Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice.

Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome. Circulating BMP9 (bone morphogenetic protein 9) is emerging as an important regulator of pulmonary vascular homeostasis. Objectives:To determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity and whether loss of endogenous BMP9 occurs during LPS challenge. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice, and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human lung endothelial cells. The impact of BMP9 administration was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and from endotoxemic mice. Measurements and Main Results: Subacute neutralization of endogenous BMP9 in mice (N = 12) resulted in increased lung vascular permeability (P = 0.022), interstitial edema (P = 0.0047), and neutrophil extravasation (P = 0.029) compared with IgG control treatment (N = 6). In pulmonary endothelial cells, BMP9 regulated transcriptome pathways implicated in vascular permeability and cell-membrane integrity. Augmentation of BMP9 signaling in mice (N = 8) prevented inhaled LPS-induced lung injury (P = 0.0027) and edema (P < 0.0001). In endotoxemic mice (N = 12), endogenous circulating BMP9 concentrations were markedly reduced, the causes of which include a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human patients with sepsis (N = 10), circulating concentratons of BMP9 were also markedly reduced (P < 0.0001). Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial-protective factor, downregulated during inflammation. Exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in lung injury.

Cardiac rehabilitation availability and characteristics in Latin America and the Caribbean: A Global Comparison.

BACKGROUND: This study aimed to establish availability and characteristics of cardiac rehabilitation (CR) in Latin America and the Caribbean (LAC), where cardiovascular disease is highly prevalent. METHODS: In this cross-sectional sub-analysis focusing on the 35 LAC countries, local cardiovascular societies identified CR programs globally. An online survey was administered to identified programs, assessing capacity and characteristics. CR need was computed relative to ischemic heart disease (IHD) incidence from the Global Burden of Disease study. RESULTS: ≥1 CR program was identified in 24 LAC countries (68.5% availability; median = 3 programs/country). Data were collected in 20/24 countries (83.3%); 139/255 programs responded (54.5%), and compared to responses from 1082 programs in 111 countries. LAC density was 1 CR spot per 24 IHD patients/year (vs 18 globally). Greatest need was observed in Brazil, Dominican Republic and Mexico (all with >150,000 spots needed/year). In 62.8% (vs 37.2% globally P < .001) of CR programs, patients pay out-of-pocket for some or all of CR. CR teams were comprised of a mean of 5.0 ± 2.3 staff (vs 6.0 ± 2.8 globally; P < .001); Social workers, dietitians, kinesiologists, and nurses were significantly less common on CR teams than globally. Median number of core components offered was 8 (vs 9 globally; P < .001). Median dose of CR was 36 sessions (vs 24 globally; P < .001). Only 27 (20.9%) programs offered alternative CR models (vs 31.1% globally; P < .01). CONCLUSION: In LAC countries, there is very limited CR capacity in relation to need. CR dose is high, but comprehensiveness low, which could be rectified with a more multidisciplinary team.

Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension.

Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260).Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.

The Prodomain-bound Form of Bone Morphogenetic Protein 10 Is Biologically Active on Endothelial Cells.

BMP10 is highly expressed in the developing heart and plays essential roles in cardiogenesis. BMP10 deletion in mice results in embryonic lethality because of impaired cardiac development. In adults, BMP10 expression is restricted to the right atrium, though ventricular hypertrophy is accompanied by increased BMP10 expression in a rat hypertension model. However, reports of BMP10 activity in the circulation are inconclusive. In particular, it is not known whether in vivo secreted BMP10 is active or whether additional factors are required to achieve its bioactivity. It has been shown that high-affinity binding of the BMP10 prodomain to the mature ligand inhibits BMP10 signaling activity in C2C12 cells, and it was proposed that prodomain-bound BMP10 (pBMP10) complex is latent. In this study, we demonstrated that the BMP10 prodomain did not inhibit BMP10 signaling activity in multiple endothelial cells, and that recombinant human pBMP10 complex, expressed in mammalian cells and purified under native conditions, was fully active. In addition, both BMP10 in human plasma and BMP10 secreted from the mouse right atrium were fully active. Finally, we confirmed that active BMP10 secreted from mouse right atrium was in the prodomain-bound form. Our data suggest that circulating BMP10 in adults is fully active and that the reported vascular quiescence function of BMP10 in vivo is due to the direct activity of pBMP10 and does not require an additional activation step. Moreover, being an active ligand, recombinant pBMP10 may have therapeutic potential as an endothelial-selective BMP ligand, in conditions characterized by loss of BMP9/10 signaling.

