Implementing the National Heart, Lung, and Blood Institute's Strategic Vision in the Division of Cardiovascular Sciences.

As we commemorate the 70th Anniversary of the National Heart, Lung, and Blood Institute (NHLBI) and celebrate important milestones that have been achieved by the Division of Cardiovascular Sciences (DCVS), it is imperative that DCVS and the Extramural Research community at-large continue to address critical public health challenges that persist within the area of Cardiovascular Diseases (CVD). The NHLBI's Strategic Vision, developed with extensive input from the extramural research community and published in 2016, included overarching goals and strategic objectives that serve to provide a general blueprint for sustaining the legacy of the Institute by leveraging opportunities in emerging scientific areas (e.g., regenerative medicine, omics technology, data science, precision medicine, and mobile health), finding new ways to address enduring challenges (e.g., social determinants of health, health inequities, prevention, and health promotion), and training the next generation of heart, lung, blood, and sleep researchers. DCVS has developed a strategic vision implementation plan to provide a cardiovascular framing for the pursuit of the Institute's overarching goals and strategic objectives garnered from the input of the broader NHLBI community. This plan highlights six scientific focus areas that demonstrate a cross-cutting and multifaceted approach to addressing cardiovascular sciences, including 1) addressing social determinants of cardiovascular health (CVH) and health inequities, 2) enhancing resilience, 3) promoting CVH and preventing CVD Across the lifespan, 4) eliminating hypertension-related CVD, 5) reducing the burden of heart failure, and 6) preventing vascular dementia. These priorities will guide our efforts in Institute-driven activities in the coming years but will not exclude development of other novel ideas or the support of investigator-initiated grant awards. The DCVS Strategic Vision implementation plan is a living document that will evolve with iterative dialogue with the NHLBI community and adapt as the dynamic scientific landscape changes to seize emerging opportunities.

Portfolio analysis on preeclampsia and pregnancy-associated hypertension research funded by the National Heart, Lung, and Blood Institute.

Chronic hypertension and preeclampsia are the most common complications of pregnancy. To clarify the contributions of the National Heart, Lung, and Blood Institute (NHLBI) to the field and identify potential research gaps, we performed portfolio analysis of awards related to preeclampsia and pregnancy-associated hypertension. A list of National Institutes of Health (NIH)-funded awards between fiscal years 2008-present was obtained through an NIH RePORTER search using the following terms: "preeclampsia" and "pregnancy-associated hypertension." More in-depth analyses were performed on currently active awards supported by the NHLBI. The NHLBI is the lead institute at the NIH in funding research related to pregnancy-associated hypertension and second leading in funding research related to preeclampsia. The NHLBI currently supports 38 awards related to preeclampsia and six awards related to pregnancy-associated hypertension, with a combined total dollar investment of $21 million. Of the currently active, NHLBI-supported awards on preeclampsia and pregnancy-associated hypertension combined, 47% are related to basic science research, 30% to clinical, 14% to clinical trials, and 9% to early translational research. The focus of NHLBI-funded awards is primarily on vascular mechanisms and short and long-term cardiovascular complications of preeclampsia and pregnancy-associated hypertension. Despite steady funding for research on preeclampsia and pregnancy-associated hypertension, several gaps in knowledge exist. NHLBI held a workshop entitled Predicting, Preventing and Treating Preeclampsia to address some of these gaps and inform future research directions for the institute.

Sex differences in micro- and macro-vascular complications of diabetes mellitus.

