Pharmacogenomics of Antihypertensive Drugs in Brazil: recent progress and clinical implications

Background: The available antihypertensive drugs are effective and well tolerated agents. However, only about half of patients with treated hypertension achieve appropriate blood pressure control. Genetic and non-genetic factors contribute to the interindividual variability of the therapeutic response Objective: This review constitutes a comprehensive update of the pharmacogenomics of antihypertensive drugs and their clinical implications in Brazil. Results: Twenty-five studies explored the influence of gene variants on drug response in patients with primary, resistant, or gestational hypertension. Variants in BDKRB2, NOS3, PRKCA, and VEGFA influenced the response to enalapril in patients with primary hypertension. AGT and MMP2 variants were associated with high risk of resistance to antihypertensive treatment, whereas NOS2 variants were related to low risk. Moreover, NAT2 slow acetylators showed an increased response to hydralazine in patients with resistant hypertension. HMOX1, NAMPT, MMP9, NOS3 and TIMP1 variants might be markers of drug responsiveness in hypertensive or preeclamptic pregnant women. Power and replication of studies, polygenic nature of response to therapy, and treatment with multiple drugs were important challenges to be overcome for identifying genetic predictors of antihypertensive response in Brazil. Conclusion: Pharmacogenomic studies in Brazilian cohorts provide some evidences of variants, mainly in pharmacodynamics genes, which influence the response to antihypertensive drugs. However, some findings are limited by cohort size or therapeutic scheme and may be influenced by interactions with other genetic and non-genetic factors. Therefore, further investigations are needed to elucidate the contribution of pharmacogenomics to the efficacy and safety of antihypertensive therapy.

In silico trial of baroreflex activation therapy for the treatment of obesity-induced hypertension

Clinical trials evaluating the efficacy of chronic electrical stimulation of the carotid baroreflex for the treatment of hypertension (HTN) are ongoing. However, the mechanisms by which this device lowers blood pressure (BP) are unclear, and it is uncertain which patients are most likely to receive clinical benefit. Mathematical modeling provides the ability to analyze complicated interrelated effects across multiple physiological systems. Our current model HumMod is a large physiological simulator that has been used previously to investigate mechanisms responsible for BP lowering during baroreflex activation therapy (BAT). First, we used HumMod to create a virtual population in which model parameters (n = 335) were randomly varied, resulting in unique models (n = 6092) that we define as a virtual population. This population was calibrated using data from hypertensive obese dogs (n = 6) subjected to BAT. The resultant calibrated virtual population (n = 60) was based on tuning model parameters to match the experimental population in 3 key variables: BP, glomerular filtration rate, and plasma renin activity, both before and after BAT. In the calibrated population, responses of these 3 key variables to chronic BAT were statistically similar to experimental findings. Moreover, blocking suppression of renal sympathetic nerve activity (RSNA) and/or increased secretion of atrial natriuretic peptide (ANP) during BAT markedly blunted the antihypertensive response in the virtual population. These data suggest that in obesity-mediated HTN, RSNA and ANP responses are key factors that contribute to BP lowering during BAT. This modeling approach may be of value in predicting BAT responses in future clinical studies.

Pharmacogenomics of hypertension in chronic kidney disease: the CKD-PGX study

ABSTRACTBackgroundPatients with chronic kidney disease (CKD) often have uncontrolled hypertension despite polypharmacy. Pharmacogenomic drug-gene interactions (DGIs) may impact the metabolism or efficacy of antihypertensive agents. We hypothesized that providing a panel of 11 pharmacogenomic predictors of antihypertensive response would improve hypertension control.MethodsA prospective cohort with CKD and hypertension was followed to assess the effect of pharmacogenomic testing on blood pressure control. The analysis population included 382 hypertensive subjects genotyped for cross-sectional assessment of drug-gene interactions and 335 subjects followed for 1 year to assess systolic (SBP) and diastolic blood pressure (DBP).ResultsMost participants (58.2%) with uncontrolled hypertension had a DGI reducing the efficacy of one or more antihypertensive agents. Subjects with a DGI had 1.88-fold (95% CI 1.2-2.8) higher odds of uncontrolled hypertension as compared to those without a DGI, adjusted for race and CKD grade. CYP2C9 reduced metabolism genotypes were associated with losartan response and uncontrolled hypertension (Odds Ratio 5.2, CI 1.9 -14.7). CYP2D6 intermediate or poor metabolizers had less frequent uncontrolled hypertension compared to normal metabolizers taking metoprolol or carvedilol (OR 0.55, CI 0.3-0.95). In 335 subjects completing 1 year follow-up, SBP (−4.0 mmHg, CI 1.6-6.5) and DBP (−3.3 mmHg, CI 2.0-4.6) were improved. The magnitude of reductions in SBP (−14.8 mmHg, CI 10.3-19.3) and DBP (−8.4 mmHg, CI 5.9-10.9) were greatest in the 90 individuals with uncontrolled hypertension and an actionable genotype.ConclusionsThere is a potential role for the addition of pharmacogenomic testing to optimize antihypertensive regimens in patients with CKD.

