Revisiting sex as a biological variable in hypertension research.

Half of adults in the United States have hypertension as defined by clinical practice guidelines. Interestingly, women are generally more likely to be aware of their hypertension and have their blood pressure controlled with treatment compared with men, yet hypertension-related mortality is greater in women. This may reflect the fact that the female sex remains underrepresented in clinical and basic science studies investigating the effectiveness of therapies and the mechanisms controlling blood pressure. This Review provides an overview of the impact of the way hypertension research has explored sex as a biological variable (SABV). Emphasis is placed on epidemiological studies, hypertension clinical trials, the genetics of hypertension, sex differences in immunology and gut microbiota in hypertension, and the effect of sex on the central control of blood pressure. The goal is to offer historical perspective on SABV in hypertension, highlight recent studies that include SABV, and identify key gaps in SABV inclusion and questions that remain in the field. Through continued awareness campaigns and engagement/education at the level of funding agencies, individual investigators, and in the editorial peer review system, investigation of SABV in the field of hypertension research will ultimately lead to improved clinical outcomes.

Blood pressure management strategies and podocyte health.

Hypertension (HTN) is one of the key global cardiovascular risk factors, which is tightly linked to kidney health and disease development. Podocytes, glomerular epithelial cells that play a pivotal role in maintenance of the renal filtration barrier, are significantly affected by increased glomerular capillary pressure in HTN. Damage or loss of these cells causes proteinuria, which marks the initiation of the HTN-driven renal damage. It goes without saying that effective BP management should not only mitigate cardiovascular risks but also preserve renal function by protecting podocyte integrity. This review offers a comprehensive examination of current blood pressure (BP) management strategies and their implications for podocyte structure and function and emphasizes strategies for the reduction of proteinuria in HTN. We explore primary and secondary antihypertensive agents, including ACE inhibitors, ARBs, calcium channel blockers, diuretics, as well as newer therapies (SGLT2 blocking and endothelin receptor antagonism), emphasizing their mechanistic roles in safeguarding podocytes and curtailing proteinuria.

Cause-specific and all-cause mortalities in vegetarian compared with those in nonvegetarian participants from the Adventist Health Study-2 cohort.

BACKGROUND: There have been mixed results reported internationally when associating vegetarian dietary patterns with all-cause and cause-specific mortalities. OBJECTIVES: This study aimed to extend our previous results by evaluating, with a larger number of deaths (N = 12,515), cause-specific mortalities comparing different vegetarian types with nonvegetarians. METHODS: This prospective study used data from the Adventist Health Study-2 cohort. Mortality was ascertained between study baseline, 2002-2007, and follow-up through 2015. Dietary data were collected at baseline using a validated quantitative food frequency questionnaire and then categorized into 5 dietary patterns: nonvegetarian, semivegetarian, pescovegetarian, lacto-ovovegetarian, and vegan. Main outcomes and measures include all-cause and cause-specific mortalities using Cox proportional hazards regression models and competing risk methods. RESULTS: The analytic sample included 88,400 participants who provided 971,424 person-years of follow-up. We report results pairwise as estimated at ages 65 and 85 y owing to age dependence of many hazard ratios (HRs). Compared with nonvegetarians, vegetarians had lower risks of mortality, overall (HR: 0.89; 95% confidence interval [CI]: 0.83, 0.95; HR: 0.98; 95% CI: 0.91, 1.04), from renal failure (HR: 0.52; 95% CI: 0.38, 0.70; HR: 0.65; 95% CI: 0.55, 0.76), infectious disease (HR: 0.57; 95% CI: 0.40, 0.82; HR: 0.90; 95% CI: 0.70, 1.17), diabetes (HR: 0.51; 95% CI: 0.33, 0.78; HR: 0.69; 95% CI: 0.53, 0.88), select cardiac (HR: 0.75; 95% CI: 0.65, 0.87; HR: 0.89; 95% CI: 0.83, 0.95), and ischemic heart disease causes (HR: 0.73; 95% CI: 0.59, 0.90; HR: 0.84; 95% CI: 0.75,0.94). Vegans, lacto-ovovegetarians, and pescovegetarians were also observed to have lower risks of total mortality and several similar cause-specific mortalities. However, higher cause-specified neurologic mortalities were observed among older vegetarians (estimated at age 85 y), specifically stroke (HR: 1.17; 95% CI: 1.02, 1.33), dementia (HR: 1.13; 95% CI: 1.00, 1.27), and Parkinson's disease (HR: 1.37; 95% CI: 0.98, 1.91). Results in Black subjects for vegetarian/nonvegetarian comparisons largely followed the same trends, but HRs were less precise owing to smaller numbers. CONCLUSIONS: Vegetarian diets are associated with lower risk for all-cause and many cause-specific mortalities, especially among males and in younger subjects. However, higher risks are observed among older vegetarians for stroke and dementia. These results need further support and investigation.

