The VO(2)-on kinetics in constant load exercise sub-anaerobic threshold reflects endothelial function and dysfunction in muscle microcirculation.

To propose a test to evaluate endothelial function, based on VO(2) on-transition kinetics in sub-anaerobic threshold (AT) constant load exercise, we tested healthy subjects and patients with ischemic-hypertensive cardiopathy by two cardiopulmonary tests on a cycle ergometer endowed with an electric motor to overcome initial inertia: a pre-test and, after at least 24 h, one 6 min constant load exercise at 90 % AT. We measured net phase 3 VO(2)-on kinetics and, by phase 2 time constant (tau), valued endothelial dysfunction. We found shorter tau in repeated tests, shorter time between first and second test, by persisting endothelium-dependent arteriolar vasodilatation and/or several other mechanisms. Reducing load to 80 % and 90 % AT did not produce significant changes in tau of healthy volunteers, while in heart patients an AT load of 70 %, compared to 80 % AT, shortened tau (delta=4.38+/-1.65 s, p=0.013). In heart patients, no correlation was found between NYHA class, ejection fraction (EF), and the two variables derived from incremental cycle cardio-pulmonary exercise, as well as between EF and tau; while NYHA class groups were well correlated with tau duration (r=0.92, p=0.0001). Doxazosin and tadalafil also significantly reduced tau. In conclusion, the O(2) consumption kinetics during the on-transition of constant load exercise below the anaerobic threshold are highly sensitive to endothelial function in muscular microcirculation, and constitute a marker for the evaluation of endothelial dysfunction.

VO2 kinetics in supra-anaerobic threshold constant tests allow the visualization and quantification of the O2 saving after cytochrome c oxidase inhibition by aerobic training or nitrate administration.

We tested whether the known cytochrome c oxidase (COX) inhibition by nitric oxide (NO) could be quantified by VO(2) kinetics during constant load supra-Anaerobic Threshold (AT) exercises in healthy trained or untrained subjects following aerobic training or nitrate administration. In cycle ergometer constant load exercises supra-AT, identified in previous incremental tests, VO(2) kinetics describe a double exponential curve, one rapid and one appreciably slower, allowing the area between them to be calculate in O(2) l. After training, with increased NO availability, this area decreases in inverse ratio to treatment efficacy. In fact, in 11 healthy subjects after aerobic training for 6-7 weeks, area was decreased on average by 51 %. In 11 untrained subjects, following the assumption of an NO donor, 20 mg isosorbide 5 mononitrate, area was decreased on average by 53 %. In conclusion, supra-AT VO(2) kinetics in constant load exercises permit the quantification of the inhibitory effect NO-dependent on COX after either physical training or nitrate assumption.

Predictors of the short-term effect of isoleucine-proline-proline/valine-proline-proline lactotripeptides from casein on office and ambulatory blood pressure in subjects with pharmacologically untreated high-normal blood pressure or first-degree hypertension.

Our aim was to evaluate the predictors of Isoleucine-Proline-Proline/Valine-Proline-Proline (IPP-VPP) lactotripeptides (LTPs) antihypertensive effect in the context of a short-term large double-blind randomized clinical trial involving 164 pharmacologically untreated subjects in primary prevention for cardiovascular disease. When compared with the baseline, office systolic blood pressure (SBP) (-3.42 mm Hg, P < .001) and diastolic blood pressure (DBP) (-2.35 mm Hg, P < .001) significantly decreased, in the LTP-treated patients only. No significant change in predictors during the study of ambulatory blood pressure measurement (ABPM) parameters was observed. A short-term supplementation with LTPs significantly improves the office SBP and DBP, especially in male subjects. The main predictor of LTP antihypertensive effect was the baseline BP.

Fixed combinations of delapril plus indapamide vs fosinopril plus hydrochlorothiazide in mild to moderate essential hypertension.

