Safety and Efficacy of Anti-Hypertensive Medications in Patients with Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-analysis.

INTRODUCTION: Hypertension (HTN) is a co-morbidity that is commonly associated with heart failure with preserved ejection fraction (HFpEF). However, it remains unclear whether treatment of hypertension in HFpEF patients is associated with improved cardiovascular outcomes. AIM: The purpose of this meta-analysis is to evaluate the association of anti-hypertensive medical therapy with cardiovascular outcomes in patients with HFpEF. METHODS: We performed a database search for studies reporting on the association of anti-hypertensive medications with cardiovascular outcomes and safety endpoints in patients with HFpEF. The databases searched include OVID Medline, Web of Science, and Embase. The primary endpoint was all-cause mortality. Secondary endpoints include cardiovascular (CV) mortality, worsening heart failure (HF), CV hospitalization, composite major adverse cardiovascular events (MACE), hyperkalemia, worsening renal function, and hypotension. RESULTS: A total of 12 studies with 14062 HFpEF participants (7010 treated with medical therapy versus 7052 treated with placebo) met inclusion criteria. Use of anti-hypertensive medications was not associated with lower all-cause mortality, CV mortality or CV hospitalization compared to treatment with placebo (OR 1.02, 95% CI 0.77-1.35; p = 0.9, OR 0.88, 95% CI 0.73-1.06; p = 0.19, OR 0.99, 95% CI 0.87-1.12; p = 0.83, OR 0.90, 95% CI 0.79-1.03; p = 0.11). Anti-hypertensive medications were not associated with lower risk of subsequent acute myocardial infarction (AMI) (OR 0.53, 95% CI 0.07-3.73; p = 0.5). Use of anti-hypertensive medications was associated with a statistically significant lower risk of MACE (OR 0.90, 95% CI 0.83-0.98; p = 0.02). CONCLUSIONS: While treatment with anti-hypertensive medications was not associated with lower risk of all-cause mortality, their use may be associated with reduce risk of adverse cardiovascular outcomes in patients with HFpEF regardless of whether they have HTN. Additional high quality studies are required to clarify this association and determine the effect based on specific classes of medications.

Utility of coronary revascularization in patients with ischemic left ventricular dysfunction.

BACKGROUND: Revascularization in patients with left ventricular (LV) dysfunction has been a subject of ongoing uncertainty and conflicting results. This is further complicated by factors including viability, severity of LV dysfunction, and method of revascularization using percutaneous coronary intervention (PCI) versus coronary-artery bypass grafting (CABG). OBJECTIVES: The purpose of this meta-analysis is to evaluate the association of coronary revascularization with outcomes in patients with ischemic LV dysfunction. METHODS: A literature search was conducted for studies reporting on cardiovascular outcomes after revascularization compared to optimal medical therapy (OMT) in patients with ischemic LV dysfunction. RESULTS: A total of 23 studies with 10,110 participants met inclusion criteria. Revascularization was significantly associated with lower all-cause mortality and CV mortality compared to OMT. The association was statistically significant regardless of severity of LV dysfunction or method of revascularization. Subgroup analysis demonstrated that revascularization was significantly associated with lower all-cause and CV mortality compared to OMT for patients with viable myocardium and mixed cohorts with variable viability, but not patients without viable myocardium. Revascularization was not associated with a significant difference in risk of heart failure (HF) hospitalization or acute myocardial infarction (AMI) compared to OMT. CONCLUSIONS: Revascularization in patients with ischemic LV dysfunction is associated with lower risk of all-cause and CV mortality independent of severity of LV dysfunction or method of revascularization. Revascularization is not associated with lower risk of mortality in patients without evidence of viable myocardium and is not associated with lower risk of AMI or HF hospitalization.

Utility of native T1 mapping and myocardial extracellular volume fraction in patients with nonischemic dilated cardiomyopathy: A systematic review and meta-analysis.