Cardiorenal Syndrome in Right Heart Failure Due to Pulmonary Arterial Hypertension-The Right Ventricle as a Therapeutic Target to Improve Renal Function.

Cardiorenal syndrome (CRS) due to right ventricular (RV) failure is a disease entity emerging as a key indicator of morbidity and mortality. The multifactorial aspects of CRS and the left-right ventricular interdependence complicate the link between RV failure and renal function. RV failure has a direct pathophysiological link to renal dysfunction by leading to systemic venous congestion in certain circumstances and low cardiac output in other situations, both leading to impaired renal perfusion. Indeed, renal dysfunction is known to be an independent predictor of mortality in patients with pulmonary arterial hypertension (PAH) and RV failure. Thus, it is important to further understand the interaction between the RV and renal function. RV adaptation is critical to long-term survival in patients with PAH. The RV is also known for its remarkable capacity to recover once the aggravating factor is addressed or mitigated. However, less is known about the renal potential for recovery following the resolution of chronic RV failure. In this review, we provide an overview of the intricate relationship between RV dysfunction and the subsequent development of CRS, with a particular emphasis on PAH. Additionally, we summarize potential RV-targeted therapies and their potential beneficial impact on renal function.

Patterns of Statin Therapy Use and Associated Outcomes in Older Veterans Across Kidney Function.

BACKGROUND: Despite significant morbidity and mortality related to atherosclerotic cardiovascular disease, to date, most major clinical trials studying the effects of statin therapy have excluded older adults. The objective of this analysis was to evaluate the effect of initiating statin therapy on incident dementia and mortality among individuals 75 years of age or older across the complete spectrum of kidney function. METHODS: We conducted a retrospective cohort study of 640,191 VA health system patients who turned 75 years of age between 2000 and 2018. Patients on statin therapy received the medication for an average of 6.3 years (standard deviation 4.6 years). The primary outcome of interest included incident dementia diagnosis during the study period. The secondary outcome was all-cause mortality. Cox proportional hazard analysis was used to evaluate the adjusted association of statin initiation with these outcomes. RESULTS: There was a higher rate of incident dementia in the No Statin group (4.7%) vs the Statin group (3.2%). Additionally, we observed a 22% all-cause mortality benefit associated with statin therapy. We did not observe a treatment effect with respect to primary or secondary outcomes across varying levels of kidney function. CONCLUSION: This large cohort study did not reveal an association between the initiation of statin therapy and incident dementia. A survival benefit was seen in statin users compared with nonusers. Prospective studies in more diverse populations including older adults will be needed to verify these findings.

Body Mass Index and Clinical and Health Status Outcomes in Chronic Coronary Disease and Advanced Kidney Disease in the ISCHEMIA-CKD Trial.

OBJECTIVE: This study aimed to assess whether an obesity paradox (lower event rates with higher body mass index [BMI]) exists in participants with advanced chronic kidney disease (CKD) and chronic coronary disease in the International Study of Comparative Health Effectiveness of Medical and Invasive Approaches (ISCHEMIA)-CKD, and whether BMI modified the effect of initial treatment strategy. METHODS: Baseline BMI was analyzed as both a continuous and categorical variable (< 25, ≥ 25 to < 30, ≥ 30 kg/m2). Associations between BMI and the primary outcome of all-cause death or myocardial infarction (D/MI), and all-cause death, cardiovascular death, and MI individually were estimated. Associations with health status were also evaluated using the Seattle Angina Questionnaire-7, the Rose Dyspnea Scale, and the EuroQol-5D Visual Analog Scale. RESULTS: Body mass index ≥ 30 kg/m2 vs < 25 kg/m2 demonstrated increased risk for MI (hazard ratio [HR] [95% confidence interval] = 1.81 [1.12-2.92]) and for D/MI (HR 1.45 [1.06-1.96]) with a HR for MI of 1.22 (1.05-1.40) per 5 kg/m2 increase in BMI in unadjusted analysis. In multivariate analyses, a BMI ≥ 30 kg/m2 was marginally associated with D/MI (HR 1.43 [1.00-2.04]) and greater dyspnea throughout follow-up (P < .05 at all time points). Heterogeneity of treatment effect between baseline BMI was not evident for any outcome. CONCLUSIONS: In the ISCHEMIA-CKD trial, an obesity paradox was not detected. Higher BMI was associated with worse dyspnea, and a trend toward increased D/MI and MI risk. Larger studies to validate these findings are warranted.