This 12-week randomized, parallel-group, multicenter study compared fixed combinations of delapril (D) 30 mg plus indapamide (I) 2.5 mg and fosinopril (F) 20 mg plus hydrochlorothiazide (H) 12.5 mg in 171 adult patients with mild to moderate essential hypertension. After a 2-week placebo run-in, sitting and standing systolic (SBP) and diastolic blood pressure (DBP) was measured by conventional sphygmomanometry. The primary efficacy endpoint was the percentage of normalized (sitting DBP < or =90 mm Hg) and responder (sitting DBP reduction of 10 mm Hg or DBP < or =90 mm Hg) patients. Treatment effects were analyzed in the intention-to-treat (ITT; n = 171) and the per-protocol (PP; n = 167) populations. The percentage of normalized and responder patients did not differ significantly between the D + I (87.4% and 92%) and the F + H (81% and 86.9%) ITT groups. Similar results were seen in the PP population. In ITT and PP patients, sitting and standing SBP and DBP values were comparable at baseline in the two groups and were significantly (P<.01) and similarly reduced at weeks 4, 8, and 12. Neither treatment induced reflex tachycardia, and both regimens were well tolerated. Four patients in the F + H group dropped out because of adverse events. In this study, the efficacy and safety of D + I were comparable to those of F + H in patients with mild to moderate essential hypertension.

Anti-ischemic effects of angiotensin-converting enzyme inhibitors: a future therapeutic perspective.

The renin-angiotensin system and angiotensin-converting enzyme (ACE) are increasingly being implicated in the pathogenesis of coronary artery disease and its sequelae and the potential of ACE inhibitors to protect the heart is a topic that has emerged recently as a matter for scientific discussion. Experimental and clinical studies have shown the beneficial effects of ACE inhibitors on the metabolism, function and structure of healthy and damaged hearts and these data support the concept of both primary and secondary cardioprotection with this class of drugs. Animal studies have demonstrated the potential beneficial effects of ACE inhibition at a variety of sites, including improvement of endothelial function, inhibition of platelet aggregation, prevention of atherosclerotic lesions and inhibition of myointimal proliferation, extending the concept to a more general definition of cardiovascular protection with ACE inhibitors involving both the heart and the vessels. ACE inhibitors prevent stimulation of smooth muscle cell angiotensin-II (A-II) receptors, thereby blocking both contractile and proliferative actions of A-II. In addition, ACE inhibition of kininase inhibits the breakdown of bradykinin, a direct stimulant of nitric oxide release from the intact endothelial cell. Thus, at the cellular level ACE inhibition shifts the balance of ongoing mechanisms in favour of those promoting vasodilatory, anti-aggregatory, antithrombotic and antiproliferative effects. Although these data have not all been validated in human studies, the reduction of ischemic events in studies of ACE inhibition in left ventricular dysfunction (LVD) and, more recently, also in patients without LVD, cannot be explained solely by improved hemodynamics, and it is possible that actions on the endothelium, the atherosclerotic process and platelets are at least in part responsible. So, the available data underlie the potential benefits of ACE inhibition in the field of ischemic heart disease and atherosclerosis; the results of ongoing studies in humans looking more directly at the influence of ACE inhibitors in this setting are awaited with interest.

Beta-blockade in hypertension and congestive heart failure.

Hypertension is common and increases the risk of death from coronary artery disease and cerebral vascular disease. The reason for treating hypertension is to prevent the long-term complications of this disorder. Many studies of antihypertensive therapy have produced only modest reductions in coronary events; in particular, with the use of beta-blockers. Clinical trials and meta-analyses have shown a lesser effect of these drugs on primary prevention of coronary events, cardiovascular and total mortality with respect to other antihypertensive approaches based on the use of low-dose diuretic therapy, especially in the elderly, even if the reduction of stroke and heart failure (HF) were similar. New beta-blockers with vasodilating properties due to the capacity to enhance the release of endothelial nitric oxide, then lessening a contributory mechanism to the pathogenesis of atherosclerosis as endothelial damage and dysfunction, seem to possess considerable potential in the treatment of hypertension, particularly in terms of improvement of cardiovascular outcome of patients. In HF, there is now considerable interest in the therapeutic use of beta-blockade. Some recent clinical trials have demonstrated conclusive evidence of the beneficial effects of beta-blocker therapy on survival in chronic HF. As a result of these data, beta-blocker therapy has become part of standard therapy for patients with chronic HF, in addition to angiotensin-converting enzyme-inhibitors and diuretics. The treatment is, in general, well tolerated. There are, however, some unanswered questions. One is whether some beta-blockers may be better than others. The major mortality benefit is probably a class-effect of beta1-adrenoceptor blockade, but the differences between beta-blockers might be clinically relevant. For example, it is under debate whether ancillary properties of some beta-blockers, such as the capability of exerting antioxidant effects or enhancing the nitric oxide production, may contribute to the clinical effects of these drugs. Future clinical trials will report over the next few years and help to answer the question about differences in mortality effects among types of beta-blocking agents, thus correctly defining the precise role of these drugs in the wide spectrum of cardiovascular disease.

