Urocortin 2 - a protective effect in hypertension?

Urocortin 2, an endogenous selective ligand for the corticotropin-releasing hormone receptor type 2, has been suggested to exert cardioprotective effects. We analyzed the possible relationship between the level of Ucn2 and specific indicators of cardiovascular risk factors in patients with untreated hypertension and in healthy subjects. Sixty seven subjects were recruited: 38 with newly diagnosed treatment-naive hypertension (with no pharmacological treatment - HT group) and 29 healthy subjects without hypertension (nHT group). We evaluated ambulatory blood pressure monitoring, Ucn2 levels and metabolic indices. Multivariable regression analyses were performed to assess the effects of gender, age, and Ucn2 levels on metabolic indices or blood pressure (BP) level. Log of Ucn2 levels were higher in healthy subjects than in hypertensive patients (2.44±0.7 versus 2.09±0.66, p<.05) and correlated inversely with 24-hour diastolic blood pressure, and both night-time systolic and diastolic blood pressure regardless of age and gender (R2=0.06; R2=0.06; R2=0.052; respectively). Furthermore, Ucn2 levels inversely correlated with cholesterol and low-density cholesterol (LDL) concentrations in healthy subjects only. Ucn2 was independently related to total cholesterol (but not to LDL) regardless of age, gender and the presence of hypertension (R2=0.18). However, we did not find any relationship between urocortin 2, body mass index or waist-hip ratio as well as parameters of glucose metabolism. Our data indicates that higher levels of urocortin 2 are related to more favorable lipid profiles and lower blood pressure.

In vitro fertilization exacerbates stroke size and neurological disability in wildtype mice.

BACKGROUND AND PURPOSE: Assisted reproductive technologies (ART) induce premature vascular aging in human offspring. The related alterations are well-established risk factors for stroke and predictors of adverse stroke outcome. However, given the young age of the human ART population there is no information on the incidence and outcome of cerebrovascular complications in humans. In mice, ART alters the cardiovascular phenotype similarly to humans, thereby offering the possibility to study this problem. METHODS: We investigated the morphological and clinical outcome after ischemia/reperfusion brain injury induced by transient (45 min) middle cerebral artery occlusion in ART and control mice. RESULTS: We found that stroke volumes were almost 3-fold larger in ART than in control mice (P < 0.001). In line with these morphological differences, neurological performance assessed by the Bederson and RotaRod tests 24 and 48 h after artery occlusion was significantly worse in ART compared with control mice. Plasma levels of TNF-alpha, were also significantly increased in ART vs. control mice after stroke (P < 0.05). As potential underlying mechanisms, we identified increased blood-brain barrier permeability evidenced by increased IgG extravasation associated with decreased tight junctional protein claudin-5 and occludin expression, increased oxidative stress and decreased NO-bioactivity in ART compared with control mice. CONCLUSIONS: In wildtype mice, ART predisposes to significantly worse morphological and functional stroke outcomes, related at least in part to altered blood-brain barrier permeability. These findings demonstrate that ART, by inducing premature vascular aging, not only is a likely risk factor for stroke-occurrence, but also a mediator of adverse stroke-outcome. TRANSLATIONAL PERSPECTIVE: This study highlights that ART not only is a likely risk factor for stroke-occurrence, but also a mediator of adverse stroke-outcome. The findings should raise awareness in the ever-growing human ART population in whom these techniques cause similar alterations of the cardiovascular phenotype and encourage early preventive and diagnostic efforts.

Optimal blood pressure targets in 2014 - Does the guideline recommendation match the evidence base?

Various scientific societies have recently published practice guidelines for the diagnosis and management of arterial hypertension with no clear consensus on a blood pressure target. This article reviews those recommendations and critically examines if they are based on sound evidence.

Cardioprotection with beta-blockers: myths, facts and Pascal's wager.

