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RATIONALE AND OBJECTIVE: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in those with and without CKD. STUDY DESIGN: Neuroimaging substudy of a randomized trial. SETTING & PARTICIPANTS: A subset of participants in the Systolic Blood Pressure Intervention Trial who underwent brain MRI studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR). INTERVENTION: Participants were randomly assigned to intensive (systolic BP 30 mg/g (N=151), the effects of intensive versus standard BP treatment on change in global cerebral blood flow, WMLs and total brain volume were 1.91 ml/100g/min (95% CI −3.01, 6.82), 0.003 cm(3) (asinh transformed, 95% CI −0.13, 0.13), and −7.0 cm(3) (95% CI −13.3, −0.3), respectively. The overall treatment effects on cerebral blood flow and total brain volume were not modified by baseline eGFR or UACR; however the effect on WMLs was attenuated in participants with albuminuria (interaction p-value 0.04). LIMITATIONS: Measurement variability due to multi-site design. CONCLUSIONS: Among hypertensive adults with primarily early kidney disease, intensive versus standard blood pressure treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive blood pressure treatment targets on brain health in persons with early kidney disease. FUNDING: The Systolic Blood Pressure Intervention Trial was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases. TRIAL REGISTRATION: SPRINT was registered at ClinicalTrials.gov with the study number NCT01206062.

Humans have had a long and complex relationship with salt. Although highly valued in many societies, dietary salt has long been associated with high blood pressure1–3 and, more recently, with other diseases.4–6 Some individuals with hypertension often display salt-sensitive blood pressure changes, which is a condition more prevalent among blacks, older people, and individuals with renal insufficiency or diabetes mellitus.7–9 In general, for those with salt-sensitive hypertension, excess sodium intake is associated with higher blood pressure, whereas a low-salt diet decreases blood pressure.3 In spite of this well-known association, the basic molecular and cellular mechanisms underlying the effects of salt on blood pressure regulation are still not well understood. Furthermore, individuals with high blood pressure are at increased risk for multiple diseases (ie, coronary artery disease, heart failure, stroke, and renal disease) although at present whether or not a high dietary salt intake can directly lead to these diseases (ie, in the absence of hypertension) is not known. Our understanding of the effect of salt on health has grown even more complex recently. Researchers have reported a new connection between salt and autoimmunity: a high-salt diet was shown to accelerate autoimmune activity in a mouse model of multiple sclerosis.10,11 In addition, a close connection between hypertension and the immune system has been revealed.12–16 However, the causal relationships between salt, immunity, and hypertension (eg, how salt could mediate interactions between the immune system and the vasculature, brain, or kidney to increase blood pressure) are not well understood. The National Heart, Lung, and Blood Institute convened a Working Group (WG) in 2014 to discuss this new emerging scientific area in hypertension research. The WG brought together experts from diverse backgrounds including hypertension, epidemiology, preeclampsia, cardiovascular disease, …

The National Institutes of Health (NIH) remains the largest source of funding for biomedical research in the United States. However, the current tight fiscal climate is creating concerns related to the success in obtaining NIH funding. In this report, we focused on analyzing the trend of new and renewal competing R01 applications, as a measure of the most prevalent NIH funding mechanism that supports many US laboratories, and the new science being proposed in the field. We analyzed data on R01 applications submitted to the NIH, the National Heart, Lung, and Blood Institute (NHLBI), the Division of Cardiovascular Sciences, and the Vascular Biology and Hypertension Branch for fiscal years 2010 through 2014. This comparative analysis at multiple levels allowed us to position the situation of cardiovascular research R01s, from within the big picture of NIH funding to looking at specific trends at the level of particular areas of investigation within Vascular Biology and Hypertension Branch. We found that the success rates of competing R01s decreased at all levels: NIH, NHLBI, Division of Cardiovascular Sciences, and Vascular Biology and Hypertension Branch. Interestingly, we found that competitive renewal R01 applications remained more successful (≈2×) than new R01 applications at all levels during this period. By identifying and analyzing some variances to the general trends, we found that some successes may be attributed to effectively using the specific R01 structure that supports team science (ie, Multiple Principal Investigator awards), which enables the active collaborations among investigators with different expertise to pursue together a novel scientific hypothesis. National Institutes of Health (NIH) is the largest funding source for biomedical research and development in the world1 and supports research projects, resources, facilities, and personnel costs via various funding mechanisms. NIH investments in extramural research contribute to the overall economy in many ways, through creation …

