Hypertension is a significant risk factor for cardiovascular disease and mortality worldwide. The kidney is a major regulator of blood pressure and electrolyte homeostasis, with monogenic disorders ...indicating a link between abnormal ion transport and salt-sensitive hypertension. However, the association between salt and hypertension remains controversial. Thus, there is continued interest in deciphering the molecular mechanisms behind these processes. Uromodulin (UMOD) is the most abundant protein in the normal urine and is primarily synthesized by the thick ascending limb epithelial cells of the kidney. Genome-wide association studies have linked common UMOD variants with kidney function, susceptibility to chronic kidney disease and hypertension independent of renal excretory function. This review will discuss and provide predictions on the role of the UMOD protein in renal ion transport and hypertension based on current observational, biochemical, genetic, pharmacological and clinical evidence.
Purpose of Review
Hypertension is recognised as the biggest contributor to the global burden of disease, but it is controlled in less than a fifth of patients worldwide, despite being relatively easy ...to detect and the availability of inexpensive safe generic drugs. Blood pressure is regulated by a complex network of physiologic pathways with currently available drugs targeting key receptors or enzymes in the top pathways. Major advances in the dissection of both monogenic and polygenic determinants of blood pressure regulation and variation have not resulted in rapid translation of these discoveries into clinical applications or precision medicine.
Recent Findings
Uromodulin is an example of a novel gene for hypertension identified from genome-wide association studies, currently the basis of a clinical trial to reposition loop diuretics in hypertension management. Gene-editing studies have established a genome-wide association studies (GWAS) SNP in chromosome 6p24, implicated in six conditions including hypertension, as a distal regulator of the endothelin-1 gene around 3000 base pairs away. Genomics of aldosterone-producing adenomas bring to focus the paradox in genomic medicine where availability of cheap generic drugs may render precision medicine uneconomical.
Summary
The speed of technology-driven genomic discoveries and the sluggish traditional pathways of drug development and translation need harmonisation to make a timely and early impact on global public health. This requires a directed collaborative effort for which we propose a hypertension moonshot to make a quantum leap in hypertension management and cardiovascular risk reduction by bringing together traditional bioscience, omics, engineering, digital technology and data science.
The recent progress in molecular biology generates an increasing interest in investigating molecular biomarkers as markers of response to treatments. The present work is motivated by a study, where ...the objective was to explore the potential of the molecular biomarkers of renin-angiotensin-aldosterone system (RAAS) to identify the undertaken antihypertensive treatments in the general population. Population-based studies offer an opportunity to assess the effectiveness of treatments in real-world scenarios. However, lack of quality documentation, especially when electronic health record linkage is unavailable, leads to inaccurate reporting and classification bias.
We present a machine learning clustering technique to determine the potential of measured RAAS biomarkers for the identification of undertaken treatments in the general population. The biomarkers were simultaneously determined through a novel mass-spectrometry analysis in 800 participants of the Cooperative Health Research In South Tyrol (CHRIS) study with documented antihypertensive treatments. We assessed the agreement, sensitivity and specificity of the resulting clusters against known treatment types. Through the lasso penalized regression, we identified clinical characteristics associated with the biomarkers, accounting for the effects of cluster and treatment classifications.
We identified three well-separated clusters: cluster 1 (n = 444) preferentially including individuals not receiving RAAS-targeting drugs; cluster 2 (n = 235) identifying angiotensin type 1 receptor blockers (ARB) users (weighted kappa κ
= 74%; sensitivity = 73%; specificity = 83%); and cluster 3 (n = 121) well discriminating angiotensin-converting enzyme inhibitors (ACEi) users (κ
= 81%; sensitivity = 55%; specificity = 90%). Individuals in clusters 2 and 3 had higher frequency of diabetes as well as higher fasting glucose and BMI levels. Age, sex and kidney function were strong predictors of the RAAS biomarkers independently of the cluster structure.
Unsupervised clustering of angiotensin-based biomarkers is a viable technique to identify individuals on specific antihypertensive treatments, pointing to a potential application of the biomarkers as useful clinical diagnostic tools even outside of a controlled clinical setting.
OBJECTIVES:The current international, 12-week, double-blind, randomized, controlled trial assessed the efficacy and safety of indapamide sustained release/amlodipine single-pill combination (SPC) in ...mild-to-moderate hypertensive patients.
