Hypertension and the roles of the 9p21.3 risk locus: Classic findings and new association data.

BACKGROUND: The band 9p21.3 contains an established genomic risk zone for cardiovascular disease (CVD). Since the initial 2007 Wellcome Trust Case Control Consortium study (WTCCC), the increased CVD risk associated with 9p21.3 has been confirmed by multiple studies in different continents. However, many years later there was still no confirmed report of a corresponding association of 9p21.3 with hypertension, a major CV risk factor, nor with blood pressure (BP). THEORY: In this contribution, we review the bipartite haplotype structure of the 9p21.3 risk locus: one block is devoid of protein-coding genes but contains the lead CVD risk SNPs, while the other block contains the first exon and regulatory DNA of the gene for the cell cycle inhibitor p15. We consider how findings from molecular biology offer possibilities of an involvement of p15 in hypertension etiology, with expression of the p15 gene modulated by genetic variation from within the 9p21.3 risk locus. RESULTS: We present original results from a Colombian study revealing moderate but persistent association signals for BP and hypertension within the classic 9p21.3 CVD risk locus. These SNPs are mostly confined to a 'hypertension island' that spans less than 60 kb and coincides with the p15 haplotype block. We find confirmation in data originating from much larger, recent European BP studies, albeit with opposite effect directions. CONCLUSION: Although more work will be needed to elucidate possible mechanisms, previous findings and new data prompt reconsidering the question of how variation in 9p21.3 might influence hypertension components of cardiovascular risk.

Assessment and management of blood-pressure variability.

Blood pressure (BP) is characterized by marked short-term fluctuations occurring within a 24 h period (beat-to-beat, minute-to-minute, hour-to-hour, and day-to-night changes) and also by long-term fluctuations occurring over more-prolonged periods of time (days, weeks, months, seasons, and even years). Rather than representing 'background noise' or a randomly occurring phenomenon, these variations have been shown to be the result of complex interactions between extrinsic environmental and behavioural factors and intrinsic cardiovascular regulatory mechanisms. Although the adverse cardiovascular consequences of hypertension largely depend on absolute BP values, evidence from observational studies and post-hoc analyses of data from clinical trials have indicated that these outcomes might also depend on increased BP variability (BPV). Increased short-term and long-term BPV are associated with the development, progression, and severity of cardiac, vascular, and renal damage and with an increased risk of cardiovascular events and mortality. Of particular interest are the findings from post-hoc analyses of large intervention trials in hypertension, showing that within-patient visit-to-visit BPV is strongly prognostic for cardiovascular morbidity and mortality. This result has prompted discussion on whether antihypertensive treatment should be targeted not only towards reducing mean BP levels but also to stabilizing BPV with the aim of achieving consistent BP control over time, which might favour cardiovascular protection.

Blood pressure variability, cardiovascular risk, and risk for renal disease progression.

The adverse cardiovascular consequences of high blood pressure (BP) not only depend on absolute BP values, but also on BP variability (BPV). Evidence has been provided that independently of mean BP levels, BP variations in the short- and long-term are associated with the development, progression and severity of cardiac, vascular and renal organ damage, and with an increased risk of CV events and mortality. Alterations in BPV have also been shown to be predictive of the development and progression of renal damage, which is of relevance if considering that impaired renal function in a hypertensive patient constitutes a very potent predictor of future CV events and mortality even in treated subjects. This review will address whether antihypertensive treatment should target alterations in BPV, in addition to reducing absolute BP levels, in order to achieve the highest CV and renal protection in hypertensive and renal patients.

Evaluación hemodinámica no invasiva con cardiografía de impedancia: aplicaciones en falla cardíaca y en hipertensión arterial / Non-invasive hemodynamic evaluation with impedance cardiography: applications in heart failure and hypertension

La cardiografía de impendancia (CGI) representa un método no invasivo para la evaluación del estado hemodinámico latido a latido. Aunque se introdujo por primera vez hace más de 40 años, la CGI ha mostrado un resurgimiento en la última década, a partir de una serie de estudios clínicos que han demostrado su precisión en la estimación del volumen latido, tanto contra el "gold-standard" invasivo (termodilución), como contra los métodos de referencia no invasivos (ecocardiografía). Diversos estudios demuestran la utilidad de esta técnica en el manejo del paciente con falla cardíaca y en el enfoque diagnóstico y terapéutico de la hipertensión arterial, por lo cual constituyen actualmente dos de las aplicaciones clínicas más importantes de la CGI. En falla cardiaca, los cambios en el volumen de líquido del tórax y del gasto cardíaco evaluados por CGI, han demostrado ser predictores de descompensación aguda, incluso semanas antes del inicio de la sintomatología respiratoria; además, permiten identificar el origen cardiogénico o respiratorio de la disnea cuando el examen físico y los demás paraclínicos no son concluyentes. En los pacientes con hipertensión arterial no controlada o resistente, la CGI permite realizar una mejor caracterización del fenotipo hipertensivo y elegir la estrategia farmacológica más específica para intervenir la alteración hemodinámica predominante (resistencia vascular vs. gasto cardiaco elevado). En este artículo se realiza una revisión de los principios biofísicos de la CGI y su utilidad en la evaluación no invasiva del estado hemodinámico, así como una evaluación crítica de la literatura que da soporte a su aplicación clínica en el tratamiento de la falla cardíaca y la hipertensión arterial.