Sodium-glucose cotransporter 2 inhibitors and cardiorenal outcomes in kidney transplantation.

PURPOSE OF REVIEW: This review aims to explore the current evidence regarding cardiovascular and kidney outcomes in patients who undergo treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) post kidney transplantation. RECENT FINDINGS: Summary findings from individual studies included in this review showed largely favorable results in the kidney transplant recipients (KTRs) being treated with SGLT2i.These outcomes included parameters such as allograft function, glycemic control, proteinuria, blood pressure, weight loss and safety profile, among others. Almost all the studies reported an initial 'dip' in eGFR, followed by recovery, after the initiation of SGLT2i treatment. None of the studies reported significant interaction of SGLT2i with immunosuppressive medications. The most common adverse effects noted in these studies were infection-related including UTI and genital mycosis. None of the studies reported acute graft rejection attributable to SGLT2i therapy. SUMMARY: SGLT2i can play a significant role in improving health outcomes in KTRs. However, clinical trials with larger representation of KTRs longer follow-up period are needed to draw more substantial conclusions.

Impact of arteriovenous fistula on flow states in the evaluation of aortic stenosis among ESKD patients on dialysis.

INTRODUCTION: An arteriovenous fistula (AVF) in patients with end-stage kidney disease (ESKD) can influence flow states. We sought to evaluate if assessment of aortic stenosis (AS) by transthoracic echocardiographic (TTE) differs in the presence of AVF compared to other dialysis accesses in patients on dialysis. METHODS: We identified consecutive ESKD patients on dialysis and concomitant AS from a single center between January 2000 and March 2021. We analyzed TTE parameters of AS severity (velocities, gradients, aortic valve area [AVA]) and hemodynamics (cardiac output [CO], valvuloarterial impedance [Zva]) and compared AS parameters in patients with AVF versus other dialysis access. RESULTS: The cohort included 94 patients with co-prevalent ESKD and AS; mean age 66 years, 71% male; 43% Black, 24% severe AS. Dialysis access: 53% AVF, 47% others. In the overall cohort, no significant differences were noted between AVF versus non-AVF in AVA/CO/Zva, but with notable subgroup differences. In mild AS, CO was significantly higher in AVF versus non-AVF (6.3 vs. 5.2 L/min; p = .04). In severe AS, Zva was higher in the AVF versus non-AVF (4.6 vs. 3.6 mm Hg/mL/m2 ). With increasing AS severity in the AVF group, CO decreased, coupled with increase in Zva, likely counterbalancing the net hemodynamic impact of the AVF. CONCLUSION: Among ESKD patients with AS, TTE parameters of flow states and AS severity differed in those with AVF versus other dialysis accesses and varied with progression in severity of AS. Future longitudinal assessment of hemodynamic parameters in a larger cohort of co-prevalent ESRD and AS would be valuable.

Cardiovascular Disease in Diabetes and Chronic Kidney Disease.

Chronic kidney disease (CKD) is a common occurrence in patients with diabetes mellitus (DM), occurring in approximately 40% of cases. DM is also an important risk factor for cardiovascular disease (CVD), but CKD is an important mediator of this risk. Multiple CVD outcomes trials have revealed a greater risk for CVD events in patients with diabetes with CKD versus those without. Thus, reducing the risk of CKD in diabetes should result in improved CVD outcomes. To date, of blood pressure (BP) control, glycemic control, and inhibition of the renin-angiotensin system (RASI), glycemic control appears to have the best evidence for preventing CKD development. In established CKD, especially with albuminuria, RASI slows the progression of CKD. More recently, sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide receptor agonists (GLP1RA) have revolutionized the care of patients with diabetes with and without CKD. SGLT2i and GLP1RA have proven to reduce mortality, heart failure (HF) hospitalizations, and worsening CKD in patients with diabetes with and without existing CKD. The future of limiting CVD in diabetes and CKD is promising, and more evidence is forthcoming regarding combinations of evidence-based therapies to further minimize CVD events.

Proportional troponin changes and risk for outcomes with intervention strategies in non-ST-elevation acute coronary syndrome across kidney function.

