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Chronic hypertension and diabetes produce both macrovascular and microvascular pathophysiological changes. Greater arterial stiffness increases central systolic and pulse pressure, which raises left ventricular afterload and reduces coronary perfusion. Resistance arteries remodelling and capillary rarefaction increase peripheral resistance, thereby contributing to hypertension and amplifying the detrimental haemodynamic effects of arterial stiffening. The result is target organ impairment, such as left ventricular hypertrophy, decreased coronary perfusion pressure, reduced coronary reserve and further vascular remodelling, culminating in coronary artery disease and stroke. Therapeutic intervention is possible and necessary to stop these vascular changes. Vasodilating antihypertensive drugs, such as the perindopril/indapamide combination, have been shown to modify both arterial and arteriolar remodelling, leading to reduced central systolic blood pressure and enhancing vascular bed perfusion. These effects probably underpin the benefits of these agents in reducing cardiovascular morbidity and mortality.

In addition to the prevention and treatment of macro- and microvascular complications, management goals for patients with type 2 diabetes include reducing the risk of cardiovascular events with a view to improving quality of life. A number of epidemiological and observational cohort studies have been published in Italy and France in an effort to determine the patient profile of individuals with type 2 diabetes in these countries and to gather data on current clinical practice and prescribing patterns. The results of the studies confirm that cardiovascular risk factors, such as hypertension and elevated cholesterol, commonly occur in patients with type 2 diabetes and that these co-morbid conditions are not well controlled. As a consequence, both macro- and microvascular complications are prevalent in this patient population. It is clear that the management of type 2 diabetes in France and Italy is suboptimal. In both primary and specialist care, treatment guidelines need to be reinforced and a more aggressive approach needs to be adopted in the treatment of modifiable cardiovascular risk factors and in particular hypertension. Collectively, the available data highlight the importance of managing global cardiovascular risk within the context of diabetes care. Greater adherence to therapeutic targets recommended in guidelines will ensure that greater proportions of patients attain these treatment goals thereby reducing diabetes-related morbidity and mortality.

The importance of left ventricular hypertrophy (LVH) as a powerful predictor of cardiovascular morbidity and mortality, independent from blood pressure and other cardiovascular risk factors, is widely recognized. Women have a lower prevalence of LVH than men for any given level of blood pressure. The occurrence of LVH increases progressively with older age and LVH becomes more common in women after menopause. Available data indicate that both hypertension and LVH are stronger risk factors for stroke and for heart failure in women than in men. Women are more likely to maintain a better left ventricular systolic function than men with similar heart failure symptoms, and heart failure due to diastolic dysfunction is more common in women than in men. Few studies have demonstrated that patients who fail to achieve a reduction of LVH are much more likely to suffer cardiovascular events than those in whom the left ventricular mass is reduced by antihypertensive treatment. Reversal of LVH therefore represents a major goal in the treatment of hypertensive patients. The degree of cardiac hypertrophy reduction is influenced by baseline severity of LVH, by the duration of treatment and by the degree of 24-h blood pressure control. In addition, beyond the control of blood pressure, different classes of antihypertensive drugs may differently interfere with several non-hemodynamic stimuli, and therefore have a different effect on left ventricular mass. Data regarding the effect of antihypertensive therapy on LVH in women are not adequate. Few studies have suggested a possible additive effect of estrogen replacement therapy on left ventricular mass changes in hypertensive postmenopausal women. Many of the major heart failure intervention trials did not include women or had only a small proportion of female patients. In the SAVE, AIRE, TRACE and SOLVD trials, treatment with angiotensin-converting enzyme inhibitors resulted in similar benefit to women and in men. In studies evaluating the effect of beta-blocker treatment in patients with heart failure, the benefit was statistically significant in men but not in women. Results from further multicenter ongoing trials are awaited to definitely evaluate whether regression of LVH carries a similar benefit in women and men, and whether different therapeutic strategies may be applied to women to regress LVH and to prevent the progression to heart failure.