Objective: Bicuspid aortic valve is a common risk factor for thoracic aortic aneurysm and dissection. Guidelines for elective ascending aortic intervention (AAI) in bicuspid aortic valve are derived from limited evidence, and the extent of practice variation due to patient and provider characteristics is unknown. Using data from 2 large cardiovascular registries, we investigated factors that influence decisions for AAI. Methods: All bicuspid aortic valve cases with known aortic diameters and surgical status were included. We used multivariable logistic regression to profile predictors of isolated aortic valve replacement (AVR) or AVR+AAI, stratified by patient characteristics, surgical indications, and institution. Results: We studied 2861 subjects at 18 institutions from 1996 to 2015. The median aortic diameter of patients who underwent AVR+AAI varied widely across institutions (39-52 mm). Aortic diameters were

Previous data suggest women are at increased risk of death from aortic dissection. Therefore, we analyzed data from the GenTAC registry, the NIH-sponsored program that collects information about individuals with genetically triggered thoracic aortic aneurysms and cardiovascular conditions. We performed cross-sectional analyses in adults with Marfan syndrome (MFS), familial thoracic aortic aneurysm or dissection (FTAAD), bicuspid aortic valve (BAV) with thoracic aortic aneurysm or dissection, and subjects under 50 years of age with thoracic aortic aneurysm or dissection (TAAD50 years). Women comprised 32% of 1,449 subjects and were 21% of subjects with BAV, 34% with FTAAD, 22% with TAAD50 years, and 47% with MFS. Thoracic aortic dissections occurred with equal gender frequency yet women with BAV had more extensive dissections. Aortic size was smaller in women but was similar after controlling for BSA. Age at operation for aortic valve dysfunction, aneurysm or dissection did not differ by gender. Multivariate analysis (adjusting for age, BSA, hypertension, study site, diabetes, and subgroup diagnoses) showed that women had fewer total aortic surgeries (OR = 0.65, P0.01) and were less likely to receive angiotensin converting enzyme inhibitors (ACEi; OR = 0.68, P0.05). As in BAV, other genetically triggered aortic diseases such as FTAAD and TAAD50 are more common in males. In women, decreased prevalence of aortic operations and less treatment with ACEi may be due to their smaller absolute aortic diameters. Longitudinal studies are needed to determine if women are at higher risk for adverse events.

The present study was initiated because of concerns expressed by NHLBI-funded mid-career investigators regarding perceived difficulties in the renewal of their grant awards. This led us to ask: "Are mid-career investigators experiencing disproportionate difficulties in the advancement of their professional careers?" Our portfolio analysis indicates that there has been a significant and evolving shift in the demographics of research project grant (RPG) awardees at NHLBI. In 1998, mid-career (ages 41-55) investigators constituted approximately 60% of all investigators with the remaining 40% being equally divided between early-stage (ages 24-40) investigators and established (ages 56 to 70 and older) investigators. However, since 1998, the proportion of established RPG awardees has been increasing in a slowly progressive and strikingly linear fashion. At the same time the proportion of early-stage awardees fell precipitously until 2006 and then stabilized. During the same period, the proportion of mid-career awardees, which had been relatively stable through 2006, began to fall significantly. In examining potential causes of these demographic shifts we have identified certain inherent properties within the RPG award system that appear to promote an increasingly more established awardee population and a persistent decrease in the proportion of mid-career investigators. A collateral result of these demographic shifts, when combined with level or declining funding, is a significant reduction in the number of RPG awards received by NHLBI mid-career investigators and a corresponding decrease in the number of independent research laboratories.