Background: Cardiac magnetic resonance imaging (CMR) based T1 mapping and extracellular volume fraction (ECV) are powerful tools for identifying myocardial fibrosis. This systematic review and meta-analysis aims to characterize the utility of native T1 mapping and ECV in patients with non-ischemic cardiomyopathy (NICM) and to clarify the prognostic significance of elevated values. Methods: A literature search was conducted for studies reporting on use of CMR-based native T1 mapping and ECV measurement in NICM patients and their association with major adverse cardiac events (MACE), ventricular arrhythmias (VAs), and left ventricular reverse remodeling (LVRR). Databases searched included: Ovid MEDLINE, EMBASE, Web of Science, and Google Scholar. The search was not restricted to time or publication status. Results: Native T1 and ECV were significantly higher in NICM patients compared to controls (MD 78.80, 95 % CI 50.00, 107.59; p < 0.01; MD 5.86, 95 % CI 4.55, 7.16; p < 0.01). NICM patients who experienced MACE had higher native T1 and ECV (MD 52.87, 95 % CI 26.59, 79.15; p < 0.01; MD 6.03, 95 % CI 3.79, 8.26; p < 0.01). There was a non-statistically significant trend toward higher native T1 time in NICM patients who experienced VAs. NICM patients who were poor treatment responders had higher baseline native T1 and ECV (MD 40.58, 95 % CI 12.90, 68.25; p < 0.01; MD 3.29, 95 % CI 2.25, 4.33; p < 0.01). Conclusions: CMR-based native T1 and ECV quantification may be useful tools for risk stratification of patients with NICM. They may provide additional diagnostic utility in combination with LGE, which poorly characterizes fibrosis in patients with diffuse myocardial involvement.

Association of antiplatelet therapy with clinical outcomes in patients with peripheral artery disease.

BACKGROUND: The beneficial role of dual anti-platelet therapy (DAPT) in coronary artery disease is well established. However, there is limited data describing the effects of DAPT in patients with atherosclerotic peripheral artery disease (PAD). The aim of this meta-analysis is to compare clinical outcomes associated with DAPT versus single anti-platelet therapy (SAPT) in patients with symptomatic PAD. METHODS: We performed a literature search for studies assessing the risk of adverse cardiovascular and limb events in cohorts receiving either DAPT or SAPT. The primary endpoint was all cause mortality. The secondary endpoints included graft failure, amputation, total bleeding, severe bleeding and fatal bleeding. The search included the following databases: Ovid MEDLINE, EMBASE, Web of Science, and Google Scholar. The search was not restricted to time or publication status. RESULTS: A total of 11 studies with 54,331 participants (24,449 on SAPT and 29,882 on DAPT) were included. Patients with PAD treated with SAPT had higher all-cause mortality compared to patients treated with DAPT (OR 1.37, 95 % CI 1.09-1.74; p < 0.01). There was no difference in risk of graft failure or amputation between patients treated with SAPT or DAPT (OR 0.9, 95 % CI 0.77-1.06; p = 0.19; OR 1.11, 95 % CI 0.88-1.41; p = 0.37). Patients treated with SAPT had lower total bleeds compared to patients treated with DAPT (OR 0.53, 95 % CI 0.36-0.77; p < 0.01). However, For SAPT plus AC vs SAPT, a total of 8 studies with 17,100 participants (3447 with SAPT plus AC and 8619 with only SAPT) were included. Patients on SAPT plus AC did not have a statistically significant difference in risk for all-cause mortality, (OR 0.91, 95 % CI 0.67-1.24; p = 0.56). SAPT plus AC had significantly lower risk of MI (OR 0.82, 95 % CI 0.69-0.97; p = 0.02), amputation (OR 0.72, 95 % CI 0.53-0.97; p = 0.03), and graft failure (OR 0.66, 95 % CI 0.48-0.93; p = 0.02). There was no significant different in risk of fatal bleeding be-tween the two groups (OR 1.60, 95 % CI 0.76-3.35; p = 0.22). CONCLUSIONS: In patients with symptomatic PAD, a strategy of DAPT may confer a mortality benefit when compared to SAPT without significantly increasing the risk of serious bleeding events.

Outcomes and Medical Therapy in Myocardial Infarction With Nonobstructive Coronary Arteries: A Systematic Review and Meta-Analysis.

Myocardial infarction with nonobstructive coronary arteries (MINOCAs) is a disease that has been poorly characterized with unclear clinical and therapeutic outcomes. The association of medical therapy with cardiovascular outcomes in patients with MINOCA has been inadequately assessed. The purpose of this meta-analysis is to evaluate the association of MINOCA at risk of adverse cardiovascular outcomes as compared with myocardial infarction with coronary artery disease (MICAD) and the efficacy of medical therapy in reducing the risk of adverse outcomes. A literature search was conducted for studies reporting on the association of MINOCA at risk of adverse outcomes as compared with MICAD. A literature search was also conducted for studies reporting on the association of medical therapy at risk of adverse outcomes in patients with MINOCA. A total of 29 studies with 893,134 participants met inclusion criteria comparing MINOCA to MICAD. Patients with MINOCA had a significantly lower risk of adverse outcomes as compared with MICAD. Nine studies with 27,731 MINOCA patients met inclusion criteria for evaluating the utility of medical therapy. Medical therapy did not significantly reduce risk of MACE; however, there was a trend toward lower risk in patients treated with ß blockers. In conclusion, our results suggest that MINOCA is associated with a lower risk of in-hospital and long-term adverse outcomes compared with MICAD. Standard medical therapy is not associated with a lower risk of adverse cardiovascular outcomes in patients with MINOCA. Additional high-quality studies are required to evaluate the utility of specific medication classes for the treatment of specific etiologies of MINOCA.