LVH AND RISK: Left ventricular hypertrophy (LVH) is a powerful predictor of cardiovascular morbidity and mortality, independent from blood pressure and other cardiovascular risk factors. Available data indicate that patients who fail to achieve a reduction in LVH are much more likely to suffer cardiovascular events than those in whom LVH is reduced or even normalized using antihypertensive treatment. Reversal of LVH, therefore, represents a major goal in the treatment of hypertensive patients. REGRESSION OF LVH: Since obesity and dietary sodium intake may modulate the degree of LVH, non-pharmacological intervention has achieved a successful reduction in left ventricular mass (LVM). LVM is more closely related to 24-h blood pressure values than to clinical blood pressure values. Recent evidence from the Study on Ambulatory Monitoring of Blood Pressure and Lisinopril Evaluation has shown that the regression of cardiac hypertrophy is predicted to a greater degree by the effect of antihypertensive treatment on 24-h average blood pressure than by that on clinic or home blood pressure. The increase in blood pressure variability may also be an independent determinant of cardiovascular target-organ damage, particularly of cardiac hypertrophy. However, the effects of antihypertensive drugs on blood pressure variability can be difficult to determine, mainly because a correct measurement of variability requires a beat-to-beat measurement of ambulatory blood pressure; several measures have been proposed to evaluate the smoothness of blood pressure control during antihypertensive treatment. Other important determinants of LVH reduction are represented by baseline values of LVM, extent of blood pressure reduction and duration of treatment. Furthermore, the degree of cardiac hypertrophy reduction is not the same for the different classes of antihypertensive drugs because, beyond the control of blood pressure, they may interfere differently with several non-haemodynamic stimuli, including the renin-angiotensin-aldosterone and the adrenergic systems or other growth factors. A more pronounced reduction in LVM with angiotensin converting enzyme inhibitors and calcium antagonists has been demonstrated in several recent meta-analyses. The results of further multicenter on-going trials are awaited to evaluate definitely whether various antihypertensive strategies differ in their ability to reverse LVH and to adequately assess the relationship between changes in LVM and subsequent prognosis, with serial control of blood pressure values measured in the clinic and by ambulatory monitoring.

Objective: Left ventricular hypertrophy (LVH) and depressed left ventricular performance have been shown to be associated to an adverse prognosis in hypertensive patients. It has not been established, however, whether, during chronic antihypertensive treatment, the increased cardiovascular risk is more strictly related to the presence of LVH or of a low left ventricular performance., Design and Methods: A total of 215 patients with uncomplicated hypertension (129 males, 86 females; age range 18-70 years, mean +/- SD 45 +/- 11) underwent an echocardiographic evaluation of left ventricular anatomy and function. In 151 patients (87 males, 64 females; age range 18-70 years, mean 45 +/- 10.4) the echocardiogram was repeated on average 10 +/- 1 years after the initial study. The presence of LVH (left ventricular mass index > 134 g/m2 in males and 110 g/m2 in females) and the midwall left ventricular shortening/end-systolic stress relationship were prospectively analysed as predictors of cardiovascular non-fatal events (n = 23) in patients who were seen at follow-up., Results: The incidence of non-fatal cardiovascular events was greater in patients with LVH (n = 17, P < 0.0001) and in those with a lower midwall performance (n = 14, P < 0.01) at baseline. At follow-up, the incidence of non-fatal cardiovascular events was significantly greater in patients without a reduction in the left ventricular mass index, after adjusting for traditional risk factors (relative risk 3.52 versus 1.38 in patients with persistence and regression of LVH, respectively; P < 0.01). The baseline midwall fractional shortening was lower in patients with both persistence or regression of LVH (analysis of variance, P < 0.0001) than in patients with a normal left ventricular mass index. In logistic analysis, the left ventricular mass index at follow-up and age were independent determinants of non-fatal cardiovascular events (P < 0.001); without the left ventricular mass index at follow-up, this analysis showed that age, systolic blood pressure at follow-up and baseline midwall fractional shortening were independent determinants of non-fatal cardiovascular events., Conclusions: Our results suggest that lack of regression of LVH is a stronger indicator of cardiovascular risk than a depressed baseline midwall left ventricular performance.

