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.

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.

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.

Central blood volume: a determinant of early cardiac adaptation in arterial hypertension?

OBJECTIVES: This study was undertaken to assess the influence of the fluid volume state on cardiac adaptation to hypertension. BACKGROUND: Left ventricular hypertrophy is an important predictor of hypertensive complications. We analyzed volume status and its impact on cardiac structural changes in early hypertension. METHODS: In 33 normotensive subjects, 40 patients with borderline hypertension and 63 patients with established essential hypertension, mean arterial pressure was measured invasively; total blood volume was measured by iodine-125-labeled plasma albumin and hematocrit; central blood volume by indocyanine green dye dilution curve; and diastolic diameter and left ventricular mass by two-dimensional-guided M-mode echocardiography. RESULTS: Central blood volume was approximately 20% higher in patients with stage I borderline hypertension than in normotensive subjects ([mean +/- SD] 3,001 +/- 663 vs. 2,493 +/- 542 ml, p < 0.05), whereas total blood volume was similar in all three groups. This shift in intravascular volume toward the cardiopulmonary circulation was accompanied by a significant increase in diastolic diameter (5.29 +/- 0.80 vs. 4.86 +/- 0.77 cm, p < 0.05) and in left ventricular mass (239.4 +/- 90.6 vs. 183.5 +/- 68.8 g, p < 0.05) in patients with borderline hypertension compared with subjects with normotension. In patients with established essential hypertension, volume status of stroke volume and diastolic dimension returned to normal values, whereas left ventricular mass increased further. CONCLUSIONS: We conclude that the early phase of hypertension is characterized by centripetal distribution of intravascular volume, leading to an increased preload to the left ventricle. This change in volume status appears to be related to cardiac structural adaptation to an increase in arterial pressure.

Preserved ventricular pump function after a marked reduction of left ventricular mass.

OBJECTIVES: This study was designed to evaluate the long-term effects of combination therapy with an angiotensin-converting enzyme inhibitor and a beta-adrenergic blocking agent on the relation between the decrease in arterial pressure at rest and during exercise and the decrease in left ventricular mass. BACKGROUND: A variety of antihypertensive drugs including angiotensin-converting enzyme inhibitors and beta-blockers have been shown to reduce ventricular hypertrophy, although little is known about combination therapy and the time course of such a reduction. METHODS: Twenty-one patients with previously untreated essential hypertension were treated with a low dose combination of 50 mg of atenolol and 10 mg of enalapril once daily for 39 months. Cardiovascular findings were assessed by two-dimensionally guided M-mode echocardiography in the pretreatment phase and after 6 and 39 months of combination therapy. RESULTS: Combination therapy reduced arterial pressure at rest from 161/108 to 130/86 mm Hg (p less than 0.001) and exercise arterial pressure at 100 W from 192/112 to 167/95 mm Hg (p less than 0.001). After 6 months of treatment, significant decreases in interventricular septal thickness (9%, p less than 0.001), posterior wall thickness (9%, p less than 0.001) and left ventricular mass index (16%, p less than 0.001) were demonstrated on the echocardiogram. After 39 months of therapy, reductions in these values were 28% (p less than 0.001), 29% (p less than 0.001) and 40% (p less than 0.001), respectively. CONCLUSIONS: Long-term treatment with combination therapy of atenolol and enalapril produced significant reductions in arterial pressure at rest and during exercise accompanied by a marked reduction of left ventricular mass. However, whereas arterial pressure decreased immediately and remained unchanged, left ventricular mass decreased more gradually and continued to decrease throughout the treatment period of greater than 3 years. Despite this marked reduction in left ventricular mass, left ventricular pump function was well preserved during rest and exercise.

Immediate and short-term cardiovascular effects of fosinopril, a new angiotensin-converting enzyme inhibitor, in patients with essential hypertension.

Immediate and short-term cardiovascular effects of a new angiotensin-converting enzyme inhibitor, fosinopril, were assessed in 10 patients with mild to moderate essential hypertension. Administration of a 10 mg oral dose of fosinopril reduced mean arterial pressure (p less than 0.001) as a result of a 24% fall in total peripheral resistance (p less than 0.001). Short-term therapy (12 weeks) maintained the decrease in mean arterial pressure (p less than 0.05) by decreasing total peripheral resistance (p less than 0.01), without reflexive cardiac stimulation or expanding intravascular volume. Renal vascular resistance decreased (p less than 0.05) while renal blood flow, glomerular filtration rate and filtration fraction remained unchanged. The response pattern to mental, isometric and orthostatic stress was similarly unchanged. Left ventricular mass diminished by 11% (p less than 0.01); myocardial contractility was unaffected. Afterload was reduced (p less than 0.05), and velocity of circumferential fiber shortening and stroke volume increased (p less than 0.05). Thus, arterial pressure reduction produced by fosinopril was associated with improved systemic and renal hemodynamics and reduced left ventricular mass.

