Aberrant activation of with no lysine (WNK) kinases causes familial hyperkalemic hypertension (FHHt). Thiazide diuretics treat the disease, fostering the view that hyperactivation of the ...thiazide-sensitive sodium-chloride cotransporter (NCC) in the distal convoluted tubule (DCT) is solely responsible. However, aberrant signaling in the aldosterone-sensitive distal nephron (ASDN) and inhibition of the potassium-excretory renal outer medullary potassium (ROMK) channel have also been implicated. To test these ideas, we introduced kinase-activating mutations after Lox-P sites in the mouse
gene, which encodes the terminal kinase in the WNK signaling pathway, Ste20-related proline-alanine-rich kinase (SPAK). Renal expression of the constitutively active (CA)-SPAK mutant was specifically targeted to the early DCT using a DCT-driven Cre recombinase. CA-SPAK mice displayed thiazide-treatable hypertension and hyperkalemia, concurrent with NCC hyperphosphorylation. However, thiazide-mediated inhibition of NCC and consequent restoration of sodium excretion did not immediately restore urinary potassium excretion in CA-SPAK mice. Notably, CA-SPAK mice exhibited ASDN remodeling, involving a reduction in connecting tubule mass and attenuation of epithelial sodium channel (ENaC) and ROMK expression and apical localization. Blocking hyperactive NCC in the DCT gradually restored ASDN structure and ENaC and ROMK expression, concurrent with the restoration of urinary potassium excretion. These findings verify that NCC hyperactivity underlies FHHt but also reveal that NCC-dependent changes in the driving force for potassium secretion are not sufficient to explain hyperkalemia. Instead, a DCT-ASDN coupling process controls potassium balance in health and becomes aberrantly activated in FHHt.
Embolism from the heart or the thoracic aorta often leads to clinically significant morbidity and mortality due to transient ischemic attack, stroke or occlusion of peripheral arteries. Transthoracic ...and transesophageal echocardiography are the key diagnostic modalities for evaluation, diagnosis, and management of stroke, systemic and pulmonary embolism. This document provides comprehensive American Society of Echocardiography guidelines on the use of echocardiography for evaluation of cardiac sources of embolism. It describes general mechanisms of stroke and systemic embolism; the specific role of cardiac and aortic sources in stroke, and systemic and pulmonary embolism; the role of echocardiography in evaluation, diagnosis, and management of cardiac and aortic sources of emboli including the incremental value of contrast and 3D echocardiography; and a brief description of alternative imaging techniques and their role in the evaluation of cardiac sources of emboli. Specific guidelines are provided for each category of embolic sources including the left atrium and left atrial appendage, left ventricle, heart valves, cardiac tumors, and thoracic aorta. In addition, there are recommendation regarding pulmonary embolism, and embolism related to cardiovascular surgery and percutaneous procedures. The guidelines also include a dedicated section on cardiac sources of embolism in pediatric populations.
Summary Background Hyperglycaemia is associated with increased risk of cardiovascular complications in people with type 2 diabetes. We investigated whether reduction of blood glucose concentration ...decreases the rate of microvascular complications in people with type 2 diabetes. Methods ACCORD was a parallel-group, randomised trial done in 77 clinical sites in North America. People with diabetes, high HbA1c concentrations (>7·5%), and cardiovascular disease (or ≥2 cardiovascular risk factors) were randomly assigned by central randomisation to intensive (target haemoglobin A1c HbA1c of <6·0%) or standard (7·0–7·9%) glycaemic therapy. In this analysis, the prespecified composite outcomes were: dialysis or renal transplantation, high serum creatinine (>291·7 μmol/L), or retinal photocoagulation or vitrectomy (first composite outcome); or peripheral neuropathy plus the first composite outcome (second composite outcome). 13 prespecified secondary measures of kidney, eye, and peripheral nerve function were also assessed. Investigators and participants were aware of treatment group assignment. Analysis was done for all patients who were assessed for microvascular outcomes, on the basis of treatment assignment, irrespective of treatments received or compliance to therapies. ACCORD is registered with ClinicalTrials.gov , number NCT00000620. Findings 10 251 patients were randomly assigned, 5128 to the intensive glycaemia control group and 5123 to standard group. Intensive therapy was stopped before study end because of higher mortality in that group, and patients were transitioned to standard therapy. At transition, the first composite outcome was recorded in 443 of 5107 patients in the intensive group versus 444 of 5108 in the standard group (HR 1·00, 95% CI 0·88–1·14; p=1·00), and the second composite outcome was noted in 1591 of 5107 versus 1659 of 5108 (0·96, 0·89–1·02; p=0·19). Results were similar at study end (first composite outcome 556 of 5119 vs 586 of 5115 HR 0·95, 95% CI 0·85–1·07, p=0·42; and second 1956 of 5119 vs 2046 of 5115, respectively 0·95, 0·89–1·01, p=0·12). Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Six secondary measures at study end favoured intensive therapy (p<0·05). Interpretation Microvascular benefits of intensive therapy should be weighed against the increase in total and cardiovascular disease-related mortality, increased weight gain, and high risk for severe hypoglycaemia. Funding US National Institutes of Health; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; and General Clinical Research Centers.