Objective: To assess whether regression of left ventricular hypertrophy (LVH) can be used as a surrogate end-point for morbid events in hypertension treatment trials., Design and Methods: Statistical, epidemiologic and treatment trial literature was reviewed to identify the criteria that should be met by a surrogate end-point and to determine whether these criteria are met by existing data on the regression of LVH., Results: Relevant criteria include: (1) a consistent relationship between LVH and subsequent morbid events; (2) prediction of lower or higher complication rates by LVH regression or progression; (3) evidence that the relationship between LVH regression/progression and morbidity/mortality is consistent in different populations and with different treatments; and (4) demonstration of a quantitative relationship that allows prediction of a change in clinical risk from a measured change in LVH. The results of seven electrocardiographic and 10 echocardiographic studies with a total of about 20000 subjects have shown consistently higher risks of morbid events in subjects with than without LVH (odds ratios 1.4-5.4). The available data (four studies, 1145 subjects) suggest that morbid events will occur in a higher proportion of subjects in whom LVH progresses (13-59%) rather than regresses (7-12%). However, the latter data are derived almost entirely from white subjects, predominantly male, with incomplete knowledge of interim treatment and blood pressure in most instances; no information on the mathematical relationship between change in LVH and subsequent morbidity and mortality is yet available., Conclusions: A strict definition of the information required to establish a fully adequate surrogate end-point for morbid events in antihypertensive has been partially but not completely satisfied. The consistent relationship between baseline LVH and subsequent morbid events and the initial evidence of a parallelism between LVH change and prognosis need to be supplemented by additional studies that examine the latter relationship in diverse populations under varied treatments, and which examine the quantitative relationship between measured change in LVH and the subsequent rates of morbid events. Additional data will come from ongoing treatment trials (approximately 12 000 subjects) and observational studies (approximately 8000 subjects) with serial assessments of LVH.

The effects of calcium antagonists in reducing blood pressure at rest and during exercise were examined in patients with mild-to-moderate essential hypertension. The haemodynamic effects of calcium antagonists were evaluated at rest and during exercise. We also examined 10 patients with mild-to-moderate essential hypertension taking lacidipine, a new dihydropyridine calcium antagonist (4 mg once a day, at 0700 h). Compared with placebo, lacidipine induced significant mean reductions in 24-h blood pressure (P less than 0.001 for systolic blood pressure; P less than 0.002 for diastolic blood pressure). After 24 h, the blood pressure reductions were still significant (P less than 0.02 for systolic blood pressure; P less than 0.04 for diastolic blood pressure). The heart rate did not change. During dynamic exercise, blood pressure at maximal effort was reduced (P less than 0.01 for systolic and diastolic blood pressure) and the external workload reached at the anaerobic threshold was significantly increased (P less than 0.001), but not at maximum effort. Ventilation and tidal volume were similar at both the anaerobic threshold and peak exercise, while oxygen uptake and carbon dioxide production were increased at the anaerobic threshold (P less than 0.02 for carbon dioxide production) but were similar at peak exercise.

A total of 1337 patients with mild to moderate essential hypertension were included in an open, multicentre trial to assess the response rate to the diuretic etozolin (200 mg once a day) and to verify whether the addition of the calcium antagonist verapamil (120 mg twice a day) in non-responders may have a favourable effect. Etozolin lowered diastolic blood pressure to below 95 mmHg in 67.8% of patients after 4 weeks of treatment and in 62.4% of patients after 12 weeks. The patients who failed to respond to etozolin were given verapamil (120 mg twice a day), and 72.8% of these patients showed a good response to the combined treatment. Normalization of blood pressure was achieved in 83.6% of the total patients. The incidence of side effects was 14.3%; withdrawal due to side effects was reported in 2.5% of patients. Abnormalities on the ECG were recorded in 5.5% of patients. No consistent metabolic or electrolyte change was observed. In conclusion, etozolin given at a dose of 200 mg once a day seems to be an effective and safe antihypertensive agent. Its antihypertensive effect remains unaltered for 12 weeks at least. The combination with verapamil may be effective in those who do not respond to etozolin alone.

