi ≤ 60 g/m 2 subgroup and − 7.26 g/m 2 (95% CI: −11.40, −3.12, p  = 0.0011) in the baseline LVMi  〉  60 g/m 2 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.
    Type of Medium: Online Resource
    ISSN: 1475-2840
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2093769-6
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