High rates of undiagnosed and uncontrolled hypertension upon a screening campaign in rural Rwanda: a cross-sectional study.

BACKGROUND: Hypertension remains the major risk factor for cardiovascular diseases (CVDs) worldwide with a prevalence and mortality in low- and middle-income countries (LMICs) among the highest. The early detection of hypertension risk factors is a crucial pillar for CVD prevention. DESIGN AND METHOD: This cross-sectional study included 4284 subjects, mean age 46 ± 16SD, 56.4% females and mean BMI 26.6 ± 3.7 SD. Data were collected through a screening campaign in rural area of Kirehe District, Eastern of Rwanda, with the objective to characterize and examine the prevalence of elevated blood pressure (BP) and other CVD risk factors. An adapted tool from the World Health Organization STEPwise Approach was used for data collection. Elevated BP was defined as ≥ 140/90 mm/Hg and elevated blood glucose as blood glucose ≥ 100 mg/dL after a 6-h fast. RESULTS: Of the sampled population, 21.2% (n = 910) had an elevated BP at screening; BP was elevated among individuals not previously known to have HTN in 18.7% (n = 752). Among individuals with a prior diagnosis of HTN, 62.2% (n = 158 of 254) BP was uncontrolled. Age, weight, smoking, alcohol history and waist circumference were associated with BP in both univariate analyses and multivariate analysis. CONCLUSION: High rates of elevated BP identified through a health screening campaign in this Rwandan district were surprising given the rural characteristics of the district and relatively low population age. These data highlight the need to implement an adequate strategy for the prevention, diagnosis, and control of HTN that includes rural areas of Rwanda as part of a multicomponent strategy for CVD prevention.

Association of Balance Function With All-Cause and Cause-Specific Mortality Among US Adults.

Importance: Difficulty maintaining balance is common among individuals aged 40 years or older and increases the risk of falls. However, little is known about the association of balance function with long-term mortality outcomes in adults. Objective: To investigate the association of balance function with all-cause and cause-specific mortality among US adults. Design, Setting, and Participants: A prospective, population-based cohort study of a nationally representative sample of 5816 adults (weighted population, 92 260 641) from the US National Health and Nutrition Examination Survey was conducted from 1999 to 2004. Individuals aged 40 years or older who completed the modified Romberg Test of Standing Balance on Firm and Compliant Support Surfaces were included. Participants were linked to mortality data from the test date through December 31, 2015. Data analysis was conducted from February 1 to June 1, 2020. Exposures: The modified Romberg Test of Standing Balance on Firm and Compliant Support Surfaces was used to measure balance function and define balance disorder according to sensory input. Main Outcomes and Measures: Mortality associated with all causes, cardiovascular disease (CVD), and cancer. Results: A total of 5816 adults (weighted mean [SE] age, 53.6 [0.2] years; 2897 [49.8%] women) were included in this cohort study. During up to 16.8 years of follow-up (median, 12.5 years; 68 919 person-years), 1530 deaths occurred, including 342 associated with CVD and 364 associated with cancer. Participants with balance disorder were at a higher risk of death from all causes, CVD, and cancer. After adjusting for sociodemographic characteristics, lifestyle factors, and chronic conditions, the hazard ratios (HRs) among participants with balance disorder compared with those without balance disorder were 1.44 (95% CI, 1.23-1.69) for all-cause mortality, 1.65 (95% CI, 1.17-2.31) for CVD mortality, and 1.37 (95% CI, 1.03-1.83) for cancer mortality. Furthermore, vestibular balance disorder was associated with increased mortality from all causes (HR, 1.31; 95% CI, 1.08-1.58), CVD (HR, 1.59; 95% CI, 1.12-2.27), and cancer (HR, 1.39; 95% CI, 1.04-1.86). Conclusions and Relevance: In this nationally representative sample of US adults, balance disorder was associated with an increased risk of all-cause, CVD, and cancer mortality. Further studies are needed to confirm these findings and evaluate whether the observed associations represent a causal biological phenomenon and, if so, whether the effect is modifiable with a multicomponent exercise program.

Cardiorespiratory Fitness Is Associated With Early Death Among Healthy Young and Middle-Aged Baby Boomers and Generation Xers.