Regulation of the ALK1 ligands, BMP9 and BMP10.

Bone morphogenetic protein (BMP)9 and BMP10 are high affinity ligands for activin receptor-like kinase 1 (ALK1), a type I BMP receptor mainly expressed on vascular endothelial cells (ECs). ALK1-mediated BMP9/BMP10 signalling pathways have emerged as essential in EC biology and in angiogenesis. Several genetic mutations in the genes encoding the ligands and receptors of this pathway have been reported in two cardiovascular diseases, pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). Administration of recombinant BMP9 reverses experimental PAH in preclinical rodent models. Dalantercept, an Fc-fusion protein of the extracellular domain of ALK1 and a ligand trap for BMP9 and BMP10, is in phase II clinical trials for anti-tumour angiogenesis. Understanding the regulation of BMP9 and BMP10, at both gene and protein levels, under physiological and pathological conditions, will reveal essential information and potential novel prognostic markers for the BMP9/BMP10-targeted therapies.

Regulation of bone morphogenetic protein 9 (BMP9) by redox-dependent proteolysis.

BMP9, a member of the TGFß superfamily, is a homodimer that forms a signaling complex with two type I and two type II receptors. Signaling through high-affinity activin receptor-like kinase 1 (ALK1) in endothelial cells, circulating BMP9 acts as a vascular quiescence factor, maintaining endothelial homeostasis. BMP9 is also the most potent BMP for inducing osteogenic signaling in mesenchymal stem cells in vitro and promoting bone formation in vivo. This activity requires ALK1, the lower affinity type I receptor ALK2, and higher concentrations of BMP9. In adults, BMP9 is constitutively expressed in hepatocytes and secreted into the circulation. Optimum concentrations of BMP9 are essential to maintain the highly specific endothelial-protective function. Factors regulating BMP9 stability and activity remain unknown. Here, we showed by chromatography and a 1.9 Å crystal structure that stable BMP9 dimers could form either with (D-form) or without (M-form) an intermolecular disulfide bond. Although both forms of BMP9 were capable of binding to the prodomain and ALK1, the M-form demonstrated less sustained induction of Smad1/5/8 phosphorylation. The two forms could be converted into each other by changing the redox potential, and this redox switch caused a major alteration in BMP9 stability. The M-form displayed greater susceptibility to redox-dependent cleavage by proteases present in serum. This study provides a mechanism for the regulation of circulating BMP9 concentrations and may provide new rationales for approaches to modify BMP9 levels for therapeutic purposes.

Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10.

Heterozygous mutations in BMPR2 (bone morphogenetic protein (BMP) receptor type II) cause pulmonary arterial hypertension. BMPRII is a receptor for over 15 BMP ligands, but why BMPR2 mutations cause lung-specific pathology is unknown. To elucidate the molecular basis of BMP:BMPRII interactions, we report crystal structures of binary and ternary BMPRII receptor complexes with BMP10, which contain an ensemble of seven different BMP10:BMPRII 1:1 complexes. BMPRII binds BMP10 at the knuckle epitope, with the A-loop and ß4 strand making BMPRII-specific interactions. The BMPRII binding surface on BMP10 is dynamic, and the affinity is weaker in the ternary complex than in the binary complex. Hydrophobic core and A-loop interactions are important in BMPRII-mediated signalling. Our data reveal how BMPRII is a low affinity receptor, implying that forming a signalling complex requires high concentrations of BMPRII, hence mutations will impact on tissues with highest BMPR2 expression such as the lung vasculature.

Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms.

Activin receptor-like kinase 1 (ALK1)-mediated endothelial cell signalling in response to bone morphogenetic protein 9 (BMP9) and BMP10 is of significant importance in cardiovascular disease and cancer. However, detailed molecular mechanisms of ALK1-mediated signalling remain unclear. Here, we report crystal structures of the BMP10:ALK1 complex at 2.3 Å and the prodomain-bound BMP9:ALK1 complex at 3.3 Å. Structural analyses reveal a tripartite recognition mechanism that defines BMP9 and BMP10 specificity for ALK1, and predict that crossveinless 2 is not an inhibitor of BMP9, which is confirmed by experimental evidence. Introduction of BMP10-specific residues into BMP9 yields BMP10-like ligands with diminished signalling activity in C2C12 cells, validating the tripartite mechanism. The loss of osteogenic signalling in C2C12 does not translate into non-osteogenic activity in vivo and BMP10 also induces bone-formation. Collectively, these data provide insight into ALK1-mediated BMP9 and BMP10 signalling, facilitating therapeutic targeting of this important pathway.