Vascular complications are a leading cause of morbidity and mortality in both men and women with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus, however the prevalence, progression and pathophysiology of both microvascular (nephropathy, neuropathy and retinopathy) and macrovascular [coronary heart disease (CHD), myocardial infarction, peripheral arterial disease (PAD) and stroke] disease are different in the two sexes. In general, men appear to be at a higher risk for diabetic microvascular complications, while the consequences of macrovascular complications may be greater in women. Interestingly, in the absence of diabetes, women have a far lower risk of either micro- or macro-vascular disease compared with men for much of their lifespan. Thus, the presence of diabetes confers greater risk for vascular complications in women compared with men and some of the potential reasons, including contribution of sex hormones and sex-specific risk factors are discussed in this review. There is a growing body of evidence that sex hormones play an important role in the regulation of cardiovascular function. While estrogens are generally considered to be cardioprotective and androgens detrimental to cardiovascular health, recent findings challenge these assumptions and demonstrate diversity and complexity of sex hormone action on target tissues, especially in the setting of diabetes. While some progress has been made toward understanding the underlying mechanisms of sex differences in the pathophysiology of diabetic vascular complications, many questions and controversies remain. Future research leading to understanding of these mechanisms may contribute to personalized- and sex-specific treatment for diabetic micro- and macro-vascular disease.

Age at menarche and the risk of diabetic microvascular complications in patients with type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the relationship among age at onset of diabetes, age at onset of menarche and risk of diabetic nephropathy and laser-treated retinopathy in type 1 diabetes. METHODS: Data related to age at menarche were collected through questionnaires and were available for 1,304 women who participated in the Finnish Diabetic Nephropathy Study (FinnDiane). A possible association between age at menarche and diabetic nephropathy and retinopathy was investigated. RESULTS: There was an inverse relationship between the age at onset of diabetes and age at menarche: the younger the age at onset of diabetes, the higher the age at menarche (p < 0.0001). A non-linear relationship between the age of menarche and risk of diabetic microvascular complications was found in patients with diabetes onset before menarche, but there was no such association in patients with diabetes onset after menarche. Women with delayed menarche (> mean age + 2 years) had a 2.30 (95% CI 1.27, 4.17; p < 0.006) times higher risk of nephropathy compared with the women who underwent menarche at the mean age ± 2 years. Delayed menarche also increased the risk of retinopathy (OR 2.34 [95% CI 1.36, 4.01]). After excluding patients with nephropathy, the OR for retinopathy was 2.11 (95% CI 1.15, 3.90). Earlier menarche (< mean age - 2 years) did not have any effect on this risk. CONCLUSIONS/INTERPRETATION: Delayed menarche was associated with an increased risk of diabetic nephropathy and retinopathy, whereas early menarche was not. Delayed menarche may be used as a new tool to identify women at risk of diabetic microvascular complications.

Physiological effects and therapeutic potential of proinsulin C-peptide.

Connecting Peptide, or C-peptide, is a product of the insulin prohormone, and is released with and in amounts equimolar to those of insulin. While it was once thought that C-peptide was biologically inert and had little biological significance beyond its role in the proper folding of insulin, it is now known that C-peptide binds specifically to the cell membranes of a variety of tissues and initiates specific intracellular signaling cascades that are pertussis toxin sensitive. Although it is now clear that C-peptide is a biologically active molecule, controversy still remains as to the physiological significance of the peptide. Interestingly, C-peptide appears to reverse the deleterious effects of high glucose in some tissues, including the kidney, the peripheral nerves, and the vasculature. C-peptide is thus a potential therapeutic agent for the treatment of diabetes-associated long-term complications. This review addresses the possible physiologically relevant roles of C-peptide in both normal and disease states and discusses the effects of the peptide on sensory nerve, renal, and vascular function. Furthermore, we highlight the intracellular effects of the peptide and present novel strategies for the determination of the C-peptide receptor(s). Finally, a hypothesis is offered concerning the relationship between C-peptide and the development of microvascular complications of diabetes.

Workshop summary: National Institutes of Health (NIH) 2022 scientific workshop on gender and health.

In this manuscript, we summarize the goals, content, and impact of the Gender and Health: Impacts of Structural Sexism, Gender Norms, Relational Power Dynamics, and Gender Inequities workshop held by the National Institutes of Health (NIH) Office of Research on Women's Health (ORWH) in collaboration with 10 NIH Institutes, Centers, and Offices. Specifically, we outline the key points emerging from the workshop presentations, which are the focus of the collection of articles in this supplement. The overarching goals of the workshop were to convene NIH staff, the external scientific community, and the public to discuss methods, measurement, modifiable factors, interventions, and best practices in health research on gender as a social and cultural variable and to identify opportunities to advance research and foster collaborations on these key topics. Themes emerging from the workshop include the need for intersectional measures in research on gender and health, the role of multilevel interventions and analyses, and the importance of considering gender as a social and structural determinant of health. Careful, nuanced, and rigorous integration of gender in health research can contribute to knowledge about and interventions to change the social and structural forces that lead to disparate health outcomes and perpetuate inequities.