Beta-blockers were documented to reduce reinfarction rate more than 3 decades ago and subsequently touted as being cardioprotective for a broad spectrum of cardiovascular indications such as hypertension, diabetes, angina, atrial fibrillation as well as perioperatively in patients undergoing surgery. However, despite lowering blood pressure, beta-blockers have never shown to reduce morbidity and mortality in uncomplicated hypertension. Also, beta-blockers do not prevent heart failure in hypertension any better than any other antihypertensive drug class. Beta-blockers have been shown to increase the risk on new onset diabetes. When compared with nondiuretic antihypertensive drugs, beta-blockers increase all-cause mortality by 8% and stroke by 30% in patients with new onset diabetes. Beta-blockers are useful for rate control in patients with chronic atrial fibrillation but do not help restore sinus rhythm or have antifibrillatory effects in the atria. Beta-blockers provide symptomatic relief in patients with chronic stable angina but do not reduce the risk of myocardial infarction. Adverse effects of beta-blockers are common including fatigue, dizziness, depression and sexual dysfunction. However, beta-blockers remain a cornerstone in the management of patients having suffered a myocardial infarction and for patients with heart failure. Thus, recent evidence argues against universal cardioprotective properties of beta-blockers but attest to their usefulness for specific cardiovascular indications.

Differential effect of beta-blocker therapy on insulin resistance as a function of insulin sensitizer use: results from GEMINI.

AIMS: To determine whether the beneficial effects of carvedilol on insulin resistance (IR) are affected by the concomitant use of insulin sensitizers [thiazolidinediones (TZDs) and metformin]. METHODS: Changes in HbA1c and homeostasis model assessment-insulin resistance (HOMA-IR) were assessed over 5 months, comparing carvedilol with metoprolol tartrate according to insulin sensitizer (TZDs and metformin) use. RESULTS: In TZD/metformin users, carvedilol patients showed a 5.4% decrease [95% confidence interval (CI) -11.9, 1.6; P = 0.13] and metoprolol tartrate patients showed a 2.8% decrease (95% CI -8.5, 3.2; P = 0.35) in HOMA-IR. The -2.6% difference between treatments was not significant (95% CI -10.7, 6.2; P = 0.55). In contrast, those not taking TZD/metformin experienced a 13.2% increase in HOMA-IR on metoprolol tartrate (95% CI 3.2, 24.1; P < 0.01) and a 4.8% decrease in HOMA-IR on carvedilol (95% CI -14.6, 6.0; P = 0.37), with a significant treatment difference of -15.9% favouring carvedilol (95% CI -26.6, -3.6; P = 0.01). There was no significant treatment interaction for the use of TZD/metformin and HbA1c. A statistically significant treatment difference was observed for HbA1c after 5 months favouring carvedilol after adjusting for insulin sensitizer use (-0.11%, 95% CI -0.214, -0.009; P = 0.03). CONCLUSIONS: In patients with diabetes and hypertension not taking insulin sensitizers, the use of metoprolol tartrate resulted in a worsening of insulin resistance, an effect not seen with carvedilol. However, in TZD/metformin users the difference between the beta-blockers was not statistically significant.

beta-blocker use and diabetes symptom score: results from the GEMINI study.

AIM: The Glycemic Effect in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial compared the metabolic effects of two beta-blockers in people with type 2 diabetes and hypertension treated with renin-angiotensin system (RAS) blockade and found differences in metabolic outcomes. In this paper, we report the results of a prespecified secondary analysis of GEMINI that sought to determine the effect of these two beta-blockers on commonly reported symptoms. METHODS: The Diabetes Symptom Checklist (DSC), a self-report questionnaire measuring the occurrence and perceived burden of diabetes-related symptoms, was completed by GEMINI participants at baseline and at the end of the study (maintenance month 5). The DSC assessed symptoms in eight domains: psychology (fatigue), psychology (cognitive), neuropathy (pain), neuropathy (sensory), cardiology, ophthalmology, hyperglycaemia and hypoglycaemia. RESULTS: Comparison of the mean change in self-reported diabetes-related symptoms indicated a significant treatment difference favouring carvedilol over metoprolol tartrate in overall symptom score (-0.08; 95% CI -0.15, -0.01; p = 0.02) and in the domains for hypoglycaemia symptoms (-0.12; 95% CI -0.23, -0.02; p = 0.02) and hyperglycaemia symptoms (-0.16; 95% CI -0.27, -0.05; p = 0.005). Carvedilol resulted in fewer perceived diabetes-related symptoms in patients with diabetes and hypertension. CONCLUSION: Carvedilol resulted in a lower perceived burden of diabetes-related symptoms in patients with type 2 diabetes and hypertension. The addition of a well-tolerated beta-blocker to RAS blockade may improve hypertension treatment and quality of life in patients with diabetes.