Use of statins and blood pressure control in treated hypertensive patients with hypercholesterolemia.

High serum cholesterol has been frequently reported in patients with arterial hypertension in whom it might influence the blood pressure control. The aim of this study was to compare the extent of blood pressure changes in 41 patients with hypertension and hypercholesterolemia, taking antihypertensive drugs and treated for 3 months with statins (HC-S; pravastatin or simvastatin) and compared with matched controls with high (HC-D; 44) or normal serum cholesterol (NC-D; 45) undergoing antihypertensive treatment combined with dietary treatment alone. After 3 months of follow-up, a greater reduction of systolic (SBP) and diastolic (DBP) blood pressure values was observed in HC-S patients (ASBP/DBP, -11.3 +/-3/-10.6 +/- 2%) when compared with both HC-D (deltaSBP/DBP, -6.6 +/- 2/-6.1 +/- 2%; p < 0.05) and NC-D (deltaSBP/DBP, -6.9 +/- 2/-6.8 +/- 1.5%; p < 0.05). In statin-treated patients, a slight linear relation has been found between the percentage changes in DBP and those in plasma total cholesterol (R = 0.37, p = 0.043), whereas no relation was found with SBP changes (R =0.11; p = 0.35). In conclusion, the results of this study demonstrate that the use of statins in combination with antihypertensive drugs can improve blood pressure control in patients with uncontrolled hypertension and high serum cholesterol levels. The additional blood pressure reduction observed in patients treated with statins is clinically relevant and only partially related to the lipid-lowering effect.

Effects of the administration of an angiotensin-converting enzyme inhibitor during the acute phase of myocardial infarction in patients with arterial hypertension. SMILE Study Investigators. Survival of Myocardial Infarction Long-term Evaluation.

A positive history of arterial hypertension (HBP) is present in as many as 30% of patients with acute myocardial infarction (AMI) and their clinical outcome could be greatly improved by drugs enhancing blood pressure control and preserving ventricular function. The aim of the present study was to evaluate the importance of a history of HBP on the clinical efficacy of early treatment with the angiotensin-converting enzyme (ACE) inhibitor zofenopril in patients with anterior AMI. We summarize the results of a post-hoc analysis of data from the Survival of Myocardial Infarction Long-term Evaluation (SMILE) study, which randomly evaluated the efficacy of zofenopril given within 24 h of symptom onset to patients with anterior AMI not undergoing thrombolysis. Of 1441 patients who entered the study, 565 (39.2%) had a history of HBP. The mean follow-up time was 12 months and the main outcome measures were 6-week combined occurrence of death and severe congestive heart failure (CHF) and 1-year mortality. After 6-week of treatment with zofenopril the relative risk of death or severe CHF was 0.60 (95% confidence interval [CI]: 0.45-0.81; 2P < .05) in the hypertensive group and 0.89 (0.74-1.08; 2P = .62) for normotensive patients, whereas the 1-year risk of death was 0.61 (95% CI: 0.23,0.89; 2P < .05) and 0.77 (95% CI: 0.52-1.17; 2P = .22), respectively. The 6-week prevalence of mild-to-moderate CHF was also significantly reduced by zofenopril in the hypertensive population (14.1% v 9.4%; 2P < .05). The present data suggest that treatment with zofenopril started within 24 h of the onset of anterior AMI could be highly beneficial in patients with a history of HBP.

[Clinical approach to the hypertensive patient. New guidelines]. / Approccio clinico al paziente iperteso. Nuove linee guida.

