Papers by Gianpaolo Reboldi
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Blood pressure (BP) decreases by 10% to 20% from day to night. However, in 25% to 35% of hyperten... more Blood pressure (BP) decreases by 10% to 20% from day to night. However, in 25% to 35% of hypertensive subjects there is some reduction in the day-night BP decline. In 3% to 5% of uncomplicated hypertensive subjects there is actually an increase, not a decrease, in BP from day to night. Many studies from independent centers showed that not only left ventricular hypertrophy, but also ventricular arrhythmias, silent cerebrovascular disease, microalbuminuria and progression of renal damage are more advanced in subjects with blunted or abolished fall in BP from day to night than in those with normal day-night BP difference. There is also evidence from longitudinal studies that a blunted, abolished or even reversed BP drop from day to night is associated with an increase in the risk of serious cardiovascular complications. However, if the quantity or quality of sleep is poor during overnight BP monitoring, night-time BP rises and its prognostic significance is no longer reliable. Studies which compared the prognostic value of daytime BP with that of night-time BP inevitably found the superiority of the latter for predicting prognosis. The exciting potential therapeutic implication that the control of night-time BP could be more rewarding, in terms of prevention of cardiovascular disease, than that of daytime BP has yet to be addressed in appropriately designed intervention trials. Of note, 24-hour ABP monitoring is the only practical way to assess the day-night rhythm of BP.
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An association has been shown between plasma renin activity (PRA) and the risk of cardiovascular ... more An association has been shown between plasma renin activity (PRA) and the risk of cardiovascular disease. There is also evidence that angiotensin II exerts detrimental effects on progression and instabilization of atherosclerotic plaque. The renin-angiotensin system (RAS) can be inhibited through inhibition of angiotensin I (Ang I) generation from angiotensinogen by direct renin inhibitors, inhibition of angiotensin II (Ang II) generation from angiotensin I by angiotensin-converting enzyme inhibitors and fi nally by direct inhibition of the action of Ang II receptor level. Aliskiren, the fi rst direct renin inhibitor to reach the market, is a low-molecular-weight, orally active, hydrophilic nonpeptide. Aliskiren blocks Ang I generation, while plasma renin concentration increases because the drugs blocks the negative feedback exerted by Ang II on renin synthesis. Because of its long pharmacological half-life, aliskiren is suitable for once-daily administration. Its through-to-peak ratio approximates 98% for the 300 mg/day dose. Because of its mechanism of action, aliskiren might offer the additional opportunity to inhibit progression of atherosclerosis at tissue level. Hypertension is an approved indication for this drug, which is also promising for the treatment of heart failure. The effi cacy of this drug in reducing major clinical events is being tested in large ongoing clinical trials.
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Cardiovascular and renal disease can be regarded as progressing along a sort of continuum which s... more Cardiovascular and renal disease can be regarded as progressing along a sort of continuum which starts with cardiovascular risk factors (hypertension, diabetes, dyslipidemia, smoking, etc), evolves with progression of atherosclerotic lesions and organ damage, and then becomes clinically manifest with the major clinical syndromes (myocardial infarction, stroke, heart failure, end-stage renal disease). The blood pressure control remains a fundamental mechanism for prevention of cardiovascular disease. The renin–angiotensin system is believed to play an important role along different steps of the cardiovascular disease continuum. Convincing evidence accumulated over the last decade that therapeutic intervention with angiotensin receptor blockers (ARBs) is effective to slow down or block the progression of cardiovascular disease at different steps of the continuum, with measurable clinical benefits. However, despite the shared mechanism of action, each ARB is characterized by specific pharmacological properties that may influence its clinical efficacy. Indeed, important differences among available ARBs emerged from clinical studies. Therefore, generalization of results obtained with a specific ARB to all available ARBs may be misleading. The present review provides a comparative assessment of the different ARBs in their efficacy on major clinical endpoints along the different steps of the cardiovascular disease continuum. According to the chain of events described some years ago by Dzau and Braunwald, cardiovascular and renal disease, the most frequent causes of morbidity and mortality in industrial countries, can be regarded as progressing along a sort of continuum (Figure 1). 1,2 The continuum starts with cardiovascular risk factors (hypertension, diabetes, dyslipidemia, smoking, etc) and evolves with progression of atherosclerotic lesions and organ damage. Hence, the continuum may become clinically manifest with the major clinical syndromes (myocardial infarction, stroke, heart failure, end-stage renal disease), which may ultimately lead to death. 1,2 The outcome associated with late stages of the continuum is remarkably poor. For example, one out of two patients with New York Heart Association (NYHA) stage IV congestive heart failure dies within one year, and approximately 80% of all patients with congestive heart failure die within 10 years. 3 It is important to note that therapeutic interventions at each step of the continuum can slow down or block its progression, with potentially measurable outcome benefits. In this setting, the blood pressure control remains a fundamental mechanism for prevention of cardiovascular disease.