Utility of Fractional Flow Reserve Computed Tomography Angiography in Patients With Stable Coronary Artery Disease.

Coronary computed tomography angiography is a modality with high negative predictive value for evaluation of coronary artery disease (CAD). However, its diagnostic accuracy for obstructive CAD is limited by multiple factors. Fractional flow reserve (FFR) computed tomography (FFRCT) is an emerging analysis tool for identifying flow-limiting disease; nonetheless, the prognostic value of FFRCT is not well established. This meta-analysis aims to evaluate the association of FFRCT with clinical outcomes in patients with stable CAD. A literature search was conducted for studies reporting the association between FFRCT measurements and all-cause mortality, major adverse cardiovascular events (MACEs), acute myocardial infarction (AMI), and any need for coronary revascularization. Obstructive disease was defined as a FFR value ≤0.80; nonobstructive disease was defined as an FFR value >0.80. Ten studies were identified to meet the inclusion criteria; mean follow-up was 17 months (range, 3 to 56 months). There was no difference in risk of all-cause mortality between patients with obstructive and those with nonobstructive CAD on FFRCT. However, obstructive lesions were associated with increased risk of MACE, AMI, and any need for revascularization. FFRCT is a useful adjunctive modality for further risk stratification of patients with stable CAD. Obstructive lesions identified by FFRCT are associated with increased risk of MACE, AMI, and any need for revascularization.

Markers of Iron Metabolism and Outcomes in Patients with Heart Failure: A Systematic Review.

Iron deficiency (ID) in conjunction with heart failure (HF) poses a challenge for clinicians and is associated with worse HF outcomes. Treatment of ID with IV iron supplementation for patients with HF has demonstrated benefits in quality of life (QoL) and HF-related hospitalizations. The aim of this systematic review was to summarize the evidence linking iron metabolism biomarkers with outcomes in patients with HF to assist in the optimal use of these biomarkers for patient selection. A systematic review of observational studies in English from 2010 to 2022 was conducted using PubMed, with keywords of "Heart Failure" and respective iron metabolism biomarkers ("Ferritin", "Hepcidin", "TSAT", "Serum Iron", and "Soluble Transferrin Receptor"). Studies pertaining to HF patients, with available quantitative data on serum iron metabolism biomarkers, and report of specific outcomes (mortality, hospitalization rates, functional capacity, QoL, and cardiovascular events) were included, irrespective of left ventricular ejection fraction (LVEF) or other HF characteristics. Clinical trials of iron supplementation and anemia treatment were removed. This systematic review was conducive to formal assessment of risk of bias via Newcastle-Ottawa Scale. Results were synthesized based on their respective adverse outcomes and iron metabolism biomarker(s). Initial and updated searches identified 508 unique titles once duplicates were removed. The final analysis included 26 studies: 58% focused on reduced LVEF; age range was 53-79 years; males composed 41-100% of the reported population. Statistically significant associations of ID were observed with all-cause mortality, HF hospitalization rates, functional capacity, and QoL. Increased risk for cerebrovascular events and acute renal injury have also been reported, but these findings were not consistent. Varying definitions of ID were utilized among the studies; however, most studies employed the current European Society of Cardiology criteria: serum ferritin < 100 ng/mL or the combination of ferritin between 100-299 ng/mL and transferrin saturation (TSAT) < 20%. Despite several iron metabolism biomarkers demonstrating strong association with several outcomes, TSAT better predicted all-cause mortality, as well as long-term risk for HF hospitalizations. Low ferritin was associated with short-term risk for HF hospitalizations, worsening functional capacity, poor QoL, and development of acute renal injury in acute HF. Elevated soluble transferrin receptor (sTfR) levels were associated with worse functional capacity and QoL. Finally, low serum iron was significantly associated with increased risk for cardiovascular events. Considering the lack of consistency among the iron metabolism biomarkers for association with adverse outcomes, it is important to incorporate additional biomarker data, beyond ferritin and TSAT, when assessing for ID in HF patients. These inconsistent associations question how best to define ID to ensure proper treatment. Further research, potentially tailored to specific HF phenotypes, is required to optimize patient selection for iron supplementation therapy and appropriate targets for iron stores replenishment.

Admission NT-proBNP and outcomes in patients without history of heart failure hospitalized with COVID-19.