We evaluated the left ventricular mass index (LVMI) and the functional response to cold pressor and handgrip tests in 74 untreated essential hypertensive patients and 26 age and sex-matched normals. The same measurements were repeated in 22 essential hypertensives after 6 and 12 months of treatment (captopril or nitrendipine, plus diuretic or beta-blocker in a few cases) and in 21 essential hypertensives after withdrawal of treatment, a reduction in the LVMI and a further increase in blood pressure. Left ventricular systolic function was evaluated by the relationship between left ventricular end-systolic stress and fractional shortening. Highly significant negative correlations, with similar slopes and intercepts, were found between end-systolic stress and fractional shortening under basal conditions, after regression of left ventricular hypertrophy and after withdrawal of treatment, both at rest and at the peak of stress tests. An examination of each point of the relation between end-systolic stress and fractional shortening showed that very few points were beyond the 95% prediction limits of the correlation obtained in normal volunteers. These results indicate that left ventricular systolic function is normal in most untreated essential hypertensives, and is usually well maintained after regression of left ventricular hypertrophy during long-term treatment as well as after withdrawal of treatment, both at rest and during an acutely induced afterload increase.

Structural vascular changes in the calf arteries and left ventricular mass were measured in 52 essential hypertensive patients (WHO I and II, 35 men and 17 women, age range 21-63 years). Left ventricular mass was measured on M-mode echocardiographic tracings. Structural vascular changes were evaluated indirectly by studying the minimal vascular resistance, calculated from mean arterial pressure and maximal (post-ischaemic) blood flow, measured by venous occlusion plethysmography. A statistically significant correlation between left ventricular mass and minimal vascular resistance was observed (r = 0.33, P < 0.05). The low correlation suggested that structural changes in the heart and in the systemic arteries did not develop simultaneously. In the subgroup of patients with minimal vascular resistance in the normal range, left ventricular hypertrophy was found in 15 out of 30 patients (50% of cases) whereas, in the subgroup of patients with high minimal vascular resistance, absence of left ventricular hypertrophy was found in six out of 22 patients (27% of cases). These results suggest that left ventricular hypertrophy more often precedes arterial structural changes in the calves.

In 14 essential hypertensive patients, aged 26-59 years, blood pressure, left ventricular mass index (LVMI), systolic function (M-mode echo, two-dimensionally guided), post-ischaemic 'maximal' forearm blood flow (strain gauge venous occlusion plethysmography), plasma renin activity, plasma catecholamines and aldosterone were measured before and after 6 and 12 months of treatment (eight patients were given captopril, 100 mg/day, + hydrochlorothiazide 25 mg/day in five patients, and six patients were given nitrendipine, 20 mg/day, + atenolol 50 mg/day in four patients). Minimal vascular resistance (mean blood pressure/peak forearm blood flow) was taken as an index of arterial structural changes. After 6 months of treatment significant reductions in blood pressure (P less than 0.001), LVMI (P less than 0.001) and minimal vascular resistance were observed. After 12 months of treatment blood pressure, LVMI and minimal vascular resistance were further reduced. The LVMI was normalized in nine cases and the minimal vascular resistance in two cases only. Aldosterone and plasma catecholamines did not change, whereas plasma renin activity was increased during captopril only. Before and during treatment the left-ventricular shortening fraction in relation to end-systolic stress in each patient at rest, and at peak of handgrip and cold pressor tests, fell within the 95% confidence limits of correlation obtained in normals. Thus, in essential hypertensives long-term treatment can induce normalization of LVMI before complete regression of arterial structural changes in the forearm. Left ventricular systolic function is preserved after normalization of LVMI, both at rest and during stress.