Prospective observational studies clearly show that the risks of stroke, coronary artery disease, and premature death are directly related to blood pressure levels. Yet as the results of prospective randomized intervention studies have indicated, these risks are reduced by effective blood pressure control. Over a 5-year period, an average reduction of 5-6 mmHg in diastolic blood pressure and of 10-12 mmHg in systolic blood pressure is associated with a 38% decrease in risk of stroke and a 16% decrease in risk of coronary heart disease. Although awareness of hypertension has increased markedly, and the number of patients treated for this condition has approximately doubled over the last 20 years, premature morbidity and mortality remain higher than in the normotensive population. This situation may arise from the inadequate level of blood pressure control achieved in many patients. Thus, although delineating theoretical rules to treat hypertension seems relatively easy, in real life it is not always possible to adhere to them. This difficulty highlights the need for appropriate guidelines in clinical practice. A number of national groups as well as the World Health Organization and the International Society of Hypertension have recently published recommendations for the diagnosis and treatment of hypertension. Physicians must strive to improve the management of hypertension and remember that a thorough clinical evaluation, treatment of associated cardiovascular risk factors, prevention of target organ damage, and good patient compliance are key elements affecting the success of therapy.

[Integration of therapeutic options and the candidates for treatment: the ABC of the post-infarction period]. / L'integrazione delle opzioni terapeutiche e i candidati al trattamento: ABC del postinfarto.

Acute myocardial infarction, major cause of death in Western society, has been the focus of many clinical investigations over the past decade. As the result of randomized trials involving hundreds of thousands of infarct patients worldwide, the life-saving potential of several pharmacologic interventions has been validated, and the usefulness of other commonly used treatments has been disproven or brought into question. Much of the innovative therapy has been targeted toward limiting myocardial damage by eradicating the occlusive thrombus or otherwise restoring flow through the infarct-related artery, reducing oxygen demands in the injured ventricle, and altering vascular dynamics to limit the process of ventricular remodeling. Data have accumulated showing substantially lower mortality of acute myocardial infarction with simple pharmacological interventions such as intravenous thrombolytic therapy, aspirin, beta-blockers and ACE-inhibitors. In particular, ACE-inhibitors have recently proven to be effective in infarcted patients, especially in high-risk subjects with acute anterior infarction not treated with thrombolytic agents or patients with left ventricular dysfunction. ACE-inhibitors may limit the process of ventricular remodeling after a large infarction, lessening the risk of sudden death and heart failure. Intravenous heparin has a role in maintaining patency of infarct-related vessel after rt-PA, and it seems that this combination offers some benefits with respect to streptokinase plus subcutaneous heparin. Recent studies have also demonstrated the importance of lipid-lowering agents for secondary prevention after myocardial infarction. Several previously recommended therapies (routine intravenous lidocaine, calcium channel blockers, magnesium, nitrates) have not been proven to be life-saving.

Factors associated with the development of stable hypertension in young borderline hypertensives.

OBJECTIVES: To identify factors predisposing subjects to the development of stable hypertension and to estimate their relative importance in 70 young patients with borderline hypertension monitored for 10 years. DESIGN: Longitudinal evaluation of the incidence of stable hypertension [diastolic blood pressure (DBP) > 95 mmHg]. METHODS: Patients were examined at baseline by determination of resting blood pressure, intracellular sodium level and individual pressor response to mental arithmetic and to intravenous saline loading. They were re-examined after 10 years to assess the prevalence of established hypertension and the importance of some prognostic variables identified prospectively (age, sex, intracellular sodium level, baseline blood pressure, pressor response to stress and acute salt-sensitivity). RESULTS: The prevalence of sustained hypertension (DBP > 95 mmHg) was 35.8% after 10 years of follow-up study. Subjects developing hypertension were older (26.9 +/- 1.3 versus 21.0 +/- 1.8 years) and showed a higher percentage of family history of hypertension (92 versus 64%) and of acute salt-sensitivity (72 versus 53%). The pressor response to mental arithmetic was greater in patients who developed hypertension (systolic blood pressure 26.9 +/- 1 versus 22.7 +/- 0.9 mmHg, P = 0.005 DBP = 16.6 +/- 0.8 versus 13.1 +/- 0.7 mmHg, P = 0.005), who also showed higher levels of intracellular sodium (30.7 +/- 0.6 versus 27.3 +/- 0.5 mmol/kg, P = 0.001). The same variables were found to be related to the development of hypertension in a multivariate analysis and the concomitant presence of 4-5 risk factors was associated with a reasonable predictive power for the identification of patients at high risk (sensitivity 72%, specificity 67%, predictive accuracy 76%). CONCLUSIONS: The present study demonstrates that borderline hypertensives at high risk of stable hypertension can be identified by the concomitant evaluation of some clinical and cellular characteristics directly related to long-term development of high blood pressure.

