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Concept: Thiazide

39

The WHO ranks hypertension the leading global risk factor for disease, specifically, cardiovascular disease. Blood pressure is higher in westernized populations consuming sodium-rich processed foods compared to isolated societies consuming potassium-rich natural foods. Evidence suggests that lowering dietary Na(+) is particularly beneficial in hypertensives who consume a high Na(+) diet. Nonetheless, numerous population studies demonstrate a relationship between higher dietary K(+), estimated from urinary excretion or dietary recall, and lower blood pressure regardless of sodium intake. Interventional studies with potassium supplementation suggest it provides a direct benefit; K(+) may also be a marker for other beneficial components of a “natural” diet. Recent studies in rodent models indicate mechanisms for the potassium benefit: the distal tubule Na(+)- Cl(-) cotransporter (NCC) controls Na(+) delivery downstream to the collecting duct where Na(+) reabsorbed by epithelial Na(+) channels (ENaC) drives K(+) secretion and excretion through K(+) channels in the same region. High dietary K(+) provokes a decrease in the NCC activity to drive more K(+) secretion (and Na(+) excretion, analogous to the actions of a thiazide diuretic) whether Na(+) intake is high or low; low dietary K(+) provokes an increase in NCC activity and Na(+) retention, also independent of dietary Na(+) Taken together, the findings suggest that public health efforts directed towards increasing consumption of natural potassium rich foods would reduce blood pressure and, thus, cardiovascular and kidney disease.

Concepts: Epidemiology, Blood, Hypertension, Demography, Potassium, Diuretic, Thiazide, Distal convoluted tubule

37

Thiazide diuretics are among the most widely used treatments for hypertension, but thiazide-induced hyponatremia (TIH), a clinically significant adverse effect, is poorly understood. Here, we have studied the phenotypic and genetic characteristics of patients hospitalized with TIH. In a cohort of 109 TIH patients, those with severe TIH displayed an extended phenotype of intravascular volume expansion, increased free water reabsorption, urinary prostaglandin E2 excretion, and reduced excretion of serum chloride, magnesium, zinc, and antidiuretic hormone. GWAS in a separate cohort of 48 TIH patients and 2,922 controls from the 1958 British birth cohort identified an additional 14 regions associated with TIH. We identified a suggestive association with a variant in SLCO2A1, which encodes a prostaglandin transporter in the distal nephron. Resequencing of SLCO2A1 revealed a nonsynonymous variant, rs34550074 (p.A396T), and association with this SNP was replicated in a second cohort of TIH cases. TIH patients with the p.A396T variant demonstrated increased urinary excretion of prostaglandin E2 and metabolites. Moreover, the SLCO2A1 phospho-mimic p.A396E showed loss of transporter function in vitro. These findings indicate that the phenotype of TIH involves a more extensive metabolic derangement than previously recognized. We propose one mechanism underlying TIH development in a subgroup of patients in which SLCO2A1 regulation is altered.

Concepts: Gene, Metabolism, Renal physiology, Phenotype, Vasopressin, Diuretic, Thiazide, Prostaglandin

29

Successful treatment of hypertension is difficult despite the availability of several classes of antihypertensive drug, and the value of strategies to combat the effect of adverse lifestyle behaviours on blood pressure. In this paper, we discuss two promising therapeutic alternatives for patients with resistant hypertension: novel drugs, including new pharmacological classes (such as vasopeptidase inhibitors and aldosterone synthase inhibitors) and new molecules from present pharmacological classes with additional properties in blood-pressure or metabolism pathways; and new procedures and devices, including stimulation of arterial baroreceptors and catheter-based renal denervation. Although several pharmacological targets have been discovered with promising preclinical results, the clinical development of novel antihypertensive drugs has been more difficult and less productive than expected. The effectiveness and safety of new devices and procedures should be carefully assessed in patients with resistant hypertension, thus leading to a new era of outcome trials and evidence-based guidelines.

Concepts: Pharmacology, Clinical trial, Myocardial infarction, Blood pressure, Aldosterone, Thiazide, Antihypertensive drug, Antihypertensive agents

28

To determine whether thiazides have a chronic antihypertensive effect, in the absence of diuresis, in patients with severe renal disease (creatinine clearance <30 mL/min) or in those receiving dialysis.

Concepts: Renal failure, Nephrology, Thiazide

25

In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension.

Concepts: Hypertension, Blood pressure, Renin-angiotensin system, Thiazide, Orthostatic hypotension

23

There is growing evidence that antihypertensive agents, particularly centrally acting ACE inhibitors (CACE-Is), which cross the blood-brain barrier, are associated with a reduced rate of cognitive decline. Given this, we compared the rates of cognitive decline in clinic patients with dementia receiving CACE-Is (CACE-I) with those not currently treated with CACE-Is (NoCACE-I), and with those who started CACE-Is, during their first 6 months of treatment (NewCACE-I).

Concepts: Cognition, Rates, Thiazide, Antihypertensive drug, Reaction rate, Antihypertensive agents, Community Charge, Póvoa de Varzim

17

On the basis of observational studies, the use of thiazide diuretics for the treatment of hypertension is associated with reduced fracture risk compared with nonuse. Data from randomized clinical trials are lacking.

Concepts: Clinical trial, Thiazide

10

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.

Concepts: DNA, Kidney, Genetic disorder, Mutation, Evolution, DNA repair, Diuretic, Thiazide

9

IMPORTANCE Antihypertensive agents are the most commonly prescribed class of medications in the United States. Evidence regarding the relationship between different types of antihypertensives and breast cancer risk is sparse and inconsistent, and prior studies have lacked the capacity to assess impacts of long-term use. OBJECTIVE To evaluate associations between use of various classes of antihypertensive medications and risks of invasive ductal and invasive lobular breast cancers among postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS Population-based case-control study in the 3-county Seattle-Puget Sound metropolitan area. Participants were women aged 55 to 74 years, 880 of them with invasive ductal breast cancer, 1027 with invasive lobular breast cancer, and 856 with no cancer serving as controls. EXPOSURES Recency and duration of use of antihypertensive medications. MAIN OUTCOMES AND MEASURES Risks of invasive ductal and invasive lobular breast cancers. RESULTS Current use of calcium-channel blockers for 10 or more years was associated with higher risks of ductal breast cancer (odds ratio [OR], 2.4; 95% CI, 1.2-4.9) (P = .04 for trend) and lobular breast cancer (OR, 2.6; 95% CI, 1.3-5.3) (P = .01 for trend). This relationship did not vary appreciably by type of calcium-channel blocker used (short-acting vs long-acting, dihydropyridines vs non-dihydropyridines). In contrast, use of diuretics, β-blockers, and angiotensin II antagonists were not associated with risk. CONCLUSIONS AND RELEVANCE While some studies have suggested a positive association between calcium-channel blocker use and breast cancer risk, this is the first study to observe that long-term current use of calcium-channel blockers in particular are associated with breast cancer risk. Additional research is needed to confirm this finding and to evaluate potential underlying biological mechanisms.

Concepts: Epidemiology, Cancer, Breast cancer, Thiazide

6

The effectiveness of the clinical strategy of empiric potassium supplementation in reducing the frequency of adverse clinical outcomes in patients receiving loop diuretics is unknown. We sought to examine the association between empiric potassium supplementation and 1) all-cause death and 2) outpatient-originating sudden cardiac death (SD) and ventricular arrhythmia (VA) among new starters of loop diuretics, stratified on initial loop diuretic dose.

Concepts: Hypertension, Cardiac arrest, Diuretic, Thiazide, Sudden cardiac death, Hypokalemia, Hyperkalemia, Loop diuretic