Background The risk of aortic complications associated with pregnancy in women with Marfan syndrome ( MFS ) is not fully understood. Methods and Results MFS women participating in the large National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (Gen TAC ) were evaluated. Among 184 women with MFS in whom pregnancy information was available, 94 (51%) had a total of 227 pregnancies. Among the women with pregnancies, 10 (10.6%) experienced a pregnancy‐related aortic complication (4 type A and 3 type B dissections, 1 coronary artery dissection, and 2 with significant [≥3 mm] aortic growth). Five of 7 aortic dissections, including all 3 type B, and the coronary dissection (75% of all dissections) occurred in the postpartum period. Only 5 of 8 women with pregnancy‐associated dissection were aware of their MFS diagnosis. The rate of aortic dissection was higher during the pregnancy and postpartum period (5.4 per 100 person‐years vs 0.6 per 100 person‐years of nonpregnancy; rate ratio, 8.4 [95% CI=3.9, 18.4]; P Conclusions Pregnancy in MFS is associated with an increased risk of aortic dissection, both types A and B, particularly in the immediate postpartum period. Lack of knowledge of underlying MFS diagnosis before aortic dissection is a major contributing factor. These findings underscore the need for early diagnosis, prepregnancy risk counseling, and multidisciplinary peripartum management.

Background— The associations of age and sex with phenotypic features of Marfan syndrome have not been systematically examined in a large cohort of both children and adults. Methods and Results— We evaluated 789 Marfan patients enrolled in the National Heart, Lung, and Blood Institute GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) Registry (53% male; mean age 31 [range: 1–86 years]). Females aged ≥15 and males aged ≥16 years were considered adults based on average age of skeletal maturity. Adults (n=606) were more likely than children (n=183) likely to have spontaneous pneumothorax, scoliosis, and striae but were comparable in revised Ghent systemic score, ectopia lentis, and most phenotypic features, including prevalence of aortic root dilatation. Prophylactic aortic root replacement and mitral valve surgery were rare during childhood versus adulthood (2% versus 35% and 1% versus 9%, respectively, both P P P =0.06); 44% of dissections were type B. Type B dissection was strongly associated with previous prophylactic aortic root replacement. Conclusions— Pulmonary, skeletal, and aortic complications, but not other phenotypic features, are more prevalent in adults than children in Marfan syndrome. Aortic aneurysms and prophylactic aortic surgery are more common in men. Aortic dissection, commonly type B, occurs in an appreciable proportion of Marfan patients, especially in men and after previous prophylactic aortic root replacement.

Hypertension, defined as a condition associated with ≥140-mm Hg systolic blood pressure or ≥90-mm Hg diastolic blood pressure, affects >1 billion people worldwide,1 and in 2009 it cost the US healthcare system more than $73 billion.2 Despite the availability of many antihypertensive therapies, individual responses vary, and efficacy remains a concern. Current treatments have yielded only modest reductions in the overall disease risk even in countries where therapeutics are available and affordable. The initiating causes and the pathogenic mechanisms for disease and its comorbidities remain largely unknown, and prognostic markers for adult hypertension that could improve its diagnosis, prevention, and, ultimately, its management are not yet available. As a result, ≈28% of the US population and a similar proportion of the adult Western European and Canadian populations experience what is known as “essential hypertension,”3 which is a primary component of several complex, multifactorial, multigenic conditions that are commonly associated with high levels of morbidity and mortality from diabetes mellitus, cardiovascular disease, and renal disease. If the current rise in the number of hypertension cases is not abated, total annual global healthcare costs resulting from suboptimal blood pressure for those >30 years of age could amount to $3.6 trillion more over the next 10 years.4 The causes of essential hypertension remain poorly understood, although the complex mechanisms for blood pressure (BP) regulation have been extensively characterized in both humans and animal models.5–7 Comprehensive study of >12 inbred rat strains that recapitulate many aspects of hereditary human hypertension has added substantially throughout the years to our understanding of the underlying physiological and molecular pathways, the genetic complexity of risk and treatment responses, and the pathological consequences of hypertension.8 In fact, many interventions that lead to a …