BACKGROUND: Increased mortality associated with low cardiorespiratory fitness has shown to take effect during late adulthood in previous generations. A recent rise in early death was observed in the United States. We investigated the impact of low cardiorespiratory fitness during young and middle adulthood on premature death in healthy adults from recent generations. METHODS: A prospective cohort study of a nationally representative sample of US Baby Boomers and Generation Xers (born 1945-1980). Between 1999 and 2004, 3242 adults ages 20 to 49 years (weighted N = 59,888,450; mean age, 33.8 ± 0.2 years) underwent submaximal treadmill exercise test in the National Health and Nutrition Examination Survey study. Weighted Cox proportional hazards regression were used to evaluate the association of cardiorespiratory fitness with premature death at 65 years or younger. RESULTS: During a mean follow-up of 13.8 years, 104 deaths (weighted deaths N =1,326,808) occurred. Low cardiorespiratory fitness was associated with an increased risk of premature death as a result of all-cause (hazard ratio [HR], low vs high: 2.26; 95% confidence interval [CI], 1.10 to 4.64, P for trend = 0.036) and cancer mortality (HR low vs moderate/high: 6.53; 95% CI, 2.38 to 17.9). Further, this association was stronger in adults ages 35 to 49 years at baseline (HR, 4.17 [95% CI, 1.19 to 9.11]). CONCLUSION: We observed an inverse association between cardiorespiratory fitness during middle adulthood and premature death, which was not detected in preceding generations. These findings suggested that low cardiorespiratory fitness might be emerging as a new risk factor for early death among US Baby Boomers and Generation Xers.

Increased mtDNA Abundance and Improved Function in Human Barth Syndrome Patient Fibroblasts Following AAV-TAZ Gene Delivery.

Barth syndrome (BTHS) is a rare, X-linked, mitochondrial disorder caused by mutations in the gene encoding tafazzin. BTHS results in cardiomyopathy, muscle fatigue, and neutropenia in patients. Tafazzin is responsible for remodeling cardiolipin, a key structural lipid of the inner mitochondrial membrane. As symptoms can vary in severity amongst BTHS patients, we sought to compare mtDNA copy numbers, mitochondrial fragmentation, and functional parameters between primary dermal BTHS fibroblasts isolated from patients with two different mutations in the TAZ locus. To confirm cause‒effect relationships and further support the development of gene therapy for BTHS, we also characterized the BTHS cells following adeno-associated virus (AAV)-TAZ transduction. Our data show that, in response to AAV-TAZ transduction, these remarkably dynamic organelles show recovery of mtDNA copy numbers, mitochondrial structure, and mitochondrial function, providing additional evidence to support the therapeutic potential of AAV-mediated gene delivery for BTHS. This study also demonstrates the direct relationship between healthy mitochondrial membrane structure and maintenance of proper levels of mtDNA copy numbers.

AAV9-TAZ Gene Replacement Ameliorates Cardiac TMT Proteomic Profiles in a Mouse Model of Barth Syndrome.

Barth syndrome (BTHS) is a rare mitochondrial disease that causes severe cardiomyopathy and has no disease-modifying therapy. It is caused by recessive mutations in the gene tafazzin (TAZ), which encodes tafazzin-an acyltransferase that remodels the inner mitochondrial membrane lipid cardiolipin. To identify novel mechanistic pathways involved in BTHS and evaluate the effects of gene therapy on proteomic profiles, we performed a multiplex tandem mass tagging (TMT) quantitative proteomics analysis to compare protein expression profiles from heart lysates isolated from BTHS, healthy wild-type (WT), and BTHS treated with adeno-associated virus serotype 9 (AAV9)-TAZ gene replacement as neonates or adults. 197 proteins with ≥2 unique peptides were identified. Of these, 91 proteins were significantly differentially expressed in BTHS compared to WT controls. Cause-effect relationships between tafazzin deficiency and altered protein profiles were confirmed through demonstrated significant improvements in expression levels following administration of AAV9-TAZ. The importance of TMEM65 in Cx43 localization to cardiac intercalated discs was revealed as a novel consequence of tafazzin deficiency that was improved following gene therapy. This study identifies novel mechanistic pathways involved in the pathophysiology of BTHS, demonstrates the ability of gene delivery to improve protein expression profiles, and provides support for clinical translation of AAV9-TAZ gene therapy.