Nature of Cardiac Rehabilitation Around the Globe.

BACKGROUND: Cardiac rehabilitation (CR) is a clinically-effective but complex model of care. The purpose of this study was to characterize the nature of CR programs around the world, in relation to guideline recommendations, and compare this by World Health Organization (WHO) region. METHODS: In this cross-sectional study, a piloted survey was administered online to CR programs globally. Cardiac associations and local champions facilitated program identification. Quality (benchmark of ≥ 75% of programs in a given country meeting each of 20 indicators) was ranked. Results were compared by WHO region using generalized linear mixed models. FINDINGS: 111/203 (54.7%) countries in the world offer CR; data were collected in 93 (83.8%; N = 1082 surveys, 32.1% program response rate). The most commonly-accepted indications were: myocardial infarction (n = 832, 97.4%), percutaneous coronary intervention (n = 820, 96.1%; 0.10), and coronary artery bypass surgery (n = 817, 95.8%). Most programs were led by physicians (n = 680; 69.1%). The most common CR providers (mean = 5.9 ±â€¯2.8/program) were: nurses (n = 816, 88.1%; low in Africa, p < 0.001), dietitians (n = 739, 80.2%), and physiotherapists (n = 733, 79.3%). The most commonly-offered core components (mean = 8.7 ±â€¯1.9 program) were: initial assessment (n = 939, 98.8%; most commonly for hypertension, tobacco, and physical inactivity), risk factor management (n = 928, 98.2%), patient education (n = 895, 96.9%), and exercise (n = 898, 94.3%; lower in Western Pacific, p < 0.01). All regions met ≥ 16/20 quality indicators, but quality was < 75% for tobacco cessation and return-to-work counseling (lower in Americas, p = < 0.05). INTERPRETATION: This first-ever survey of CR around the globe suggests CR quality is high. However, there is significant regional variation, which could impact patient outcomes.

Cardiac Rehabilitation Availability and Density around the Globe.

BACKGROUND: Despite the epidemic of cardiovascular disease and the benefits of cardiac rehabilitation (CR), availability is known to be insufficient, although this is not quantified. This study ascertained CR availability, volumes and its drivers, and density. METHODS: A survey was administered to CR programs globally. Cardiac associations and local champions facilitated program identification. Factors associated with volumes were assessed using generalized linear mixed models, and compared by World Health Organization region. Density (i.e. annual ischemic heart disease [IHD] incidence estimate from Global Burden of Disease study divided by national CR capacity) was computed. FINDINGS: CR was available in 111/203 (54.7%) countries; data were collected in 93 (83.8% country response; N = 1082 surveys, 32.1% program response rate). Availability by region ranged from 80.7% of countries in Europe, to 17.0% in Africa (p < .001). There were 5753 programs globally that could serve 1,655,083 patients/year, despite an estimated 20,279,651 incident IHD cases globally/year. Volume was significantly greater where patients were systematically referred (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.35-1.38) and programs offered alternative models (OR = 1.05, 95%CI = 1.04-1.06), and significantly lower with private (OR = .92, 95%CI = .91-.93) or public (OR = .83, 95%CI = .82-84) funding compared to hybrid sources.Median capacity (i.e., number of patients a program could serve annually) was 246/program (Q25-Q75 = 150-390). The absolute density was one CR spot per 11 IHD cases in countries with CR, and 12 globally. INTERPRETATION: CR is available in only half of countries globally. Where offered, capacity is grossly insufficient, such that most patients will not derive the benefits associated with participation.

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-ß pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

Clinical Effectiveness of Lifestyle Health Coaching: Case Study of an Evidence-Based Program.

We have developed, tested, and successfully implemented an affordable, evidence-based, technology-enabled, data-driven, outcomes-oriented, comprehensive lifestyle health coaching (LHC) program. The LHC program has been used primarily to provide services to employees of larger employers (ie, with at least 3000 employees) but has also been implemented in a variety of other settings, including hospitals, cardiac rehabilitation centers, physician practices, and as part of multicenter clinical trials. The program is delivered mainly using the telephone and Internet. Health coaches are guided by a Web-based participant management and tracking system. Lifestyle management interventions are based on several behavior change models and strategies, especially adult learning theory, social learning theory, the stages of change model, single concept learning theory, and motivational interviewing. The program is administered by nonphysician health professionals whose services are integrated with the care provided by participants' physicians. Outcomes data from published studies, including randomized clinical trials and independent third-party conducted research, have documented the clinical effectiveness of this evidence-based approach in terms of modification of multiple risk factors in healthy persons as well as those with certain common chronic diseases.