The long-term outcomes of aortic valve-sparing (AVS) root replacement in Marfan syndrome (MFS) patients remain uncertain. The study aim was to determine the utilization and outcomes of AVS root replacement in MFS patients enrolled in the Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC).At the time of this analysis, 788 patients with MFS were enrolled in the GenTAC Registry, of whom 288 had undergone aortic root replacement. Patients who had undergone AVS procedures were compared to those who had undergone aortic valve replacement (AVR).AVS root replacement was performed in 43.5% of MFS patients, and the frequency of AVS was increased over the past five years. AVS patients were younger at the time of surgery (31.0 versus 36.3 years, p = 0.006) and more likely to have had elective rather than emergency surgery compared to AVR patients, in whom aortic valve dysfunction and aortic dissection was the more likely primary indication for surgery. After a mean follow up of 6.2 +/- 3.6 years, none of the 87 AVS patients had required reoperation; in contrast, after a mean follow up of 10.5 +/- 7.6 years, 11.5% of AVR patients required aortic root reoperation. Aortic valve function has been durable, with 95.8% of AVS patients having aortic insufficiency that was graded as mild or less.AVS root replacement is performed commonly among the MFS population, and the durability of the aortic repair and aortic valve function have been excellent to date. These results justify a continued use of the procedure in an elective setting. The GenTAC Registry will be a useful resource to assess the long-term durability of AVS root replacement in the future.

Abstract —Intravenous infusion of recombinant tissue factor pathway inhibitor (rTFPI) for 24 hours decreases neointimal thickening and luminal stenosis 1 month after balloon-induced injury to the carotid arteries in minipigs. This study was designed to determine whether the effect of rTFPI is accounted for by early decreases in procoagulant activity and thrombosis on the injured vessel wall. Vascular injury was induced by balloon hyperinflations in both carotid arteries of anesthetized pigs given no anticoagulant as a control (n=16), an intravenous infusion for 24 hours of rTFPI (0.5 mg/kg bolus and 25 μg · kg −1 · min −1 , n=14), or an intravenous infusion of unfractionated heparin (100 U · kg −1 · h −1 , n=19). Accumulation of radiolabeled autologous platelets was markedly decreased over 24 hours on injured arteries from animals given rTFPI (0.6×10 6 /cm 2 ) compared with controls (2.5×10 6 /cm 2 , P =0.0004). Deposition of radiolabeled fibrin was also decreased in rTFPI-treated animals (269±266 μg/cm 2 ) compared with controls (2389±1673 μg/cm 2 , P =0.04). Similar effects were observed with heparin. However, factor Xa activity, assayed after 24 hours by incubation of the injured arterial segments with the chromogenic substrate S-2222, was decreased more markedly on arteries from rTFPI-treated animals (0.14±0.13 OD) than those from heparin-treated animals (0.29±0.18 OD) compared with controls (0.47±0.24 OD, P =0.0007). In addition, arteries from rTFPI-treated animals showed a 4-fold lower induction of tissue factor protein compared with controls ( P =0.0002). Attenuation of procoagulant activity and tissue factor–mediated thrombin generation in response to injury may account for the promising results with rTFPI in the porcine angioplasty model.