High-fat/fructose feeding during prenatal and postnatal development in female rats increases susceptibility to renal and metabolic injury later in life.

Accumulating evidence suggests that both an adverse prenatal and early postnatal environment increase susceptibility to renal and metabolic dysfunction later in life; however, whether exposure to adverse conditions during both prenatal and postnatal development act synergistically to potentiate the severity of renal and metabolic injury remains unknown. Sprague-Dawley rats were fed either a standard diet or a diet high in fat/fructose throughout pregnancy and lactation. After being weaned, female offspring were randomized to either standard diet or the high-fat/high-fructose diet, resulting in the following treatment groups: NF-NF, offspring of mothers fed a standard diet and fed a standard diet postnatally; NF-HF, offspring of mothers fed a standard diet and fed a high-fat/fructose diet postnatally; HF-NF, offspring of mothers fed a high-fat/fructose diet and fed a standard diet postnatally; HF-HF, offspring of mothers fed a high-fat/fructose diet and fed a high-fat/fructose diet postnatally. At the time of euthanasia (17 wk of age), HF-HF offspring weighed 30% more and had 110% more visceral fat than NF-NF offspring. The HF-HF offspring also had elevated blood glucose levels, glucose intolerance, 286% increase in urine albumin excretion, and 60% increase in glomerulosclerosis compared with NF-NF. In addition, HF-HF offspring exhibited a 100% increase in transforming growth factor-ß protein expression and 116% increase in the abundance of infiltrated macrophages compared with the NF-NF offspring. These observations suggest that high-fat/fructose feeding during prenatal and throughout postnatal life increases the susceptibility to renal and metabolic injury later in life.

Hypertension in an experimental model of systemic lupus erythematosus occurs independently of the renal nerves.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder with prevalent hypertension and renal injury. In this study, we tested whether the renal nerves contribute to the development of hypertension in an established mouse model of SLE (NZBWF1). Female SLE and control (NZW/LacJ) mice were subjected to either bilateral renal denervation or a sham procedure at 32 wk of age. Two weeks later, blood pressure was assessed in conscious mice using carotid artery catheters. Blood pressure was higher in SLE mice compared with controls, as previously reported; however, blood pressure was not altered in the denervated SLE or control mice. The development of albuminuria was markedly blunted in denervated SLE mice; however, glomerulosclerosis was increased. Renal denervation reduced renal cortical expression of monocyte-chemoattractant protein in SLE mice but did not significantly alter renal monocyte/macrophage infiltration. Renal cortical TNF-α expression was also increased in sham SLE mice, but this was not impacted by denervation. This study suggests that the renal nerves do not have a significant role in the pathogenesis of hypertension, but have a complex effect on the associated renal inflammation and renal injury.

Microvascular disease precedes the decline in renal function in the streptozotocin-induced diabetic rat.

Diabetic nephropathy is a progressive and generalized vasculopathic condition associated with abnormal angiogenesis. We aim to determine whether changes in renal microvascular (MV) density correlate with and play a role in the progressive deterioration of renal function in diabetes. We hypothesize that MV changes represent the early steps of renal injury that worsen as diabetes progresses, initiating a vicious circle that leads to irreversible renal injury. Male nondiabetic (ND) or streptozotocin-induced diabetic (D) Sprague-Dawley rats were followed for 4 or 12 wk. Renal blood flow and glomerular filtration rate (GFR) were measured by PAH and (125)I-[iothalamate], respectively. Renal MV density was quantified ex vivo using three-dimensional micro computed tomography and JG-12 immunoreactivity. Vascular endothelial growth factor (VEGF) levels (ELISA) and expression of VEGF receptors and factors involved in MV remodeling were quantified in renal tissue by Western blotting. Finally, renal morphology was investigated by histology. Four weeks of diabetes was associated with increased GFR, accompanied by a 34% reduction in renal MV density and augmented renal VEGF levels. However, at 12 wk, while GFR remained similarly elevated, reduction of MV density was more pronounced (75%) and associated with increased MV remodeling, renal fibrosis, but unchanged renal VEGF compared with ND at 12 wk. The damage, loss, and subsequent remodeling of the renal MV architecture in the diabetic kidney may represent the initiating events of progressive renal injury. This study suggests a novel concept of MV disease as an early instigator of diabetic kidney disease that may precede and likely promote the decline in renal function.

