Background
Myocardial fibrosis is characterized by excessive cross‐linking and deposition of collagen type I and is involved in left ventricular stiffening and left ventricular diastolic dysfunction ...(LVDD). We investigated whether the effect of spironolactone on LVDD in patients with heart failure with preserved ejection fraction (HFpEF) depends on its effects on collagen cross‐linking and/or deposition.
Methods and results
We investigated 381 HFpEF patients from the multicentre, randomized, placebo‐controlled Aldo‐DHF trial with measures of the E:e' ratio. The ratio of serum carboxy‐terminal telopeptide of collagen type I to serum matrix metalloproteinase‐1 (CITP:MMP‐1, an inverse index of myocardial collagen cross‐linking) and serum carboxy‐terminal propeptide of procollagen type I (PICP, a direct index of myocardial collagen deposition) were determined at baseline and after 1‐year treatment with spironolactone 25 mg once daily or placebo. Patients were classified by CITP:MMP‐1 and PICP tertiles at baseline. While CITP:MMP‐1 tertiles at baseline interacted (P < 0.05) with spironolactone effect on E:e', PICP tertiles did not. In fact, while spironolactone treatment did not modify E:e' in patients with lower CITP:MMP‐1 levels, this ratio was significantly reduced in the remaining spironolactone‐treated patients. In addition, PICP was unchanged in patients with lower CITP:MMP‐1 levels but was reduced in the remaining spironolactone‐treated patients.
Conclusions
A biochemical phenotype of high collagen cross‐linking identifies HFpEF patients resistant to the beneficial effects of spironolactone on LVDD. It is suggested that excessive collagen cross‐linking, which stabilizes collagen type I fibres, diminishes the ability of spironolactone to reduce collagen deposition in these patients.
Allopurinol lowers blood pressure in adolescents and has other vasoprotective effects. Whether similar benefits occur in older individuals remains unclear. We hypothesized that allopurinol is ...associated with improved cardiovascular outcomes in older adults with hypertension. Data from the United Kingdom Clinical Research Practice Datalink were used. Multivariate Cox-proportional hazard models were applied to estimate hazard ratios for stroke and cardiac events (defined as myocardial infarction or acute coronary syndrome) associated with allopurinol use over a 10-year period in adults aged >65 years with hypertension. A propensity-matched design was used to reduce potential for confounding. Allopurinol exposure was a time-dependent variable and was defined as any exposure and then as high (≥300 mg daily) or low-dose exposure. A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were studied. Allopurinol use was associated with a significantly lower risk of both stroke (hazard ratio, 0.50; 95% confidence interval, 0.32–0.80) and cardiac events (hazard ratio, 0.61; 95% confidence interval, 0.43–0.87) than nonexposed control patients. In exposed patients, high-dose treatment with allopurinol (n=1052) was associated with a significantly lower risk of both stroke (hazard ratio, 0.58; 95% confidence interval, 0.36–0.94) and cardiac events (hazard ratio, 0.65; 95% confidence interval, 0.46–0.93) than low-dose treatment (n=980). Allopurinol use is associated with lower rates of stroke and cardiac events in older adults with hypertension, particularly at higher doses. Prospective clinical trials are needed to evaluate whether allopurinol improves cardiovascular outcomes in adults with hypertension.
Preeclampsia is a recognised cause of an increased risk of major adverse cardiovascular events when compared to the background risk in women who did not have hypertensive disorders during pregnancy. ...The Generation Scotland: Scottish Family Health Study (GS:SFHS) is a population cohort of more than 20,000 members of the Scottish population. Using the Scottish Morbidity Records, we linked the women in the GS:SFHS cohort to validated maternity and inpatient admission data. This allowed us to robustly identify cardiovascular outcomes in the form of inpatient admission for cardiovascular events, We also aimed to explore the risk of pregnancy on future cardiovascular events, using data from nulliparous and parous women.In total, 9732 women were selected. 3693 women were nulliparous, and after study exclusion, 5253 women with 9583 pregnancies remained. Pregnancies from 1980 until the end of the study period of 1st of July 2013 were included. Cardiovascular events occurred in 9.0% of nulliparous women, 4.2% of women with pregnancies and in 7.6% of women with a history of preeclampsia. A total of 218 parous women experienced cardiovascular events, 25 in the preeclampsia group and 193 in the normotensive group.Survival analysis was undertaken, with index pregnancy taken as first pregnancy in normotensive controls and first preeclampsia pregnancy in cases. Endpoint of interest was admission to hospital with first cardiovascular event. After further exclusions a total of 169 cardiovascular events occurred in the normotensive pregnancy group and 20 in the preeclampsia group. Women with a history of preeclampsia were more likely to have cardiovascular events later in life than women with normotensive deliveries., This was statistically significantly different on Kaplan Meier survival analysis, (log rank Mantel-Cox p-value < 0.001). The women in our study were middle-aged, within 33 years of pregnancy, with a mean age of 53 years in the preeclampsia cardiovascular events group.Our study supports the urgent need for uniform guidelines and implementation to improve the health in women with this medical history. Increased awareness among the public of the cardiovascular risk associated with PE is vital to aid uptake of cardiovascular prevention programmes.