AIMS: This analysis evaluates whether proportional serial cardiac troponin (cTn) change predicts benefit from an early versus delayed invasive, or conservative treatment strategies across kidney function in non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS: Patients diagnosed with NSTE-ACS in the Veterans Health Administration between 1999 and 2022 were categorized into terciles (<20%, 20 to ≤80%, >80%) of proportional change in serial cTn. Primary outcome included mortality or rehospitalization for myocardial infarction at 6 and 12 months, in survivors of index admission. Adjusted hazard ratio (HR) with 95% confidence Intervals (95% confidence interval [CI]) were calculated for the primary outcome for an early invasive (≤24 h of the index admission), delayed invasive (>24 h of index admission to 90-days postdischarge), or a conservative management. RESULTS: Chronic kidney disease (CKD) was more prevalent (45.3%) in the lowest versus 42.2% and 43% in middle and highest terciles, respectively (p < 0.001). Primary outcome is more likely for conservative versus early invasive strategy at 6 (HR: 1.44, 95% CI: 1.37-1.50) and 12 months (HR: 1.44, 95% CI: 1.39-1.50). A >80% proportional change demonstrated HR (95% CI): 0.90 (0.83-0.97) and 0.93 (0.88-1.00; p = 0.041) for primary outcome at 6 and 12 months, respectively, when an early versus delayed invasive strategy was used, across CKD stages. CONCLUSIONS: Overall, the invasive strategy was safe and associated with improved outcomes across kidney function in NSTE-ACS. Additionally, >80% proportional change in serial troponin in NSTE-ACS is associated with benefit from an early versus a delayed invasive strategy regardless of kidney function. These findings deserve confirmation in randomized controlled trials.

A Synopsis of the Evidence for the Science and Clinical Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome: A Scientific Statement From the American Heart Association.

A growing appreciation of the pathophysiological interrelatedness of metabolic risk factors such as obesity and diabetes, chronic kidney disease, and cardiovascular disease has led to the conceptualization of cardiovascular-kidney-metabolic syndrome. The confluence of metabolic risk factors and chronic kidney disease within cardiovascular-kidney-metabolic syndrome is strongly linked to risk for adverse cardiovascular and kidney outcomes. In addition, there are unique management considerations for individuals with established cardiovascular disease and coexisting metabolic risk factors, chronic kidney disease, or both. An extensive body of literature supports our scientific understanding of, and approach to, prevention and management for individuals with cardiovascular-kidney-metabolic syndrome. However, there are critical gaps in knowledge related to cardiovascular-kidney-metabolic syndrome in terms of mechanisms of disease development, heterogeneity within clinical phenotypes, interplay between social determinants of health and biological risk factors, and accurate assessments of disease incidence in the context of competing risks. There are also key limitations in the data supporting the clinical care for cardiovascular-kidney-metabolic syndrome, particularly in terms of early-life prevention, screening for risk factors, interdisciplinary care models, optimal strategies for supporting lifestyle modification and weight loss, targeting of emerging cardioprotective and kidney-protective therapies, management of patients with both cardiovascular disease and chronic kidney disease, and the impact of systematically assessing and addressing social determinants of health. This scientific statement uses a crosswalk of major guidelines, in addition to a review of the scientific literature, to summarize the evidence and fundamental gaps related to the science, screening, prevention, and management of cardiovascular-kidney-metabolic syndrome.

Cardiovascular-Kidney-Metabolic Health: A Presidential Advisory From the American Heart Association.

Cardiovascular-kidney-metabolic health reflects the interplay among metabolic risk factors, chronic kidney disease, and the cardiovascular system and has profound impacts on morbidity and mortality. There are multisystem consequences of poor cardiovascular-kidney-metabolic health, with the most significant clinical impact being the high associated incidence of cardiovascular disease events and cardiovascular mortality. There is a high prevalence of poor cardiovascular-kidney-metabolic health in the population, with a disproportionate burden seen among those with adverse social determinants of health. However, there is also a growing number of therapeutic options that favorably affect metabolic risk factors, kidney function, or both that also have cardioprotective effects. To improve cardiovascular-kidney-metabolic health and related outcomes in the population, there is a critical need for (1) more clarity on the definition of cardiovascular-kidney-metabolic syndrome; (2) an approach to cardiovascular-kidney-metabolic staging that promotes prevention across the life course; (3) prediction algorithms that include the exposures and outcomes most relevant to cardiovascular-kidney-metabolic health; and (4) strategies for the prevention and management of cardiovascular disease in relation to cardiovascular-kidney-metabolic health that reflect harmonization across major subspecialty guidelines and emerging scientific evidence. It is also critical to incorporate considerations of social determinants of health into care models for cardiovascular-kidney-metabolic syndrome and to reduce care fragmentation by facilitating approaches for patient-centered interdisciplinary care. This presidential advisory provides guidance on the definition, staging, prediction paradigms, and holistic approaches to care for patients with cardiovascular-kidney-metabolic syndrome and details a multicomponent vision for effectively and equitably enhancing cardiovascular-kidney-metabolic health in the population.