To compare effects of combinations of standard and intensive treatment of glycemia and either blood pressure (BP) or lipids in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
...ACCORD enrolled 10,251 type 2 diabetes patients aged 40-79 years at high risk for cardiovascular disease (CVD) events. Participants were randomly assigned to hemoglobin A1c goals of <6.0% (<42 mmol/mol; intensive glycemia) or 7.0-7.9% (53-63 mmol/mol; standard glycemia) and then randomized a second time to either 1) systolic BP goals of <120 mmHg (intensive BP) or <140 mmHg (standard BP) or 2) simvastatin plus fenofibrate (intensive lipid) or simvastatin plus placebo (standard lipid). Proportional hazards models were used to assess combinations of treatment assignments on the composite primary (deaths due to CVD, nonfatal myocardial infarction MI, and nonfatal stroke) and secondary outcomes.
In the BP trial, risk of the primary outcome was lower in the groups intensively treated for glycemia (hazard ratio HR 0.67; 95% CI 0.50-0.91), BP (HR 0.74; 95% CI 0.55-1.00), or both (HR 0.71; 95% CI 0.52-0.96) compared with combined standard BP and glycemia treatment. For secondary outcomes, MI was significantly reduced by intensive glycemia treatment and stroke by intensive BP treatment; most other HRs were neutral or favored intensive treatment groups. In the lipid trial, the general pattern of results showed no evidence of benefit of intensive regimens (whether single or combined) compared with combined standard lipid and glycemia treatment. The mortality HR was 1.33 (95% CI 1.02-1.74) in the standard lipid/intensive glycemia group compared with the standard lipid/standard glycemia group.
In the ACCORD BP trial, compared with combined standard treatment, intensive BP or intensive glycemia treatment alone improved major CVD outcomes, without additional benefit from combining the two. In the ACCORD lipid trial, neither intensive lipid nor glycemia treatment produced an overall benefit, but intensive glycemia treatment increased mortality.
Consumption of low dietary potassium, common with ultraprocessed foods, activates the thiazide-sensitive sodium chloride cotransporter (NCC) via the with no (K) lysine kinase/STE20/SPS1-related ...proline-alanine-rich protein kinase (WNK/SPAK) pathway to induce salt retention and elevate blood pressure (BP). However, it remains unclear how high-potassium "DASH-like" diets (dietary approaches to stop hypertension) inactivate the cotransporter and whether this decreases BP. A transcriptomics screen identified Ppp1Ca, encoding PP1A, as a potassium-upregulated gene, and its negative regulator Ppp1r1a, as a potassium-suppressed gene in the kidney. PP1A directly binds to and dephosphorylates NCC when extracellular potassium is elevated. Using mice genetically engineered to constitutively activate the NCC-regulatory kinase SPAK and thereby eliminate the effects of the WNK/SPAK kinase cascade, we confirmed that PP1A dephosphorylated NCC directly in a potassium-regulated manner. Prior adaptation to a high-potassium diet was required to maximally dephosphorylate NCC and lower BP in constitutively active SPAK mice, and this was associated with potassium-dependent suppression of Ppp1r1a and dephosphorylation of its cognate protein, inhibitory subunit 1 (I1). In conclusion, potassium-dependent activation of PP1A and inhibition of I1 drove NCC dephosphorylation, providing a mechanism to explain how high dietary K+ lowers BP. Shifting signaling of PP1A in favor of activation of WNK/SPAK may provide an improved therapeutic approach for treating salt-sensitive hypertension.
Persons with prehypertension (formerly, “borderline hypertension”) were randomly assigned in a blinded fashion to receive two years of candesartan or placebo, followed by two years of placebo for ...all. Over four years, therapy with candesartan reduced the risk of the development of hypertension by 15.6 percent (P<0.007). Further research is needed to evaluate the clinical usefulness and ultimate safety of antihypertensive treatment for prehypertension.
Persons with prehypertension were randomly assigned to receive two years of candesartan or placebo. Therapy with candesartan reduced the risk of the development of hypertension by 15.6 percent.
The name of the range of blood pressures between what is clearly normal and what is definitely hypertensive changed from “transient hypertension” in the 1940s
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to “borderline hypertension” in the 1970s,
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“high-normal blood pressure” in the 1990s,
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and most recently, “prehypertension” in 2003.
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Regardless of terminology, this condition is a precursor of hypertension
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and is associated with excess morbidity and deaths from cardiovascular causes.
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Furthermore, an association of prehypertension with other cardiovascular risk factors has been established.