AIMS: We examined the value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients admitted for coronavirus disease 2019 (COVID-19) without prior history of heart failure (HF) or cardiomyopathy. METHODS AND RESULTS: Retrospective cohort of consecutive adults (N = 679; median age 59 years; 38.7% women; 87.5% White; 7.1% Black; 5.4% Asian; 34.3% Hispanic) admitted with documented COVID-19 in an academic centre in Long Island, NY. Admission NT-proBNP was categorized using the European Society of Cardiology Heart Failure Association age-specific criteria for acute presentations. We examined (i) mortality and the composite of death or mechanical ventilation and (ii) out-of-hospital, intensive care unit (ICU)-free, and ventilator-free days at 28 days. Estimates were adjusted for confounders using a lasso selection process. Using age-specific criteria, 417 patients (61.4%) had low, 141 (20.8%) borderline, and 121 (17.8%) high NT-proBNP. Mortality was 5.8%, 20.6%, and 36.4% for patients with low, borderline, and high NT-proBNP, respectively. In lasso-adjusted models, high NT-proBNP was associated with higher mortality [hazard ratio (HR) 2.15; 95% confidence interval (CI) 1.06-4.39; P = 0.034] and composite endpoint rates (HR 1.66; 95%CI 1.04-2.66; P = 0.035). Patients with high NT-proBNP had 32%, 33%, and 33% fewer out-of-hospital, ICU-free, and ventilator-free days compared with low NT-proBNP counterparts. Results were consistent across age, sex, and race, and regardless of coronary artery disease or hypertension, except for stronger mortality signal with high NT-proBNP in women. CONCLUSIONS: In patients with COVID-19 and no HF history, high admission NT-proBNP is associated with higher mortality and healthcare resources utilization. Preventive strategies may be required for these patients.

Association of Proteinuria and Hematuria with Acute Kidney Injury and Mortality in Hospitalized Patients with COVID-19.

INTRODUCTION: Acute kidney injury (AKI) is strongly associated with poor outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19), but data on the association of proteinuria and hematuria are limited to non-US populations. In addition, admission and in-hospital measures for kidney abnormalities have not been studied separately. METHODS: This retrospective cohort study aimed to analyze these associations in 321 patients sequentially admitted between March 7, 2020 and April 1, 2020 at Stony Brook University Medical Center, New York. We investigated the association of proteinuria, hematuria, and AKI with outcomes of inflammation, intensive care unit (ICU) admission, invasive mechanical ventilation (IMV), and in-hospital death. We used ANOVA, t test, χ2 test, and Fisher's exact test for bivariate analyses and logistic regression for multivariable analysis. RESULTS: Three hundred patients met the inclusion criteria for the study cohort. Multivariable analysis demonstrated that admission proteinuria was significantly associated with risk of in-hospital AKI (OR 4.71, 95% CI 1.28-17.38), while admission hematuria was associated with ICU admission (OR 4.56, 95% CI 1.12-18.64), IMV (OR 8.79, 95% CI 2.08-37.00), and death (OR 18.03, 95% CI 2.84-114.57). During hospitalization, de novo proteinuria was significantly associated with increased risk of death (OR 8.94, 95% CI 1.19-114.4, p = 0.04). In-hospital AKI increased (OR 27.14, 95% CI 4.44-240.17) while recovery from in-hospital AKI decreased the risk of death (OR 0.001, 95% CI 0.001-0.06). CONCLUSION: Proteinuria and hematuria both at the time of admission and during hospitalization are associated with adverse clinical outcomes in hospitalized patients with COVID-19.

Human ESC-Derived Chimeric Mouse Models of Huntington's Disease Reveal Cell-Intrinsic Defects in Glial Progenitor Cell Differentiation.

Huntington's disease (HD) is characterized by hypomyelination and neuronal loss. To assess the basis for myelin loss in HD, we generated bipotential glial progenitor cells (GPCs) from human embryonic stem cells (hESCs) derived from mutant Huntingtin (mHTT) embryos or normal controls and performed RNA sequencing (RNA-seq) to assess mHTT-dependent changes in gene expression. In human GPCs (hGPCs) derived from 3 mHTT hESC lines, transcription factors associated with glial differentiation and myelin synthesis were sharply downregulated relative to normal hESC GPCs; NKX2.2, OLIG2, SOX10, MYRF, and their downstream targets were all suppressed. Accordingly, when mHTT hGPCs were transplanted into hypomyelinated shiverer mice, the resultant glial chimeras were hypomyelinated; this defect could be rescued by forced expression of SOX10 and MYRF by mHTT hGPCs. The mHTT hGPCs also manifested impaired astrocytic differentiation and developed abnormal fiber architecture. White matter involution in HD is thus a product of the cell-autonomous, mHTT-dependent suppression of glial differentiation.