Physical exercise can induce micro-albuminuria, a urinary albumin excretion rate of 20-200 micrograms/min, in diabetics without micro-albuminuria at rest (stage II of diabetic nephropathy). The aim of the present study was to evaluate the acute effects of captopril, an angiotensin converting enzyme (ACE) inhibitor, and nifedipine, a calcium channel blocker, on exercise-induced micro-albuminuria in hypertensive diabetics with stage II nephropathy. Eleven hypertensive World Health Organisation (WHO) stages I-II non-obese diabetics (five insulin-dependent diabetics, six non-insulin dependent diabetics) underwent five submaximal cycloergometric tests, the first two in basal conditions, the other three after 24-h administration of captopril (25 mg twice a day), placebo (1 tablet twice a day) or nifedipine AR (20 mg twice a day) according to a randomized double-blind design. Our results demonstrate that despite a lower reduction in exercise blood pressure, captopril is more effective than nifedipine in blunting diabetic exercise-induced micro-albuminuria.

In hypertension, changes of cardiac anatomy and function are not just a simple consequence of the increased pressure load. The sympathetic nervous system activity is one of the factors which may influence the cardiac performance, and possibly also the cardiac anatomy of hypertensive patients. Several clinical studies have provided evidence of a subset of patients, usually with mild or borderline hypertension, with an increased cardiac performance, higher plasma catecholamine concentrations and/or greater response to beta-adrenergic stimulation. Animal studies have strongly suggested a possible role of adrenergic factors in the development of left ventricular hypertrophy (LVH). In man, plasma catecholamines are usually higher in hypertensive patients with LVH, and a correlation between left ventricular mass and plasma noradrenaline has also been observed. An impaired response to beta-adrenergic stimulation has been reported in hypertensive animals and in patients with LVH. Several studies have also suggested that reversal of LVH may be more easily induced by those antihypertensive drugs that reduce, or at least do not stimulate, the sympathetic activity, although exceptions to this statement may be observed.

In this study we compared the antihypertensive efficacy and tolerability of captopril at 25 mg twice daily, hydrochlorothiazide (HCTZ), 12.5 mg twice daily and placebo in a multicentre, double-blind, randomized study that included 152 essential hypertensive patients (77 males, 75 females, 87 WHO stage I, 65 WHO stage II, aged 69 +/- 4 years, mean +/- s.d.). Supine and standing blood pressure were similarly reduced by captopril and HCTZ (P less than 0.01 for both compared with placebo). The heart rate did not change. Captopril (25-30 mg twice daily) and HCTZ (12.5 mg twice daily), alone or in combination, maintained their antihypertensive effect during a 24-week single-blind follow-up study. During the follow-up, diastolic blood pressure remained less than 100 mmHg in seven essential hypertensives on placebo, in 45 on captopril and in 25 on HCTZ. Side effects were observed in seven essential hypertensives during placebo (treatment withdrawn in two), in eight during HCTZ and in three during captopril. Serum potassium was reduced (P less than 0.05) and uric acid was increased (P less than 0.01) only during HCTZ. We conclude that captopril and HCTZ have similar antihypertensive efficacy in the elderly; however, captopril appears to be better tolerated.

Reduction in density of beta-adrenoceptors has been demonstrated in the hypertrophied left ventricle (LV) of renovascular hypertensive rats (RHR). In order to investigate the relative role of cardiac hypertrophy as distinct from hypertension, LV beta-receptors were determined in RHR four days after nephrectomy of the clipped kidney (RHR-Nx) when blood pressure was reduced but hypertrophy still evident; the results were compared with those obtained in age-matched untreated RHR and sham operated rats (SHAM). As expected, blood pressure (BP) was reduced four days after nephrectomy (150 +/- 3 versus 212 +/- 11 mmHg untreated RHR, P less than 0.001) but LV hypertrophy had not regressed (3.07 +/- 0.16 versus 3.58 +/- 0.24 mg/g, NS). Ventricular beta-receptor density was reduced in both RHR (1.601 +/- 0.078 pmol/g) and RHR-Nx (1.667 +/- 0.124 pmol/g) compared with SHAM (2.033 +/- 0.06 pmol/g, P less than 0.05 for both). The dissociation constant (Kd) was not different among the three groups. Thus, the reduction of beta-adrenergic receptors in the hypertrophied LV of RHR persisted even when BP was lowered by nephrectomy, suggesting that hypertrophy per se rather than hypertension accounted for that reduction in cardiac beta-receptors.