Combined inhibition of aromatase activity and dihydrotestosterone supplementation attenuates renal injury in male streptozotocin (STZ)-induced diabetic rats.

Our previous studies showed that streptozotocin (STZ)-induced diabetic male rats have increased estradiol and decreased testosterone levels that correlate with renal injury (Xu Q, Wells CC, Garman GH, Asico L, Escano CS, Maric C. Hypertension 51: 1218-1224, 2008). We further showed that either supplementing dihydrotestosterone (DHT) or inhibiting estradiol biosynthesis in these diabetic rats was only partially renoprotective (Manigrasso MB, Sawyer RT, Marbury DC, Flynn ER, Maric C. Am J Physiol Renal Physiol 301: F634-F640, 2011; Xu Q, Prabhu A, Xu S, Manigrassso MB, Maric C. Am J Physiol 297: F307-F315, 2009). The aim of this study was to test the hypothesis that the combined therapy of DHT supplementation and inhibition of estradiol synthesis would afford better renoprotection than either treatment alone. The study was performed in 12-wk-old male nondiabetic (ND), STZ-induced diabetic (D), and STZ-induced diabetic rats that received the combined therapy of 0.75 mg/day of DHT along with 0.15 mg · kg(-1) · day(-1) of an aromatase inhibitor, anastrozole (Dta), for 12 wk. Treatment with the combined therapy resulted in attenuation of albuminuria by 84%, glomerulosclerosis by 55%, and tubulointerstitial fibrosis by 62%. In addition, the combined treatment decreased the density of renal cortical CD68-positive cells by 70% and decreased protein expression of transforming growth factor-ß protein expression by 60%, collagen type IV by 65%, TNF-α by 55%, and IL-6 by 60%. We conclude that the combined treatment of DHT and blocking aromatase activity in diabetic male STZ-induced diabetic rats provides superior treatment than either treatment alone in the prevention of diabetic renal disease.

Exposure to maternal overnutrition and a high-fat diet during early postnatal development increases susceptibility to renal and metabolic injury later in life.

Overnutrition during pre- and postnatal development both confer increased susceptibility to renal and metabolic risks later in life; however, whether they have an additive effect on the severity of renal and metabolic injury remains unknown. The present study tested the hypothesis that a combination of a pre- and postnatal diet high in fat/fructose would exacerbate renal and metabolic injury in male offspring later in life. Male offspring born to high fat/high-fructose-fed mothers and fed a high-fat/high-fructose diet postnatally (HF-HF) had increased urine albumin excretion (450%), glomerulosclerosis (190%), and tubulointerstitial fibrosis (101%) compared with offspring born to mothers fed a standard diet and fed a standard diet postnatally (NF-NF). No changes in blood pressure or glomerular filtration were observed between any of the treatment groups. The HF-HF offspring weighed ∼23% more than offspring born to mothers fed a high-fat/high-fructose diet and fed a normal diet postnatally (HF-NF), as well as offspring born to mothers fed a standard diet regardless of their postnatal diet. The HF-HF rats also had increased (and more variable) blood glucose levels over 12 wk of being fed a high-fat/high-fructose diet. A combination of exposure to a high-fat/high-fructose diet in utero and postnatally increased plasma insulin levels by 140% compared with NF-NF offspring. Our data suggest that the combined exposure to overnutrition during fetal development and early postnatal development potentiate the susceptibility to renal and metabolic disturbances later in life.