AAV-Mediated TAZ Gene Replacement Restores Mitochondrial and Cardioskeletal Function in Barth Syndrome.

Barth syndrome (BTHS) is a rare mitochondrial disease that affects heart and skeletal muscle and has no curative treatment. It is caused by recessive mutations in the X-linked gene TAZ, which encodes tafazzin. To develop a clinically relevant gene therapy to restore tafazzin function and treat BTHS, three different adeno-associated virus serotype 9 vectors were tested and compared to identify the optimal promoter-cytomegalovirus (CMV), desmin (Des), or a native tafazzin promoter (Taz)-for TAZ expression following intravenous administration of 1 × 1013 vector genomes/kilogram to a mouse model of BTHS as either neonates (1-2 days of age) or adults (3 months of age). At 5 months of age, evaluations of biodistribution and TAZ expression levels, mouse activity assessments, fatigue in response to exercise, muscle strength, cardiac function, mitochondrial structure, oxygen consumption, and electron transport chain complex activity assays were performed to measure the extent of improvement in treated mice. Each promoter was scored for significant improvement over untreated control mice and significant improvement compared with the other two promoters for every measurement and within each age of administration. All three of the promoters resulted in significant improvements in a majority of the assessments compared with untreated BTHS controls. When scored for overall effectiveness as a gene therapy, the Des promoter was found to provide improvement in the most assessments, followed by the CMV promoter, and finally Taz regardless of injection age. This study provides substantial support for translation of an adeno-associated virus serotype 9-mediated TAZ gene replacement strategy using a Des promoter for human BTHS patients in the clinic.

Right ventricular function in preterm and term neonates: reference values for right ventricle areas and fractional area of change.

BACKGROUND: Right ventricular (RV) fractional area of change (FAC) is a quantitative two-dimensional echocardiographic measurement of RV function. RV FAC expresses the percentage change in the RV chamber area between end-diastole (RV end-diastolic area [RVEDA]) to end-systole (RV end-systolic area [RVESA]). The objectives of this study were to determine the maturational (age- and weight-related) changes in RV FAC and RV areas and to establish reference values in healthy preterm and term neonates. METHODS: A prospective longitudinal study was conducted in 115 preterm infants (23-28 weeks' gestational age at birth, 500-1,500 g). RV FAC was measured at 24 hours of age, 72 hours of age, and 32 and 36 weeks' postmenstrual age (PMA). The maturational patterns of RVEDA, RVESA, and RV FAC were compared with those in 60 healthy full-term infants in a cross-sectional study (≥37 weeks, 3.5 ± 1 kg), who underwent echocardiography at birth (n = 25) and 1 month of age (n = 35). RVEDA and RVESA were traced in the RV-focused apical four-chamber view, and FAC was calculated using the formula 100 × [(RVEDA - RVESA)/RVEDA)]. Premature infants who developed chronic lung disease or had clinically and hemodynamically significant patent ductus arteriosus were excluded (n = 55) from the reference values. Intra- and interobserver reproducibility analysis was performed. RESULTS: RV FAC ranged from 26% at birth to 35% by 36 weeks' PMA in preterm infants (n = 60) and increased almost 2 times faster in the first month of age compared with healthy term infants (n = 60). Similarly, RVEDA and RVESA increased throughout maturation in both term and preterm infants. RV FAC and RV areas were correlated with weight (r = 0.81, P < .001) but were independent of gestational age at birth (r = 0.3, P = .45). RVEDA and RVESA were correlated with PMA in weeks (r = 0.81, P < .001). RV FAC trended lower in preterm infants with bronchopulmonary dysplasia (P = .04) but was not correlated with size of patent ductus arteriosus (P = .56). There was no difference in RV FAC based on gender or need for mechanical ventilation. CONCLUSIONS: This study establishes reference values of RV areas (RVEDA and RVESA) and RV FAC in healthy term and preterm infants and tracks their maturational changes during postnatal development. These measures increase from birth to 36 weeks' PMA, and this is reflective of the postnatal cardiac growth as a contributor to the maturation of cardiac function These measures are also linearly associated with increasing weight throughout maturation. This study suggests that two-dimensional RV FAC can be used as a complementary modality to assess global RV systolic function in neonates and facilitates its incorporation into clinical pediatric and neonatal guidelines.