Plasma metabolomics profiles in Black and White participants of the Adventist Health Study-2 cohort.

BACKGROUND: Black Americans suffer disparities in risk for cardiometabolic and other chronic diseases. Findings from the Adventist Health Study-2 (AHS-2) cohort have shown associations of plant-based dietary patterns and healthy lifestyle factors with prevention of such diseases. Hence, it is likely that racial differences in metabolic profiles correlating with disparities in chronic diseases are explained largely by diet and lifestyle, besides social determinants of health. METHODS: Untargeted plasma metabolomics screening was performed on plasma samples from 350 participants of the AHS-2, including 171 Black and 179 White participants, using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and a global platform of 892 metabolites. Differences in metabolites or biochemical subclasses by race were analyzed using linear regression, considering various models adjusted for known confounders, dietary and/or other lifestyle behaviors, social vulnerability, and psychosocial stress. The Storey permutation approach was used to adjust for false discovery at FDR < 0.05. RESULTS: Linear regression revealed differential abundance of over 40% of individual metabolites or biochemical subclasses when comparing Black with White participants after adjustment for false discovery (FDR < 0.05), with the vast majority showing lower abundance in Blacks. Associations were not appreciably altered with adjustment for dietary patterns and socioeconomic or psychosocial stress. Metabolite subclasses showing consistently lower abundance in Black participants included various lipids, such as lysophospholipids, phosphatidylethanolamines, monoacylglycerols, diacylglycerols, and long-chain monounsaturated fatty acids, among other subclasses or lipid categories. Among all biochemical subclasses, creatine metabolism exclusively showed higher abundance in Black participants, although among metabolites within this subclass, only creatine showed differential abundance after adjustment for glomerular filtration rate. Notable metabolites in higher abundance in Black participants included methyl and propyl paraben sulfates, piperine metabolites, and a considerable proportion of acetylated amino acids, including many previously found associated with glomerular filtration rate. CONCLUSIONS: Differences in metabolic profiles were evident when comparing Black and White participants of the AHS-2 cohort. These differences are likely attributed in part to dietary behaviors not adequately explained by dietary pattern covariates, besides other environmental or genetic factors. Alterations in these metabolites and associated subclasses may have implications for the prevention of chronic diseases in Black Americans.

Outcomes of Severe Acute Kidney Injury in Pediatric Trauma Patients; The Trauma Quality Improvement Program Database Study.

INTRODUCTION: Acute kidney injury (AKI) has been associated with higher mortality and morbidity in trauma victims. There is a paucity of information regarding the outcomes of severe AKI (sAKI) in pediatric trauma patients. Therefore, the trauma quality improvement program database (TQIP) was used to assess that hypothesis sAKI will be associated with higher mortality among pediatric trauma patients. METHODS: The TQIP database was accessed for the study. Patients aged <18 years old admitted to the hospital after sustaining injury were included in the study. Demographics, injury severity score (ISS) and Glasgow coma scale (GCS) score, other body regions injuries, and available comorbidities were included in the study. Propensity score matching analysis was performed to compare the two groups, sAKI vs. no sAKI on patients' characteristics and outcomes. All p values are two-sided. A p-value <0.05 is considered statistically significant. RESULTS: Out of 139,832 patients who qualified for the study, 106 (0.1%) patients suffered from sAKI. Pair-matched analysis showed no significant difference between the groups, sAKI, and no sAKI, regarding the in-hospital mortality (14.3% vs. 12.4%, P = 0.838). There was a prolonged hospital length of stay in the sAKI group when compared to the no sAKI group, (27 days [21-33] vs. 10 [9-14], P < 0.001). There was a higher incidence of deep vein thrombosis (DVT) (12.4% vs. 2.9%, P = 0.024) in the sAKI group as well. CONCLUSION: The sAKI patients stayed in the hospital approximately three times longer and had a 4-fold increase in the occurrence of DVT. No significant difference was found between the groups in in-hospital mortality. TYPE OF STUDY: Retrospective cohort study.