Human primary or essential hypertension is a complex, polygenic trait with some 50% contribution from genes and environment. Richard Lifton and colleagues provided elegant dissection of several rare ...Mendelian forms of hypertension, exemplified by the glucocorticoid remediable aldosteronism and Liddleʼs syndrome. These discoveries illustrate that a single gene mutation can explain the entire pathogenesis of severe, early onset hypertension as well as dictating the best treatment. The dissection of the much more common polygenic hypertension has proven much more difficult. Early studies used a single polymorphic marker such as the I/D polymorphism in the ACE gene and small numbers of cases and controls. Candidate gene studies have been largely non-informative and non-reproducible. These were followed by linkage studies, which used approximately 300 microsatellite markers distributed across the genome. These studies resulted in large peaks covering regions with 50–100 genes, with no easy way to quickly focus on a few genes of causal relevance. The real breakthrough came with the initiation of the genome wide association studies (GWAS) characterised by a much more thorough coverage of the genome with thousands single nucleotide polymorphisms (SNPs). Typically 500,000 – 2,5000,000 SNPs have been used for the big, collaborative GWAS for hypertension. These studies resulted in several “hits” or signals with a genome-wide significance and a high level of reproducibility between studies. These “hits” have been used successfully to calculate genetic risk scores for cardiovascular complications such as left ventricular hypertrophy, stroke and coronary artery disease. Intragenic signals, such as for example Uromodulin, are being used to
Major depressive and bipolar disorders predispose to atherosclerosis, and there is accruing data from animal model, epidemiological, and genomic studies that commonly used antihypertensive drugs may ...have a role in the pathogenesis or course of mood disorders. In this study, we propose to determine whether antihypertensive drugs have an impact on mood disorders through the analysis of patients on monotherapy with different classes of antihypertensive drugs from a large hospital database of 525 046 patients with follow-up for 5 years. There were 144 066 eligible patients fulfilling the inclusion criteriaage 40 to 80 years old at time of antihypertensive prescription and medication exposure >90 days. The burden of comorbidity assessed by Charlson and Elixhauser scores showed an independent linear association with mood disorder diagnosis. The median time to hospital admission with mood disorder was 847 days for the 299 admissions (641 685 person-years of follow-up). Patients on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers had the lowest risk for mood disorder admissions, and compared with this group, those on β-blockers (hazard ratio=2.11; 95% confidence interval, 1.12–3.98; P=0.02) and calcium antagonists (2.28 95% confidence interval, 1.13–4.58; P=0.02) showed higher risk, whereas those on no antihypertensives (1.63 95% confidence interval, 0.94–2.82; P=0.08) and thiazide diuretics (1.56 95% confidence interval, 0.65–3.73; P=0.32) showed no significant difference. Overall, our exploratory findings suggest possible differential effects of antihypertensive medications on mood that merits further studycalcium antagonists and β-blockers may be associated with increased risk, whereas angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be associated with a decreased risk of mood disorders.
Preeclampsia and future maternal health Carty, David M; Delles, Christian; Dominiczak, Anna F
Journal of hypertension,
2010-July, Volume:
28, Issue:
7
Journal Article
Peer reviewed
Preeclampsia is a multisystem disorder that complicates 3–8% of pregnancies in the Western world, and is a major source of morbidity and mortality worldwide. Although it is a disease unique to ...pregnancy, evidence has mounted in recent years that preeclampsia has important implications for future maternal health, in particular cardiovascular health. In this review we examine epidemiological evidence for this relationship, and examine potential mechanisms such as insulin resistance, genetic factors and endothelial dysfunction that may explain the relationship. In addition we explore potential future avenues of research into the field, such as genomics, proteomics and metabolomics.
A recent genome-wide association study identified a locus on chromosome 16 in the promoter region of the uromodulin (UMOD) gene that is associated with hypertension. Here, we examined the ...hypertension signal with functional studies in Umod knockout (KO) mice. Systolic blood pressure was significantly lower in KO versus wild-type (WT) mice under basal conditions (KO116.6±0.3 mm Hg versus WT136.2±0.4 mm Hg; P<0.0001). Administration of 2% NaCl did not alter systolic blood pressure in KO mice, whereas it increased in WT mice by ≈33%, P<0.001. The average 24-hour urinary sodium excretion in the KO was greater than that of WT mice (P<0.001). Chronic renal function curves demonstrate a leftward shift in KO mice, suggesting that the relationship between UMOD and blood pressure is affected by sodium. Creatinine clearance was increased during salt loading with 2% NaCl in the KO mice, leading to augmented filtered Na excretion and further Na loss. The difference in sodium uptake that exists between WT and KO strains was explored at the molecular level. Urinary tumor necrosis factor-α levels were significantly higher in KO mice compared with WT mice (P<0.0001). Stimulation of primary thick ascending limb of the loop of Henle cells with exogenous tumor necrosis factor-α caused a reduction in NKCC2A expression (P<0.001) with a concurrent rise in the levels of UMOD mRNA (P<0.001). Collectively, we demonstrate that UMOD regulates sodium uptake in the thick ascending limb of the loop of Henle by modulating the effect of tumor necrosis factor-α on NKCC2A expression, making UMOD an important determinant of blood pressure control.
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