Renoprotective effects of C-peptide in the Dahl salt-sensitive rat.

Previous studies have demonstrated that renoprotective effects of C-peptide in experimental models of diabetes-induced renal disease may be mediated via lowering blood glucose. The present study examined the renoprotective effects of C-peptide in a model of nondiabetic renal disease, the Dahl salt-sensitive (SS/jr) rat. SS/jr rats were placed on a 2% NaCl diet for 2 wk (HS2, resulting in mild to moderate renal injury) or 4 wk (HS4, resulting in advanced renal injury) and then received either vehicle (veh) or C-peptide (Cpep) for additional 4 wk. Urine albumin (UAE) and protein (UPE) excretion rates were measured at baseline (i.e., before initiation of veh or Cpep treatment) and 4 wk later (i.e., at the time of death). Glomerular permeability, indexes of glomerulosclerosis and tubulointerstitial fibrosis, the presence of inflammatory cells, and protein expression of transforming growth factor-ß (TGF-ß) and podocin were measured at the time of death. In HS2 + veh rats, UAE and UPE increased by 74 and 92%, respectively, from baseline and the time of death. While HS2 + Cpep attenuated this increase in UAE and UPE, HS4 + Cpep had no effect on these parameters. Similarly, HS2 + Cpep reduced glomerular permeability, tubulointerstitial fibrosis, renal inflammation, TGF-ß, and podocin protein expression, while HS4 + Cpep had no effect. These studies indicate that C-peptide is renoprotective in nondiabetic experimental models with mild to moderate renal injury.

Dysglycemia in Pregnancy and Maternal/Fetal Outcomes.

Maternal dysglycemia-including diabetes, impaired glucose tolerance, and impaired fasting glucose-affects one in six pregnancies worldwide and represents a significant health risk to the mother and the fetus. Maternal dysglycemia is an independent risk factor for perinatal mortality, major congenital anomalies, and miscarriages. Furthermore, it increases the longer-term risk of type 2 diabetes mellitus, metabolic syndrome, cardiovascular morbidity, malignancies, and ophthalmic, psychiatric, and renal diseases in the mother. The most commonly encountered form of maternal dysglycemia is gestational diabetes. Currently, international consensus does not exist for diagnostic criteria defining gestational diabetes at 24-28 weeks gestation, and potential diagnostic glucose thresholds earlier in gestation require further investigation. Likewise, recommendations regarding the timing and modality (e.g., lifestyle or pharmacological) of treatment vary greatly. Because a precise diagnosis determines the appropriate treatment and outcome of the pregnancy, it is imperative that a better definition of maternal dysglycemia and its treatment be achieved. This article will address some of the controversies related to diagnosing and managing maternal dysglycemia. In addition, the article will discuss the impact of maternal dysglycemia on complications experienced by the mother and infant, both at birth and in later life.

Maternal Morbidity and Mortality: Are We Getting to the "Heart" of the Matter?

Cardiovascular disease (CVD), including hypertensive disorders of pregnancy (HDP) and peripartum cardiomyopathy, is a leading cause of pregnancy-related death in the United States. Women who are African American or American Indian/Alaskan Native, have HDP, are medically underserved, are older, or are obese have a major risk for the onset and/or progression of CVD during and after pregnancy. Paradoxically, women with no preexisting chronic conditions or risk factors also experience significant pregnancy-related cardiovascular (CV) complications. The question remains whether substantial physiologic stress on the CV system during pregnancy reflected in hemodynamic, hematological, and metabolic changes uncovers subclinical prepregnancy CVD in these otherwise healthy women. Equally important and similarly understudied is the concept that women's long-term CV health could be detrimentally affected by adverse pregnancy outcomes, such as preeclampsia, gestational hypertension, and diabetes, and preterm birth. Thus, a critical life span perspective in the assessment of women's CV risk factors is needed to help women and health care providers recognize and appreciate not only optimal CV health but also risk factors present before, during, and after pregnancy. In this review article, we highlight new advancements in understanding adverse, pregnancy-related CV conditions and will discuss promising strategies or interventions for their prevention, diagnosis, and treatment.