Diabetes-related microvascular and macrovascular diseases in the physical therapy setting.

Physical therapists commonly treat people with diabetes for a wide variety of diabetes-associated impairments, including those from diabetes-related vascular disease. Diabetes is associated with both microvascular and macrovascular diseases affecting several organs, including muscle, skin, heart, brain, and kidneys. A common etiology links the different types of diabetes-associated vascular disease. Common risk factors for vascular disease in people with diabetes, specifically type 2 diabetes, include hyperglycemia, insulin resistance, dyslipidemia, hypertension, tobacco use, and obesity. Mechanisms for vascular disease in diabetes include the pathologic effects of advanced glycation end product accumulation, impaired vasodilatory response attributable to nitric oxide inhibition, smooth muscle cell dysfunction, overproduction of endothelial growth factors, chronic inflammation, hemodynamic dysregulation, impaired fibrinolytic ability, and enhanced platelet aggregation. It is becoming increasingly important for physical therapists to be aware of diabetes-related vascular complications as more patients present with insulin resistance and diabetes. The opportunities for effective physical therapy interventions (such as exercise) are significant.

The human immunodeficiency virus and the cardiometabolic syndrome in the developing world: an African perspective.

The advent of highly active antiretroviral therapy (HAART) has transformed human immunodeficiency virus (HIV)/AIDS into a manageable chronic disorder. Clinical care, however, needs to address the metabolic, anthropometric, and cardiovascular changes associated with HIV infection and HAART. Studies in developing countries suggest an increasing incidence of HIV-associated cardiometabolic syndrome (CMS), especially in urban settings. Predictions indicate that the greatest increase in the prevalence of diabetes will occur in Africa over the next 2 decades due to lifestyle changes. This, coupled with increased access to HAART, may exponentially increase the prevalence of CMS in developing countries, where HIV infection is prevalent. Appropriate evaluation and intervention programs need to be implemented in the developing world, especially sub-Saharan Africa, to curtail HIV-related CMS. This should include routine cardiovascular risk assessments, management of HIV infection with more "metabolically friendly" HAART, and encouragement of lifestyle modifications, particularly smoking cessation, weight management, regular exercise, and adherence to a healthy diet.

HIV-protease inhibitors induce expression of suppressor of cytokine signaling-1 in insulin-sensitive tissues and promote insulin resistance and type 2 diabetes mellitus.

Insulin resistance, hyperglycemia, and type 2 diabetes are among the sequelae of metabolic syndromes that occur in 60-80% of human immunodeficiency virus (HIV)-positive patients treated with HIV-protease inhibitors (PIs). Studies to elucidate the molecular mechanism(s) contributing to these changes, however, have mainly focused on acute, in vitro actions of PIs. Here, we examined the chronic (7 wk) in vivo effects of the PI indinavir (IDV) in male Zucker diabetic fatty (fa/fa) (ZDF) rats. IDV exposure accelerated the diabetic state and dramatically exacerbated hyperglycemia and oral glucose intolerance in the ZDF rats, compared with vehicle-treated ZDF rats. Oligonucleotide gene array analyses revealed upregulation of suppressor of cytokine signaling-1 (SOCS-1) expression in insulin-sensitive tissues of IDV rats. SOCS-1 is a known inducer of insulin resistance and diabetes, and immunoblotting analyses revealed increases in SOCS-1 protein expression in adipose, skeletal muscle, and liver tissues of IDV-administered ZDF rats. This was associated with increases in the upstream regulator TNF-alpha and downstream effector sterol regulatory element-binding protein-1 and a decrease in IRS-2. IDV and other PIs currently in clinical use induced the SOCS-1 signaling cascade also in L6 myotubes and 3T3-L1 adipocytes exposed acutely to PIs under normal culturing conditions and in tissues from Zucker wild-type lean control rats administered PIs for 3 wk, suggesting an effect of these drugs even in the absence of background hyperglycemia/hyperlipidemia. Our findings therefore indicate that induction of the SOCS-1 signaling cascade by PIs could be an important contributing factor in the development of metabolic dysregulation associated with long-term exposures to HIV-PIs.