A review of stroke in patients with hypertension and coronary artery disease: Focus on calcium channel blockers.

Stroke is a major cause of morbidity and mortality worldwide. Hypertension is one of the most important risk factors for stroke - increasing the risk significantly. The presence and severity of coronary artery disease (CAD), which often coexists with hypertension, also predicts an increased risk of stroke. Lowering blood pressure (BP) to target in patients with hypertension can significantly reduce the incidence of fatal and non-fatal stroke. Effective BP control is even more important in CAD patients who are at greater risk of stroke. Data regarding the effects of antihypertensive therapy on stroke in patients with angina or CAD are limited and have been variable. To date, BP management strategies in patients with CAD have relied on small subsets of data based on high-risk hypertensive patients. Results with calcium channel blockers (CCBs) have been more positive than those with other classes of antihypertensive agents. Findings from the ACTION trial have provided a significant insight into the benefits of CCBs in patients with CAD and hypertension. Nifedipine gastrointestinal therapeutic system (GITS), in addition to best practice therapy for stable angina pectoris, contributes to a significant reduction in the risk of stroke in patients with CAD and hypertension who are at high risk and require effective BP control. Moreover, the incidence of stroke is significantly related to baseline BP, which may be an important factor to consider when deciding on treatment strategies in high-risk patients with CAD.

Diuretic induced hyponatraemia in elderly hypertensive women.

Diuretics are recommended as first-line antihypertensive treatment in elderly patients. Although attention is usually paid to prevent hypokalaemia with diuretic therapy, risk of hyponatraemia is often ignored. We performed this study to characterise hypertensive patients at increased risk to develop hyponatraemia. We reviewed charts of hypertensive patients hospitalised in Chaim Sheba Medical Center for hyponatraemia from 1990 to 1997. Patients with other causes of hyponatraemia were excluded. The General Practice Maccabi database was used to estimate age and sex distribution of patients prescribed diuretics for hypertension. We identified 180 hypertensive patients (149 F, 31 M; mean age 76.4 +/- 9.2 years) hospitalised because of hyponatraemia. Across all age groups, odds ratio (OR) to develop hyponatraemia was three times higher for women vs men (OR 3.10, 95% confidence interval (CI): 2.07-4.67). One hundred and sixty-two patients (90%) were older than 65 years. Patients of both sexes older than 65 years were 10 times (and if they were older than 75 years 16 times) more likely to develop hyponatraemia than those younger than 65 years (OR 9.87, 95%, CI: 5.93-16.64). Most patients (74.5%) used a thiazide-based diuretic; only 10% used a low dose (<25 mg/day). In 37% of patients diuretics were used for more than 1 year before hyponatraemia developed. Diuretic-induced hyponatraemia may be insidious and appear even after prolonged diuretics use. Elderly women seem to be at particularly high risk. In this population diuretic use should be associated with close monitoring of sodium and potassium levels.

Doxazosin and congestive heart failure.

Congestive heart failure (CHF) is the most devastating cardiac sequella of long-standing hypertension. Recent data from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) have shown the risk of CHF to be twice as high with doxazosin than with chlorthalidone. Although some questions remain regarding the diagnosis and mortality of CHF in the doxazosin arm and regarding the risk of dying from malignancy in the diuretic arm of ALLHAT, drugs used to treat hypertension should lower the CHF risk. Therefore, until ironclad safety data are provided, doxazosin, and probably all alpha-blockers, should no longer be used as first-line antihypertensive therapy.

The choice of first-line therapy: rationale for low-dose combinations of an angiotensin converting enzyme inhibitor and a diuretic.

More than 50% of patients with mild uncomplicated hypertension will need combination therapy to reach target blood pressure, as defined by the Joint National Committee. This percentage is even higher in hypertensive patients with diabetes, renal impairment and congestive heart failure in whom target blood pressures are lower. Combination therapy of angiotensin converting enzyme inhibitor and low dose diuretic offers distinct advantages in the treatment of essential hypertension. The two drug classes may have a synergistic effect on hypertensive target organ disease and blood pressure. Triple therapy with a calcium antagonist may be needed to achieve blood pressure control in more severely hypertensive patients.