METHODS:Following a 4-week run-in period on amlodipine 5 mg, patients (SBP 150–180 mmHg and/or DBP < 110 mmHg) were randomized to indapamide 1.5 mg sustained release/amlodipine 5 mg SPC or amlodipine 5 mg/valsartan 80 mg SPC with conditional uptitration at week 6. Office blood pressure (BP) was assessed at baseline, weeks 6 and 12; ambulatory and home blood pressure monitoring (ABPM/HBPM) at baseline and week 12.
RESULTS:Baseline characteristics were similar in both groups (57 years, 51% men, BP 160/92 mmHg). 233 patients were randomized to IndSR/Aml and 232 to amlodipine/valsartan, of whom 48 and 57% were uptitrated, respectively. After 12 weeks, office SBP/DBP decreased similarly with both treatments (−21/−8 vs. −20/−8 mmHg) leading to BP control in 50% and BP response in 70% of patients. Uptitration was effective (P < 0.001) with both regimens, in favour of IndSR/Aml (SBP/DBP −12/−6 vs. −7/−3 mmHg, respectively). ABPM (n = 273) and HBPM (n = 194) confirmed 24-h efficacy of both regimens. In the subgroup of patients with sustained uncontrolled hypertension assessed by ABPM (n = 216), office SBP/DBP decreased by −23/−13 vs. −18/−10 mmHg, respectively (P = 0.016/P = 0.135, post-hoc analysis). Both treatments were generally well tolerated.
CONCLUSION:Both regimens produced effective BP reductions confirmed by ABPM/HBPM. Both treatments were well tolerated, in accordance with the individual agents’ safety profile.
TRIAL REGISTRATION NUMBER:EUDRA CT no. 2012-001690-84.
Proteome analysis has emerged as a powerful technology to decipher biological processes. One of the main goals is to discover biomarkers for diseases from tissues and body fluids. However, the ...complexity and wide dynamic range of protein expression present an enormous challenge to separation technologies and mass spectrometry (MS). In this review, we examine the limitations of proteomics, and aim towards the definition of the current key prerequisites. We focus on capillary electrophoresis coupled to mass spectrometry (CE-MS), because this technique continues to show great promise. We discuss CE-MS from an application point of view, and evaluate its merits and vices for biomarker discovery and clinical applications. Finally, we present several examples on the use of CE-MS to determine urinary biomarkers and implications for disease diagnosis, prognosis, and therapy evaluation.
GS:SFHS is a family-based genetic epidemiology study with DNA and socio-demographic and clinical data from about 24 000 volunteers across Scotland aged 18-98 years, from February 2006 to March 2011. ...Biological samples and anonymized data form a resource for research on the genetics of health, disease and quantitative traits of current and projected public health importance. Specific and important features of GS:SFHS include the family-based recruitment, with the intent of obtaining family groups; the breadth and depth of phenotype information, including detailed data on cognitive function, personality traits and mental health; consent and mechanisms for linkage of all data to comprehensive routine health-care records; and 'broad' consent from participants to use their data and samples for a wide range of medical research, including commercial research, and for re-contact for the potential collection of other data or samples, or for participation in related studies and the design and review of the protocol in parallel with in-depth sociological research on (potential) participants and users of the research outcomes. These features were designed to maximize the power of the resource to identify, replicate or control for genetic factors associated with a wide spectrum of illnesses and risk factors, both now and in the future.
Abstract
BACKGROUND
Left ventricular hypertrophy (LVH) is a well-known target organ damage. Concentric hypertrophy is the strongest predictor of increased risk of cardiovascular events, but the ...predictive value of individual echocardiographic parameters remains unclear.
The aim of this study was to search for echocardiographic and hemodynamic variables associated with concentric and eccentric remodeling and their association with long-term cardiovascular outcomes.
METHODS
Patients with echocardiography performed within 1 year prior to the initial clinic visit were included into the study. Logistic regression and multivariable Cox-proportional hazards were calculated according to several risk factors and variables. Additionally, cubic spline interpolation was used.
RESULTS
We observed 690 patients for 10 years. There was a total of 177 major adverse cardiac and cerebrovascular events (MACCE) and 90 deaths over a 10-year period. Left ventricular concentric hypertrophy is associated with worse outcomes than eccentric hypertrophy in hypertensive subjects. Interestingly, different echocardiographic parameters contributed to risk depending on type of hypertrophy. In concentric hypertrophy, relative wall thickness provides linear prediction of risk for all-cause mortality (ACM) and composite endpoint. Systolic blood pressure is a significant predictor of MACCE. Blood pressure variability also showed significant predictive value for MACCE and ACM.
CONCLUSIONS
These data indicate risk stratification based on LVH need to consider different measures based on the type of remodeling.
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