Multicenter Study of Temporal Trends in the Achievement of Atherosclerotic Cardiovascular Disease Risk Factor Goals During Cardiac Rehabilitation.

PURPOSE: Secondary prevention risk factor goals have been established by the American Heart Association/American College of Cardiology, and the American Heart Association has further delineated ideal cardiovascular health metrics. We evaluated risk factor goal achievement during early-outpatient cardiac rehabilitation (CR) and temporal trends in risk factor control. METHODS: Patients completed assessments on entry into and exit from CR at 35 centers between 2000 and 2009 and were categorized into 3 cohorts: entire (N = 12 984), 2000-2004 (n = 5468), and 2005-2009 (n = 7516) cohorts. RESULTS: Improvements occurred in multiple risk factors during CR. For the entire cohort, the percentages of patients at goal at CR completion ranged from 95.5% for smoking to 21.9% for body mass index (BMI) of <25.0 kg/m. Compared with 2000-2004, the percentage of the 2005-2009 cohort at goal was higher (P < .001) for blood pressure, low-density lipoprotein cholesterol, and physical activity, lower (P = .005) for BMI, and not significantly different (P > .05) for fasting glucose and smoking. At CR completion, of those in the entire, 2000-2004, and 2005-2009 cohorts, 4.4%, 3.9%, and 4.8% (P = .219 vs 2000-2004), respectively, had all biomarkers at the goal for ideal cardiovascular health and, of those with atherosclerotic cardiovascular disease, 70.8%, 71.5%, and 70.3% (P = .165 vs 2000-2004), respectively, were receiving statins. CONCLUSIONS: The percentage of patients at goal at CR completion increased for some, but not all, risk factors during 2005-2009 versus 2000-2004. Despite the benefits of CR, risk factor profiles are often suboptimal after CR. There remains room for improvement in risk factor management during CR and a need for continued intervention thereafter.

Effectiveness of three models for comprehensive cardiovascular disease risk reduction.

Cost and accessibility contribute to low participation rates in phase 2 cardiac rehabilitation programs in the United States. In this study, we compared the clinical effectiveness of 2 less costly and potentially more accessible approaches to cardiovascular risk reduction with that of a contemporary phase 2 cardiac rehabilitation program. Low- or moderate-risk patients (n = 155) with coronary artery disease (CAD) were randomly assigned to 12 weeks of participation in a contemporary phase 2 cardiac rehabilitation program (n = 52), a physician supervised, nurse-case-managed cardiovascular risk reduction program (n = 54), or a community-based cardiovascular risk reduction program administered by exercise physiologists guided by a computerized participant management system based on national clinical guidelines (n = 49). In all, 142 patients (91.6%) completed testing at baseline and after 12 weeks of intervention. For patients with abnormal (i.e., not at the goal level) baseline values, statistically significant (p < or =0.05) improvements were observed with all 3 interventions for multiple CAD risk factors. No statistically significant risk factor differences were observed among the 3 programs. For patients with a baseline maximal oxygen uptake < 7 metabolic equivalents, cardiorespiratory fitness increased to a greater degree in patients in the cardiac rehabilitation program and the community-based program versus the physician-supervised, nurse- case-managed program. These data have important implications for cost containment and increasing accessibility to clinically effective comprehensive cardiovascular risk reduction services in low- or moderate-risk patients with CAD.

Effectiveness of therapeutic lifestyle changes in patients with hypertension, hyperlipidemia, and/or hyperglycemia.

In this prospective study of 2,390 ethnically diverse men and women, we evaluated the clinical effectiveness of 12 weeks of participation in a community-based lifestyle management program in helping patients who had hypertension, hyperlipidemia, and/or impaired fasting glucose or diabetes mellitus achieve goal risk factor levels without using pharmacotherapeutic agents. Although further research is warranted, the findings clearly show that many patients who have conventional risk factors for coronary heart disease can achieve goal levels without medications within 12 weeks of initiating therapeutic lifestyle changes and refute the notion that intensive lifestyle intervention is not worth the effort.

Effect of exercise-based cardiac rehabilitation on multiple atherosclerotic risk factors in patients taking antidepressant medication.