Impedance cardiography (ICG) represents a non-invasive method for hemodynamic assessment in a beat-to-beat basis. Since its introduction more than forty years ago, a renewed interest in the use of this technique during the last decade has been noticed, mainly as a result of a series of clinical studies showing its precision in the estimation of stroke volume either against invasive gold standard (i.e. thermodilution) or against non-invasive reference methods (i.e. echocardiography). On the other hand, ICG has demonstrated to be useful for the management of heart failure patients and for the diagnostic and therapeutic approach to hypertension, which currently constitute two of the major applications of ICG. In heart failure patients, changes in thoracic fluid content and cardiac output tracked by ICG have shown to be predictors of acute decompensation even weeks before respiratory symptoms appear; also allowing identification of a cardiac vs. respiratory origin of dyspnea when physical examination and laboratory tests are not conclusive. In the particular case of patients with uncontrolled or severe hypertension, ICG makes possible a better characterization of hypertensive phenotype leading to a more specific choice of pharmacological agents to treat the primary hemodynamic alteration (i.e elevated peripheral resistance vs. elevated cardiac output). The present review, provides a review of the biophysical principles of ICG and its precision in measuring stroke volume and present a critical assessment of the literature supporting its clinical application in the management of heart failure and arterial hypertension.

Benefits of tight blood pressure control in diabetic patients with hypertension: importance of early and sustained implementation of effective treatment strategies.

In 2008, when the UK Prospective Diabetes Study (UKPDS) group presented their 30-year findings concerning the possible sustained effects of improved glycemic control after 10 years of extended follow-up in type 2 diabetic patients, a so-called "legacy effect" was reported to address the long-term emergent and/or sustained benefits of early improved glycemic control. Opposite results were obtained by the Hypertension in Diabetes Study (HDS) carried out in the frame of UKPDS, with no evidence of any legacy effect on cardiovascular (CV) outcomes for an initial 4-year period of tight blood pressure (BP) control. Thus, it was concluded that BP control has to be continued over time, since, although it had a short time-to-effect relationship in preventing stroke, BP control was associated with a short persistence of its clinical benefits once the intervention was discontinued. These findings are unique because, whereas most interventional trials in hypertension that included diabetic patients have shown a reduction in CV outcomes shortly after starting treatment, only the UKPDS-HDS specifically explored the possible persistence of clinical benefits after discontinuing intensive BP-lowering intervention. This article aims to provide a critical interpretation of the UKPDS findings of lack of BP legacy, in the context of the currently available evidence on the benefits of antihypertensive treatment. The importance of effective BP control in type 2 diabetic patients to prevent CV outcomes and other diabetes-related complications is underlined, with emphasis on early, tight, and continuous BP control to optimize patients' protection.

Co-existence of integumentary lesions and lung x-ray abnormalities in patients with paracoccidioidomycosis (PCM).

In paracoccidioidomycosis (PCM), the primary lung infection remains silent. In this study, attempts were done to define the primary target organ by correlating lung radiographic abnormalities with the time course of mucosal/skin lesions concurrently exhibited at diagnosis by 63 patients in whom microscopy and/or isolation of Paracoccidioides brasiliensis from respiratory secretions had been positive. Mucosal and skin lesions were found in 65.1% and 12.7% of the patients, respectively. Odynophagia and dysphagia were present in 38.1% each. All patients had lung interstitial infiltrates, and 31.7% had also alveolar lesions; fibrosis was recorded in 46% of them. An inverse correlation was shown for fibrosis and presence of either odynophagia or dysphagia. Cluster analyzes strongly supported two sets of patients: those with mucosal damage, odynophagia/dysphagia, and alveolo-interstitial infiltrates and those with dermal lesions, dyspnea, and lung fibrosis. These groups may represent novel stages in the natural course of PCM.

Disseminated histoplasmosis: a comparative study between patients with acquired immunodeficiency syndrome and non-human immunodeficiency virus-infected individuals.

We studied 52 patients with disseminated histoplasmosis, 30 with the acquired immunodeficiency syndrome (AIDS) (cohort 1) and 22 not co-infected with the human immunodeficiency virus (cohort 2). Demographic, clinical, laboratory, mycologic findings, as well as antifungal therapy and highly active antiretroviral (HAART), were analyzed. Skin lesions were significantly higher in cohort 1 than in cohort 2 (P = 0.001). Anemia, leukopenia, and an elevated erythrocyte sedimentation rate were also more pronounced in cohort 1 than in cohort 2 (P < 0.001). Histoplasma capsulatum was isolated more often in cohort 1 than in cohort 2 (P < 0.05) patients, but antibodies to H. capsulatum were detected more frequently in cohort 2 than in cohort 1 (P < 0.05). Itraconazole treatment was less effective in cohort 1 than in cohort 2 (P = 0.012). In cohort 1 patients, HAART improved response to antifungals when compared with individuals not given HAART (P = 0.003), who exhibited higher mortality rates (P = 0.025). Cohort 1 patients who were given dual antifungal and anti-retroviral therapies responded as well as the non-HIV patients in cohort 2, who were treated only with itraconazole. These results indicate the need to promote restoration of the immune system in patients with AIDS and histoplasmosis.