Low dose of ACE-inhibitor enhances sodium excretion in volume expanded patients with borderline hypertension.

The purpose of the present study was to separately investigate the effects of two different dosages of captopril on pressor, vascular and humoral response to acute extracellular volume expansion in patients with borderline hypertension (BHT). Thirty-five patients were randomly allocated in two groups undergoing acute saline infusion (0.40 ml/min/kg for 45 min and 0.15 ml/min/kg for 75 min)before and after a 7-day period of treatment with either placebo or captopril at the dose of 12.5 (LD-CAP) or 50 mg (HD-CAP) twice a day. At baseline the effects of LD-CAP were limited to an increase in PRA and to a decrease in plasma aldosterone whereas HD-CAP decreased systolic and diastolic blood pressure (SBP, DBP), forearm vascular resistance (FVR) and increased venous distensibility (VV(30)) as well. After saline loading patients treated with HD-CAP showed an increase in SBP, DBP not observed in patients allocated to LD-CAP. Urinary sodium excretion in response to NaCl loading was selectively enhanced by LD-CAP (+25%) whereas HD-CAP did not (+6.3%). The present data suggest that low-doses of ACE-inhibitors acting through a selective blockade of RAA not associated with hemodynamic changes can enhance the natriuretic response to acute volume expansion in borderline hypertensives.

[New therapeutic outlooks in the treatment of the hypertensive patient]. / Nuove prospettive terapeutiche nel trattamento del paziente iperteso.

The results of the large randomized trials in which antihypertensive drugs have been compared to placebo demonstrated that antihypertensive therapy reduces cardiovascular and cerebrovascular mortality and morbidity. Nowadays, however, it is not enough to lower blood pressure; the goal of the treatment should be to prevent progression of the underlying atherosclerotic disease, reduce major and minor complications and improve survival and quality of life. Furthermore, primary prevention and risk reduction in hypertensives are dependent not only on the antihypertensive effect of the chosen agent, but also on improved detection and management of the other cardiovascular risk factors. The potential ability of antihypertensive treatment to exert an effect on global cardiovascular risk profile has become one of the most important considerations in the selection of an antihypertensive treatment. Thus, in patients at risk for coronary events it seems important to choose a drug or drug combination with a documented effect on coronary events. In addition, both prevention of cardiovascular events and prevention of organ damage and organ disease have to be considered essential goals of antihypertensive therapy. The prevention of organ damage associated with hypertension has also been facilitated by the development of effective antihypertensive drugs. These agents have been shown to have a beneficial influence on organ damage in hypertensive patients through an effective, continuous, smooth control of blood pressure and through specific effects on some of the functional and structural alterations induced by hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

A standardized instrument to assess hazards for falls in the home of older persons.

Hazards in the home are implicated in up to half of all falls among older persons. Yet, the instruments used to identify these hazards usually have been unstandardized, have lacked specific definitions of hazards, and have not been evaluated. Therefore, in 1988, as part of the Study to Assess Falls among the Elderly, in Miami Beach, Florida, the authors evaluated the reliability of a standardized instrument used for assessing the training of evaluators and assessing home environments. Based on up to 176 observations for each potential hazard, the interviewers' assessment of hazards such as throw rugs, tripping hazards, light switch hazards, and hazardous bath surfaces had good overall reliability (kappa = 0.65-0.92). Their assessment of grab-bars and hazardous furniture was unreliable (kappa = 0.18-0.35). Variations in the reliability reflect the difficulty in creating definitions that are simple to be understood and used, yet detailed enough to produce sensitive and specific survey items. Investigators studying falls among older persons should use standardized definitions to train evaluators and assess environmental hazards.