Antidepressants might increase compliance with cardiovascular disease risk reduction interventions. However, antidepressants have been linked to deleterious metabolic effects. In the present multicenter study, we sought to determine whether patients who take antidepressants derive the expected benefits from cardiac rehabilitation in terms of improvements in multiple atherosclerotic risk factors. A cohort of 26,957 patients who had completed a baseline assessment before participating in an exercise-based cardiac rehabilitation program constituted the study population. The patients were stratified into 3 cohorts (i.e., nondepressed, depressed unmedicated, and depressed medicated) at baseline according to a self-reported history of depression and the current use of antidepressants. Risk factors were assessed at baseline and after ∼12 weeks of program participation. A self-reported history of depression was present at baseline in 5,172 patients (19.2%). Of these patients, 2,147 (41.5%) were taking antidepressants. Patients in the nondepressed cohort (49.4% completion) were more likely (p <0.001) to complete the exit assessment than patients in the depressed unmedicated (44.5% completion) or depressed medicated (43.5% completion) cohorts. Patients in all 3 cohorts who completed the exit assessment showed significant improvement in multiple risk factors. Moreover, the magnitude of improvement in blood pressure, serum lipids and lipoproteins, fasting glucose, weight, and body mass index was similar (p >0.05) in patients taking antidepressants and those who were not. In conclusion, our study is the first to show that antidepressants do not offset the average magnitude of improvement in multiple atherosclerotic risk factors that occurs with completion of a cardiac rehabilitation program.

A collaborative accountable care model in three practices showed promising early results on costs and quality of care.

Cigna's Collaborative Accountable Care initiative provides financial incentives to physician groups and integrated delivery systems to improve the quality and efficiency of care for patients in commercial open-access benefit plans. Registered nurses who serve as care coordinators employed by participating practices are a central feature of the initiative. They use patient-specific reports and practice performance reports provided by Cigna to improve care coordination, identify and close care gaps, and address other opportunities for quality improvement. We report interim quality and cost results for three geographically and structurally diverse provider practices in Arizona, New Hampshire, and Texas. Although not statistically significant, these early results revealed favorable trends in total medical costs and quality of care, suggesting that a shared-savings accountable care model and collaborative support from the payer can enable practices to take meaningful steps toward full accountability for care quality and efficiency.

Effect of comprehensive therapeutic lifestyle changes on prehypertension.

Although national clinical guidelines promulgate therapeutic lifestyle changes (TLC) as a cornerstone in the management of prehypertension, there is a perceived ineffectiveness of TLC in the real world. In this study of 2,478 ethnically diverse (African Americans n = 448, Caucasians n = 1,881) men (n = 666) and women (n = 1,812) with prehypertension and no known atherosclerotic cardiovascular disease, diabetes mellitus, or chronic kidney disease, we evaluated the clinical effectiveness of TLC in normalizing blood pressure (BP) without antihypertensive medications. Subjects were evaluated at baseline and after an average of 6 months of participation in a community-based program of TLC. TLC included exercise training, nutrition, weight management, stress management, and smoking cessation interventions. Baseline BP (125 +/- 8/79 +/- 3 mm Hg) decreased by 6 +/- 12/3 +/- 3 mm Hg (p or=30 kg/m(2). In conclusion, the present study adds to previous research by reporting on the effectiveness, rather than the efficacy, of TLC when administered in a real-world, community-based setting.

Efectos hemodinámicos y bioquímicos de la indapamida en pacientes hipertensos estudio multicentrico ecuatoriano / Hemodinamic and biochemical effects of the indapamide in hypertensive patients: multicentry ecuatorial study

Se estudiaron 85 pacientes con hipertensión arterial leve y moderada en dos poblaciones de Ecuador. Los pacientes fueron distribuidos en dos grupos: a) indapamina y b) placebo. Todos los pacientes fueron evaluados desde el punto de vista cardiovascular, haciéndosele también determinaciones de variables bioquímicas, incluyendo el perfil lipídico. También se practicaron electrocardiogramas de reposo y de esfuerzo. Los pacientes fueron seguidos por un lapso de 120 días. El análisis de los resultados finales evidencian que la indapamida, a una dosis de 2,5 mgs, ejerció una buena acción hipotensora sostenida, tanto en la tensión arterial diastólica como en la sistólica y en las tres posiciones. Los efectos secundarios fueron mínimos, mostrando una buena tolerancia. El grupo bajo indapamida mostró alza significativa en la HDL-C al igual que un descenso en el colesterol total y en la LDL, lo cual se tradujo en un descenso en las razones de riesgo aterosclerótico. En conclusión, la indapamida es un buen hipotensor, eficaz y bien tolerado