Racial differences in cardiac adaptation to essential hypertension determined by echocardiographic indexes.

Epidemiologic data point to racial differences in cardiac adaptation to hypertension. In this study, echocardiography and measurement of systemic hemodynamics were performed in 30 black and 30 white patients with untreated essential hypertension. Each black patient was matched with a white patient for age, sex and mean arterial pressure. Wall thickness measurements were similar, but left ventricular mass index was significantly increased in blacks (probability [p] less than 0.05). There was a nonsignificant increase in the number of black patients with posterior wall thickness greater than 1.1 cm. Only in black patients was posterior wall thickness related to systolic (r = 0.45; p = 0.008) and diastolic (r = 0.44; p = 0.0042) pressure and to total peripheral resistance (r = 0.32; p less than 0.046). Thus, although ventricular wall thickness changes are similar in black and white patients, qualitative differences exist in the cardiac adaptive process to systemic hypertension.

High blood pressure. A side effect of drugs, poisons, and food.

A variety of therapeutic agents or chemical substances can induce either a transient or a sustained increase in blood pressure. These agents increase arterial pressure by either causing sodium retention and extracellular volume expansion or directly or indirectly activating the sympathetic nervous system. Some agents act directly on arteriolar smooth muscle. For certain agents, the mechanism of pressure elevation is mixed or unknown. Paradoxically, some agents that are used to lower arterial pressure may acutely increase arterial pressure. Also, a rebound increase in pressure may be encountered after discontinuation of certain antihypertensive agents. In general, these chemically induced increases in arterial pressure are small and transient; however, severe hypertension involving encephalopathy, stroke, and irreversible renal failure has been reported. Careful evaluation of a patient's drug regimen may identify chemically induced hypertension and prevent the need for evaluation and therapy. This study reviews the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action.

High blood pressure. A side effect of drugs, poisons, and food.

Arterial hypertension, either transient or persistent, may be induced or aggravated by ingestion of various chemical agents, such as drugs, poisons, and food. Most of these agents either cause sodium retention and expand extracellular fluid volume or act as direct or indirect sympathomimetics. Others act directly on arteriolar smooth muscle. For a few agents, no precise mechanism has been ascertained. Hypertensive reactions may also occur as a result of drug interactions or food and drug interactions. In addition, paradoxical increases in pressure may be encountered during or after discontinuance of antihypertensive therapy. In general, these pressure increases are small and transient; however, a few have been associated with severe hypertension involving encephalopathy, strokes, and irreversible renal failure. Careful review of a patient's drug regimen, including over-the-counter preparations, may avoid chemically induced hypertension. Identification of any offending or incriminating agent will prevent the labeling of a chronic illness and obviate the need for lifelong antihypertensive therapy.

High blood pressure and diabetes mellitus: are all antihypertensive drugs created equal?

OBJECTIVE: To analyze the available data to assess the benefits of antihypertensive therapy in hypertensive patients with diabetes mellitus. METHODS: A MEDLINE search of English-language articles published until June 1999 was undertaken with the use of the terms diabetes mellitus, hypertension or blood pressure, and therapy. Pertinent articles cited in the identified reports were also reviewed. Included were only prospective randomized studies of more than 12 months' duration that evaluated the effect of drug treatment on morbidity and mortality in diabetic hypertensive patients. We estimated the risk associated with combination of diabetes mellitus and hypertension and the effect of treatment on morbidity and mortality. RESULTS: The coexistence of diabetes mellitus doubled the risk of cardiovascular events, cardiovascular mortality, and total mortality in hypertensive patients (approximate relative risk of 1.73-2.77 for cardiovascular events, 2.25-3.66 for cardiovascular mortality, and 1.73-2.18 for total mortality). Intensive blood pressure control to levels lower than 130/85 mm Hg was beneficial in diabetic hypertensive patients. All 4 drug classes-diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium antagonists-were effective in reducing cardiovascular events in diabetic hypertensive patients. In elderly diabetic patients with isolated systolic hypertension, calcium antagonists reduced the rate of cardiac end points by 63%, stroke by 73%, and total mortality by 55%. In more than 60% of diabetic hypertensive patients, combination therapy was required to control blood pressure. CONCLUSIONS: Intensive control of blood pressure reduced cardiovascular morbidity and mortality in diabetic patients regardless of whether low-dose diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, or calcium antagonists were used as a first-line treatment. A combination of more than 1 drug is frequently required to control blood pressure and may be more beneficial than monotherapy.