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The Trial of Preventing Hypertension (TROPHY)
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was an investigator-initiated study to examine whether early treatment of . . .
Objectives Our aim was to determine the feasibility and value of a protocol-driven approach to patients with cardiac resynchronization therapy (CRT) who did not exhibit a positive response long after ...implant. Background Up to one-third of patients with advanced heart failure do not exhibit a positive response to CRT. Methods A total of 75 consecutive ambulatory patients with persistent advanced heart failure symptoms and/or adverse reverse remodeling and CRT implanted >6 months underwent a comprehensive protocol-driven evaluation to determine the potential reasons for a suboptimal response. Recommendations were made to maximize the potential of CRT, and adverse events were documented. Results All patients (mean left ventricular LV ejection fraction 23 ± 9%, LV end-diastolic volume 275 ± 127 ml) underwent evaluation. Eighty-eight percent of patients had significantly better echocardiographic indexes of LV filling and LV ejection with optimal setting of their CRT compared with a temporary VVI back-up setting. Most patients had identifiable reasons for suboptimal response, including inadequate device settings (47%), suboptimal medical treatment (32%), arrhythmias (32%), inappropriate lead position (21%), or lack of baseline dyssynchrony (9%). Multidisciplinary recommendations led to changes in device settings and/or other therapy modifications in 74% of patients and were associated with fewer adverse events (13% vs. 50%, odds ratio: 0.2 95% confidence interval: 0.07 to 0.56, p = 0.002) compared with those in which no recommendation could be made. Conclusions Routine protocol-driven approach to evaluate ambulatory CRT patients who did not exhibit a positive response is feasible, and changes in device settings and/or other therapies after multidisciplinary evaluation may be associated with fewer adverse events.
In a randomized trial, 4733 patients with type 2 diabetes mellitus who were at high risk for cardiovascular events received treatment aimed at a target systolic blood pressure of less than 120 mm Hg ...or less than 140 mm Hg. At a mean follow-up of 4.7 years, the rates of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) were not significantly different between the two trial groups.
Patients with type 2 diabetes mellitus who were at high risk for cardiovascular events received treatment aimed at a target systolic blood pressure of less than 120 mm Hg or less than 140 mm Hg. At a mean follow-up of 4.7 years, the rates of the primary end point were not significantly different between the two groups.
Diabetes mellitus increases the risk of cardiovascular disease by a factor of two to three at every level of systolic blood pressure.
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Because cardiovascular risk in patients with diabetes is graded and continuous across the entire range of levels of systolic blood pressure, even at prehypertensive levels, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended beginning drug treatment in patients with diabetes who have systolic blood pressures of 130 mm Hg or higher, with a treatment goal of reducing systolic blood pressure to below 130 mm Hg. . . .
Experimental and epidemiological studies suggest that calcium and vitamin D supplements may lower blood pressure. We examined the effect of calcium plus vitamin D supplementation on blood pressure ...and the incidence of hypertension in postmenopausal women. The Womenʼs Health Initiative Calcium/Vitamin D Trial randomly assigned 36 282 postmenopausal women to receive 1000 mg of elemental calcium plus 400 IU of vitamin D3 daily or placebo in a double-blind fashion. Change in blood pressure and the incidence of hypertension were ascertained. Over a median follow-up time of 7 years, there was no significant difference in the mean change over time in systolic blood pressure (0.22 mm Hg; 95% CI−0.05 to 0.49 mm Hg) and diastolic blood pressure (0.11 mm Hg; 95% CI−0.04 to 0.27 mm Hg) between the active and placebo treatment groups. This null result was robust in analyses accounting for nonadherence to study pills and in baseline subgroups of interest, including black subjects and women with hypertension or high levels of blood pressure, with low intakes of calcium and vitamin D or low serum levels of vitamin D. In 17 122 nonhypertensive participants at baseline, the hazard ratio for incident hypertension associated with calcium/vitamin D treatment was 1.01 (95% CI0.96 to 1.06.) In postmenopausal women, calcium plus vitamin D3 supplementation did not reduce either blood pressure or the risk of developing hypertension over 7 years of follow-up.
In the ACCORD trial, a mean of 3.7 years of intensive glucose lowering increased mortality and reduced nonfatal myocardial infarctions after 5 years of follow-up. The therapy cannot be recommended ...for high-risk patients with advanced type 2 diabetes.
Type 2 diabetes mellitus is a strong, independent risk factor for cardiovascular disease and death,
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and many epidemiologic analyses have identified a progressive relationship between hyperglycemia and these outcomes.
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The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was designed to determine whether a strategy of targeting normal glycated hemoglobin levels (i.e., <6.0%) would reduce the risk of serious cardiovascular events in middle-aged and elderly people with type 2 diabetes mellitus, glycated hemoglobin levels of 7.5% or more, and additional cardiovascular risk factors.
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However, on the basis of a mean of 3.5 years' worth of data, the independent . . .
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