Present perspectives of therapy in the prevention of stroke: beta blockers.

Stroke represents the third most common cause of death in the developed world and is also a very significant cause of morbidity. Epidemiological data clearly show that hypertension is associated with an increased risk of stroke. In randomized controlled clinical trials, treatment for hypertension has been shown to reduce stroke events (both fatal and non-fatal) by 40% in all hypertensive populations. In fact, a reduction in the incidence of stroke has been demonstrated in middle-aged as well as in older hypertensive patients, and in all grades of hypertension. Beta blockers are one of the first-line therapeutic alternatives in the field of hypertension. Their role appears strongly supported also by the results of some large intervention trials in hypertensive patients. Beta blockers may have, however, different effects on the prevention of coronary events and sudden death from those of other antihypertensive drugs (i.e. diuretics), even if the benefit in terms of stroke prevention seems quite similar. Therefore the choice of the best mean of optimizing blood pressure control requires additional clinical considerations, such as the age of the patient, the presence of other risk factors and the presence of myocardial ischemia.

[Clinical pharmacology of angiotensin II antagonists]. / Farmacologia clinica degli antagonisti dell'angiotensina II.

The renin-angiotensin system (RAS) participates in both cardiovascular homeostasis and diseases. Angiotensin converting enzyme (ACE) inhibitors have been used very successfully in the treatment of hypertension and heart failure. The therapeutic effectiveness of these drugs has been ascribed to their action in limiting the activity of the RAS and suggests that other pharmacological mechanisms that block this system, such as angiotensin II receptor inhibitors, could also be of benefit. Some properties of angiotensin II receptor inhibitors offer potential advantages over ACE-inhibitors. ACE acts on other substrates in addition to angiotensin I (i.e. bradykinin) so that more specific inhibition of the RAS can be achieved with selective angiotensin II antagonists. Data on the existence of both circulating and tissue RAS have been reported, and non-ACE pathways for angiotensin II production have also been described. So, by inhibiting the interaction of the biological active peptide at its receptor level, an angiotensin II receptor antagonist will inhibit the RAS independently of the source or route of angiotensin II synthesis. Peptide angiotensin II antagonists were first reported 20 years ago and the best studied was saralasine; they are potent and selective blockers of angiotensin II responses, but their lack of oral activity, short duration of action and the concomitant partial agonistic activity limited their clinical use. Now are available nonpeptide angiotensin II antagonists with attributes appropriate for clinical development. The preliminary evaluation of these new selective nonpeptide angiotensin II antagonists show their potential therapeutic role in many cardiovascular diseases in which the RAS is involved.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of zofenopril and fosinopril in acute myocardial infarction and carotid artery disease.

The potential of angiotensin-converting enzyme (ACE) inhibitors to protect the heart is a topic that has emerged recently as matter of scientific discussion. Experimental and clinical studies have shown the beneficial effects of ACE inhibitors on the metabolism, function, and structure of healthy and damaged hearts and these studies support the concept of both primary and secondary "cardioprotection" with these drugs. More recently, the prevention of atherosclerotic lesions has been demonstrated in animal models, extending the concept to a more general definition of "cardiovascular" protection with ACE inhibitors involving both the heart and the vessels. The potential role of ACE inhibitors on the primary prevention of atherosclerotic disease in humans is currently evaluated in PHYLLIS (Plaque HYpertension Lipid Lowering Italian Study), a multicenter clinical trial in which fosinopril sodium, a new ACE inhibitor, is administered to hypertensive patients with at least one uncomplicated carotid artery lesion. The primary aim of the study is to evaluate the effect of the drug on the long-term (3 years) progression of carotid artery atherosclerosis, noninvasively detected by B-mode ultrasound imaging. In addition to studies on primary prevention, some large clinical trials have been conducted to establish the role of ACE inhibitors on secondary prevention, in particular in patients with acute myocardial infarction (MI). The beneficial effect of these drugs is well established when administered in the subacute phase of acute MI.(ABSTRACT TRUNCATED AT 250 WORDS)