Renal involvement follows cardiac enlargement in essential hypertension.

To assess the relationship between early clinically detectable involvement of hypertensive vascular disease in heart and kidneys, we obtained systemic and renal hemodynamic and M-mode echocardiographic measurements in 65 patients with essential hypertension. The results indicate that patients with and without left ventricular hypertrophy had similar renal hemodynamic findings. In contrast, patients with altered renal hemodynamic measurements (ie, reduced renal distribution of cardiac output and, therefore, absolute renal blood flow with increased renal vascular resistance) and increased serum uric acid levels also had increased left ventricular posterior and septal wall thicknesses and mass index. Moreover, these data also demonstrated that in patients with altered renal hemodynamics, the lower the renal distribution of cardiac output and the higher the serum uric acid levels, the greater were the indexes of cardiac enlargement. These results demonstrated that the pathophysiological and hemodynamic effects of essential hypertension in the heart precede those in the kidneys.

Angiotensin II receptor inhibition. A new therapeutic principle.

Angiotensin II receptor antagonists represent a new class of drugs that provide a site-specific blockade of the effects of angiotensin II. Losartan potassium, the first compound of this drug class, has recently become available in the United States. The clinical experience with angiotensin II receptor antagonists has demonstrated that these drugs are safe and efficacious for the treatment of hypertension and, possibly, congestive heart failure. Unlike with angiotensin-converting enzyme inhibitors, the incidence of cough observed with angiotensin receptor antagonists is similar to that with placebo. Although several angiotensin receptors have been characterized, the effects of losartan and other angiotensin receptor antagonists under development are selective for the angiotensin II type 1 receptor. Unlike angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists do not inhibit bradykinin metabolism or enhance prostaglandin synthesis. The antihypertensive efficacy of the angiotensin receptor antagonists has been documented to be similar to that of angiotensin-converting enzyme inhibitors. If the findings of clinical studies corroborate the initial reports on efficacy and safety, it seems likely that the angiotensin receptor antagonists will be added to the list of drugs that have been deemed suitable for first-line therapy in the treatment of hypertension and congestive heart failure.

Salt. A perpetrator of hypertensive target organ disease?

Experimental and clinical data suggest salt intake to be an important factor in the pathogenesis of essential hypertension. However, the relationship between dietary sodium and blood pressure has been found to be relatively weak, perhaps because causal blood pressure levels fluctuate considerably. We hypothesized that a closer correlation could be expected between salt intake and the degree of hypertensive target organ disease. We reviewed the literature for studies dealing with 24-hour urinary sodium excretion (as a measure of salt intake) and hypertensive target organ disease as assessed by left ventricular structure and function, microproteinuria, cerebrovascular disease, and arterial compliance. Salt intake as assessed by 24-hour urinary sodium excretion was found to be a close independent determinant of left ventricular mass in 9 different studies worldwide. A reduction in dietary sodium has been shown to reduce left ventricular hypertrophy. There is clinical and experimental evidence, particularly in salt-sensitive patients, that salt intake directly affects hypertensive renal disease, cerebrovascular disease, and compliance of large arteries. The close and partially independent correlation between salt intake and hypertensive target organ disease suggests dietary sodium to be a direct perpetrator of cardiovascular disease.

Overweight and sudden death. Increased ventricular ectopy in cardiopathy of obesity.

Obesity has been documented to be an independent risk factor for sudden death and other cardiovascular mortality. The present study was designed to monitor and quantify cardiac arrhythmias in obese subjects with and without eccentric left ventricular hypertrophy, who were matched with regard to arterial pressure, age, sex, and height with lean subjects. Prevalence of premature ventricular (but not atrial) contractions was 30 times higher in obese patients with eccentric left ventricular hypertrophy compared with lean subjects. Similarly, obese patients with left ventricular hypertrophy scored higher with regard to the classification of Lown and Wolf than those without left ventricular hypertrophy and lean subjects having the same level of arterial pressure. Patients' class in the Lown and Wolf system correlated with ventricular diastolic diameter and left ventricular mass. Thus, heart enlargement of the eccentric type as a consequence of obesity predisposes to excessive ventricular ectopy. Echocardiographic assessment and electrocardiographic monitoring allow us to identify the patients who are at highest risk of more serious arrhythmias or possibly sudden death and to subject them to the most specific preventive and therapeutic measures.