Implementation of a Renal Precision Medicine Program: Clinician Attitudes and Acceptance

A precision health initiative was implemented across a multi-hospital health system, wherein a panel of genetic variants was tested and utilized in the clinical care of chronic kidney disease (CKD) patients. Pharmacogenomic predictors of antihypertensive response and genomic predictors of CKD were provided to clinicians caring for nephrology patients. To assess clinician knowledge, attitudes, and willingness to act on genetic testing results, a Likert-scale survey was sent to and self-administered by these nephrology providers (N = 76). Most respondents agreed that utilizing pharmacogenomic-guided antihypertensive prescribing is valuable (4.0 ± 0.7 on a scale of 1 to 5, where 5 indicates strong agreement). However, the respondents also expressed reluctance to use genetic testing for CKD risk stratification due to a perceived lack of supporting evidence (3.2 ± 0.9). Exploratory sub-group analyses associated this reluctance with negative responses to both knowledge and attitude discipline questions, thus suggesting reduced exposure to and comfort with genetic information. Given the evolving nature of genomic implementation in clinical care, further education is warranted to help overcome these perception barriers.

Cardiovascular Effects Mediated by Imidazoline Drugs: An Update

Objective: Clonidine is a centrally acting antihypertensive drug. Hypotensive effect of clonidine is mediated mainly by central α2-adrenoceptors and/or imidazoline receptors located in a complex network of the brainstem. Unfortunately, clonidine produces side effects such as sedation, mouth dry, and depression. Moxonidine and rilmenidine, compounds of the second generation of imidazoline drugs, with fewer side effects, display a higher affinity for the imidazoline receptors compared with α2-adrenoceptors. The antihypertensive action of these drugs is due to inhibition of the sympathetic outflow primarily through central I1-imidazoline receptors in the RVLM, although others anatomical sites and mechanisms/receptors are involved. Agmatine is regarded as the endogenous ligand for imidazoline receptors. This amine modulates the cardiovascular function. Indeed, when administered in the RVLM mimics the hypotension of clonidine. Results: Recent findings have shown that imidazoline drugs also exert biological response directly on the cardiovascular tissues, which can contribute to their antihypertensive response. Currently, new imidazoline receptors ligands are in development. Conclusion: In the present review, we provide a brief update on the cardiovascular effects of clonidine, moxonidine, rilmenidine, and the novel imidazoline agents since representing an important therapeutic target for some cardiovascular diseases.

Pharmacogenomics in Hypertension: Where We Stand Today

Hypertension is a common and growing medical problem that leads to enormous cardiovascular and kidney disease worldwide. While many drugs exist to treat hypertension, there is large individual variation in how a given individual responds to different agents, which contributes to dismal rates of hypertension control. While demographic factors predict which drugs may work better in certain individuals, a great degree of this variation has a genetic basis. In recent years, genome wide association studies have begun to identify specific gene variants that predict drug response to particular agents. This review identifies the major genetic variants influencing antihypertensive response that have emerged from this growing body of work. For novel genetic variants without a previously known biologic basis in blood pressure, it is crucial to validate initial findings in subsequent studies. This information may eventually lead to a more personalized approach to hypertension management that will improve blood pressure control and patient outcomes. The integration of this large amount of data and its real world application will be highly challenging, but strategies to accomplish this are discussed.

Association of mononucleotide polymorphisms of angiotensinogen gene at promoter region with antihypertensive response to angiotensin receptor blockers in hypertensive Chinese

Introduction: This study aimed to investigate whether mononucleotide polymorphisms of the angiotensinogen gene at promoter were associated with the blood-pressure-lowering response to telmisartan treatment. Materials and methods: After a two-week single-blind placebo run-in period, 148 patients with mild-to-moderate primary hypertension received monotherapy with 80 mg/day of telmisartan and then were followed up for eight weeks. The -6A/G and -20A/C polymorphisms of the angiotensinogen gene at promoter were determined through polymerase chain reaction and restriction fragment length polymorphsim analysis. The relationship between these polymorphisms and changes in blood pressure was observed and evaluated after eight weeks of treatment. Results: There were no significant differences between -6A/G, -20A/C polymorphisms of the angiotensinogen gene and blood pressure reductions after treatment, p>0.05. Conclusion: It is suggested that angiotensinogen-6 A/G and angiotensinogen-20 A/C polymorphisms were not associated with the antihypertensive response to telmisartan treatment in Chinese patients with hypertension.