The National Heart, Lung, and Blood Institute (NHLBI) supports the development of innovative biomedical products, including some that may be considered too risky or insufficiently profitable by the bio/pharma industry. The Vascular Interventions/Innovations and Therapeutic Advances (VITA) Program

The National Heart, Lung, and Blood Institute convened a working group to provide basic and clinical research recommendations to the National Heart, Lung, and Blood Institute on the development of an integrated approach for identifying those individuals who are at high risk for a cardiovascular event such as acute coronary syndromes (ACS) or sudden cardiac death in the “near term.” The working group members defined near-term as occurring within 1 year of the time of assessment. The participants reviewed current clinical cardiology practices for risk assessment and state-of-the-science techniques in several areas, including biomarkers, proteomics, genetics, psychosocial factors, imaging, coagulation, and vascular and myocardial susceptibility. This report presents highlights of these reviews and a summary of suggested research directions. ### Near-Term Risk The proper deployment of preventive strategies requires an accurate classification system that allows the physician to target intensive treatments to the highest-risk patients. A commonly recommended approach is a multivariable assessment such as the Framingham Risk Score (FRS).1 Although the FRS is recommended in many guidelines on cardiovascular risk assessment,2 it has some limitations. It does not include several factors of the metabolic syndrome (glucose intolerance, central obesity, and hypertriglyceridemia), nor does it include family history. Moreover, the FRS classifies risk over a period of 10 years rather than in the near term (within 1 year). Indeed, no algorithm has been developed that accurately predicts near-term risk across diverse populations. The ability to forecast near-term risk of ACS or sudden cardiac death would represent an important advance in cardiovascular medicine because it would clarify which individuals are in most urgent need of intervention. It would help identify those rare asymptomatic, apparently healthy individuals who are in imminent danger of a cardiovascular event yet ordinarily would not receive therapy at all. In asymptomatic individuals judged to be at intermediate or …

Background Genetic disorders are an important cause of thoracic aortic aneurysms (TAAs) in young patients. Despite advances in the treatment of genetically triggered TAAs, the optimal syndrome-specific treatment approach remains undefined. We used data from the National Institutes of Health–funded, multicenter National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) to characterize the contemporary surgical treatment of patients with genetically triggered TAAs. Methods GenTAC's aim is to collect longitudinal clinical data and banked biospecimens from 2800 patients with genetically triggered TAAs. We analyzed data from the 606 patients (mean age, 37.5 years) enrolled in GenTAC to date whose clinical data were available. Results The patients' primary diagnoses included Marfan syndrome (35.8%), bicuspid aortic valve with aneurysm (29.2%), and familial TAAs and dissections (10.7%). Of these, 56.4% had undergone at least one operation; the most common indications were aneurysm (85.7%), valve dysfunction (65.8%), and dissection (25.4%). Surgical procedures included replacement of the aortic root (50.6%), ascending aorta (64.8%), aortic arch (27.9%), and descending or thoracoabdominal aorta (12.4%). Syndrome-specific differences in age, indications for operation, and procedure type were identified. Conclusions Patients with genetically transmitted TAAs evaluated in tertiary care centers frequently undergo surgical repair. Aneurysm repairs most commonly involve the aortic root and ascending aorta; distal repairs are less common. Like TAAs themselves, complications of TAAs, including dissection and aortic valve dysfunction, are important indications for intervention. Future studies will focus on syndrome- and gene-specific phenotypes, biomarkers, treatments, and outcomes to improve the treatment of patients with TAAs.