Sex Differences in Diabetic Kidney Disease.

While the global prevalence of both type 1 and type 2 diabetes mellitus is similar in men and women, the consequences of diabetes on associated end-organ complications, including diabetic kidney disease appear to be more sex-specific. Particularly, women with diabetes have higher mortality rates for diabetes-related deaths, and higher prevalence of diabetic kidney disease risk factors such as hypertension, hyperglycemia, obesity, and dyslipidemia. However, the evidence for the impact of sex on diabetic kidney disease prevalence and disease progression is limited and inconsistent. Although most studies agree that the protective effect of the female sex against the development of kidney disease is diminished in the setting of diabetes, the reasons for this observation are unclear. Whether or not sex differences exist in the risk of diabetic kidney disease is also unclear, with studies reporting either higher risk in men, women, or no sex differences. Despite the remaining controversies, some of the factors that associate with sex differences in the risk of diabetic kidney disease are age at onset, and type and duration of diabetes. There is growing appreciation of the importance of sex hormones in the regulation of renal function, with estrogens generally considered to be renoprotective. Although some progress has been made towards better understanding of the mechanisms by which sex hormones play a role in the pathophysiology of diabetic kidney disease, the translational potential of this knowledge is still underappreciated. A better understanding of sex differences in diabetic kidney disease may provide basis for personalized and sex-specific treatment of diabetic kidney disease.

Sex and the kidneys: current understanding and research opportunities.

Concerns regarding sex differences are increasingly pertinent in scientific and societal arenas. Although biological sex and socio-cultural gender are increasingly recognized as important modulators of renal function under physiological and pathophysiological conditions, gaps remain in our understanding of the mechanisms underlying sex differences in renal pathophysiology, disease development, progression and management. In this Perspectives article, we discuss specific opportunities for future research aimed at addressing these knowledge gaps. Such opportunities include the development of standardized core data elements and outcomes related to sex for use in clinical studies to establish a connection between sex hormones and renal disease development or progression, development of a knowledge portal to promote fundamental understanding of physiological differences between male and female kidneys in animal models and in humans, and the creation of new or the development of existing resources and datasets to make them more readily available for interrogation of sex differences. These ideas are intended to stimulate thought and interest among the renal research community as they consider sex as a biological variable in future research projects.

A Systematic Review of Obesity Disparities Research.

CONTEXT: A review of interventions addressing obesity disparities could reveal gaps in the literature and provide guidance on future research, particularly for populations with a high prevalence of obesity and obesity-related cardiometabolic risk. EVIDENCE ACQUISITION: A systematic review of clinical trials in obesity disparities research that were published in 2011-2016 in PubMed/MEDLINE resulted in 328 peer-reviewed articles. Articles were excluded if they had no BMI, weight, or body composition measure as primary outcome or were foreign (n=201); were epidemiologic or secondary data analyses of clinical trials (n=12); design or protocol papers (n=54); systematic reviews (n=3); or retracted or duplicates (n=9). Forty-nine published trials were summarized and supplemented with a review of ongoing obesity disparities grants being funded by the National, Heart, Lung and Blood Institute. EVIDENCE SYNTHESIS: Of the 49 peer-reviewed trials, 27 targeted adults and 22 children only or parent-child dyads (5 of 22). Interventions were individually focused; mostly in single settings (e.g., school or community); of short duration (mostly ≤12 months); and primarily used behavioral modification (e.g., self-monitoring) strategies. Many of the trials had small sample sizes and moderate to high attrition rates. A meta-analysis of 13 adult trials obtained a pooled intervention effect of BMI -1.31 (95% CI=-2.11, -0.52, p=0.0012). Institutional review identified 140 ongoing obesity-related health disparities grants, but only 19% (n=27) were clinical trials. CONCLUSIONS: The reviews call for cardiovascular-related obesity disparities research that is long term and includes population research, and multilevel, policy, and environmental, or "whole of community," interventions.