Renal artery stenosis and polycystic kidney disease.

A patient had unilateral renal artery stenosis and, at the same time, bilateral polycystic kidney disease. The renal venous renin ratio of 151:40, together with a high peripheral plasma renin activity, indicated that the hypertension was partially caused by renopressor mechanism. Correction of the obstructive lesion permitted a better control of hypertension with antihypertensive drugs, and the peripheral and renal venous renin activity returned to normal. The success in detecting one pathogenic mechanism responsible for arterial hypertension should not deter further diagnostic efforts.

Obesity and essential hypertension. Hemodynamics, intravascular volume, sodium excretion, and plasma renin activity.

Systemic hemodynamics, intravascular volume, and plasma renin activity were determined in 135 lean, midly obese, or distinctly overweight subjects who were normotensive or had borderline or established essential hypertension. Cardiac output (but not index) was higher and peripheral resistance lower in obese than in lean subjects, except in borderline hypertension. Intravascular volume was increased in obese patients, and more so when corrected for body height; correction for body weight led to relative volume contraction. Intravascular volume correlated directly with cardiac output in the entire population, as well as in the subgroups. Intravascular volume correlated inversely with total peripheral resistance in all subjects and in each subgroup. Both correlations remained significant when an approximation was used to correct influences of obesity on total blood volume. Sodium excretion was higher in obese than in lean subjects. Thus, despite the expanded intravascular volume in obesity, the pathophysiologic relationship between systemic hemodynamics and intravascular volumes remains unchanged. Relatively low peripheral resistance in obesity may decrease the risk of systemic vascular disease. Nevertheless, since circulating volume is increased, the greater venous return adds an additional load to a left ventricle that is already burdened by a high afterload caused by arterial hypertension.

Implications of a health lifestyle and medication analysis for improving hypertension control.

BACKGROUND: National Health and Nutritional Examination surveys have documented poor rates of hypertension treatment and control, leading to preventable morbidity and mortality. OBJECTIVES: To examine covariation in the medication and health lifestyle beliefs and behaviors of persons with hypertension to identify and profile distinct subgroups of patients. METHODS: A sample of 727 patients with hypertension, weighted to match the 1992 National Health Interview Survey age and sex distribution of patients with hypertension, was interviewed by telephone about their beliefs and behaviors regarding hypertension and its management. Cluster analysis of key variables was used to identify 4 patient types. RESULTS: Subgroups differed significantly. Group A members use an effective mix of medication and health lifestyle regimens to control blood pressure. Group B members are most likely to depend on medication and have high adherence rates. Yet they also have high rates of smoking (29%) and alcohol use (average, 104 times per year) and are less likely to exercise regularly. Group C members are most likely to forget to take medication, are likely to be obese, and find it most difficult to comply with lifestyle changes (except for very low rates of smoking and alcohol use). Group D members are least likely to take medication, most likely to change or stop medication without consulting their physician (20%), most likely to smoke (40%), and least likely to control diet (29%). Group A and B members have better health outcomes than group C and D members. CONCLUSIONS: Optimal management strategies are likely to differ for the 4 patient types. Further research should be conducted to validate these findings on a separate sample and to devise and test tailored management algorithms for hypertension compliance and control.

Hypertension and sudden death. Disparate effects of calcium entry blocker and diuretic therapy on cardiac dysrhythmias.

This study was designed to evaluate the impact of antihypertensive therapy on cardiac dysrhythmias in 13 hypertensive patients who received calcium entry blockers and in 10 hypertensive patients who received hydrochlorothiazide. Mean arterial pressure fell to a similar extent in both treatment groups; however, left ventricular mass index decreased (from 102 +/- 4 to 95 +/- 2 g/m2) only in patients receiving calcium entry blockers, but not in those taking hydrochlorothiazide. The prevalence of premature ventricular contractions decreased 74% from 21 +/- 14/h to 5.7 +/- 6/h in the calcium entry blocker group, but did not change in the hydrochlorothiazide group (15 +/- 17/h to 16 +/- 13/h). Couplets, multiform contractions, ventricular tachycardia, and supraventricular tachycardia were completely abolished after calcium entry blocker therapy, whereas the prevalence of these arrhythmias remained unchanged during treatment with hydrochlorothiazide. We conclude that antihypertensive therapy with calcium entry blockers (but not with thiazide diuretics) reduces left ventricular mass and the prevalence and severity of ventricular dysrhythmias. Whether this reduction will improve the ominous prognosis of left ventricular hypertrophy and diminish the risk of sudden death remains unknown.