We face an increasing global burden of cardiovascular disease, principally due to a sharp rise in developing countries experiencing health transitions. While it has long been known that hypertension, cigarette smoking, hypercholesterolemia, and diabetes are important cardiovascular risk factors, it is now increasingly appreciated that environmental factors like fine-particulate air pollution represent a serious public health threat. As noted by Rajagopolan and Brook elsewhere in this issue, household air pollution from use of coal and biomass for cooking and space heating may well have a substantial, and potentially reversible, cardiovascular impact. Rajagopolan and Brook call for a concerted research program to estimate the impact and to develop and test interventions. They correctly note that there is a need to balance the cost of research with the necessity of additional information. Further, they identify five focus areas, including exposure assessment, biological mechanisms, epidemiology, and candidate interventions and their cost-effectiveness. They argue that multidisciplinary teams are best equipped to tackle this complex issue from both scientific and societal perspectives. Research, like many other goods and services, is a scarce resource for which we have to make difficult decisions about expected returns and opportunity costs. There is no question that properly done research offers substantive benefits at reasonable rates of return. Cutler and Kadiyala analyzed the impact of research on cardiovascular health in the United States [1]. They noted the dramatic decline in cardiovascular mortality seen over the last 50 years can be attributed to three major factors: high-technology care, low-technology care, and behavioral change. Quite remarkably these declines have continued as age-adjusted death rates for coronary heart disease in the United States have declined from 187 deaths per 100,000 population in 2000 to 123 deaths per 100,000 in 2008 [2]. High-technology care includes coronary care unit, cardiac surgery, and devices such as implantable defibrillators and circulatory support pumps. Low-technology care includes medical therapy for hypertension and hypercholesterolemia, as well as aspirin prophylaxis in appropriate patients. Behavioral changes include declines in cigarette smoking and changes in dietary fat intake. For identifying all three of these areas - high-technology care, low-technology care, and behavioral change - we can confidently say that biomedical research played a critical role. Were it not for biomedical research, coronary heart disease mortality rates might well be nearly four times higher (405,000/1,579,000) in the United States [2]. Cutler and Kadiyala estimate that the societal rate of return on biomedical research and cardiovascular disease is at least 4 to 1 [1]. Cardiovascular research, at least in high-income countries, has been an outstanding investment [3]. Given the large burden of cardiovascular disease in low- and middle-income countries, the persistent use of solid fuels globally, and the hypothesized cardiovascular effects of solid fuel smoke, we see a window of opportunity for research that could lead to positive impacts on public health practice and policy.

Genetically triggered thoracic aortic conditions (GenTACs) represent an important problem for patients and their families. Accordingly, the National Heart, Lung, and Blood Institute established the first phase of its national GenTAC Registry in 2006.Between 2007 and 2010, 6 enrolling centers established the GenTAC I Registry consisting of 2,046 patients (Marfan syndrome 576 [28.2%], bicuspid aortic valve disease 504 [24.6%], aneurysm or dissection age50 years 369 [18%], and others). Biologic samples for DNA analyses (white blood cells or saliva) are available in 97%, and stored plasma is available in 60% of enrollees.Initial scientific inquiry using the GenTAC Registry has included validation studies of genetic causes for aortic syndromes, potential usefulness of transforming growth factor beta (TGFB) blood levels in Marfan subjects, and current surgical approaches to ascending aortic conditions.The second phase of GenTAC will allow biannual follow-up of GenTAC I enrollees for up to 9 years, enrollment of an additional 1,500 subjects, further integration of imaging findings with clinical and genetic data through utilization of an imaging core laboratory, important validation of phenotype-genotype correlations through a phenotyping core laboratory, and integration of a scientific advisory committee to help define the full range and depth of the Registry's scientific capabilities. The registry resources are available to the external scientific community through an application process accessible at https://gentac.rti.org.

Mouse erythroleukemia (MEL) cells provide a useful model system to examine the regulation of globin gene expression. MEL cells ordinarily do not express globin genes, but in the presence of inducers, such as dimethyl sulfoxide or hexamethylene bisacetamide, they mimic erythroid differentiation. We have developed a cell-free transcription system from uninduced MEL cells to determine the requirements for mRNA synthesis. The MEL system directs accurate transcription of adenovirus type 2 major late DNA and mouse betamaj-globin with an efficiency comparable to those of HeLa and KB cell extracts. Using the procedure of Matsui et al. (T. Matsui, J. Segall, P.A. Weil, and R.G. Roeder, J. Biol. Chem. 255:11992-11996, 1980), we have isolated three active fractions from both MEL and HeLa cell extracts which are required for accurate transcription and have shown that equivalent fractions from MEL and HeLa cell extracts are interchangeable. Our findings suggest that the components required for initiation of transcription are similar in different cell types, at least to the extent that they can be assayed in these in vitro systems.