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IMPORTANCE OF THE FIELD:
Aliskiren, a drug which inhibits the initial and rate-limiting step of t... more IMPORTANCE OF THE FIELD:
Aliskiren, a drug which inhibits the initial and rate-limiting step of the renin angiotensin aldosterone system (RAAS), recently approved for the treatment of hypertension, may become a reasonable therapeutic choice in a broad number of clinical conditions sharing an increased cardiovascular risk, where the inhibition of the RAAS has been shown to be beneficial.
AREAS COVERED IN THIS REVIEW:
The present review summarizes the pharmacokinetic and pharmacodynamic properties of aliskiren along with the clinical trials that took into account the effects of aliskiren on blood pressure control and on a number of renal and cardiovascular end points. The specific effects of aliskiren on different populations (e.g., elderly hypertensives, patients with diabetes and hypertension, patients with hypertension and renal impairment) are discussed.
WHAT THE READER WILL GAIN:
The review discusses the most recent discoveries of the cardiovascular and renal effects of aliskiren, including a comprehensive discussion of the ongoing trials and of the areas of remaining uncertainty.
TAKE HOME MESSAGE:
Aliskiren is a promising drug that may become a convenient choice in several clinical conditions. The full spectrum of the beneficial effects of aliskiren will be fully elucidated when the results of the large ongoing trials become available.
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Diabetes Care, 2004
The goal of the study was to examine risk factors in the prediction of coronary heart disease (CH... more The goal of the study was to examine risk factors in the prediction of coronary heart disease (CHD) and differences in men and women in the EURODIAB Prospective Complications Study. Baseline risk factors and CHD at follow-up were assessed in 2,329 type 1 diabetic patients without prior CHD. CHD was defined as physician-diagnosed myocardial infarction, angina pectoris, coronary artery bypass graft surgery, and/or Minnesota-coded ischemic electrocardiograms or fatal CHD. There were 151 patients who developed CHD, and the 7-year incidence rate was 8.0 (per 1,000 person-years) in men and 10.2 in women. After adjustment for age and/or duration of diabetes, the following risk factors were related to CHD in men: age, GHb, waist-to-hip ratio (WHR), HDL cholesterol, smoking, albumin excretion rate (AER), and autonomic neuropathy. The following risk factors were related to CHD in women: age, systolic blood pressure (BP), fasting triglycerides, AER, and retinopathy. Multivariate standardized Cox proportional hazards models showed that age (hazard ratio 1.5), AER (1.3 in men and 1.6 in women), WHR (1.3 in men), smoking (1.5 in men), fasting triglycerides (1.3 in women) or HDL cholesterol (0.74 in women), and systolic BP (1.3 in women) were predictors of CHD. This study supports the evidence for a strong predictive role of baseline albuminuria in the pathogenesis of CHD in type 1 diabetes. Furthermore, sex-specific risk factors such as systolic BP, fasting triglycerides (or HDL cholesterol), and WHR were found to be important in the development of CHD.
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American Journal of Kidney Diseases, 2001
Several retrospective and uncontrolled prospective studies reported blood pressure (BP) normaliza... more Several retrospective and uncontrolled prospective studies reported blood pressure (BP) normalization and left ventricular mass (LVM) reduction during daily hemodialysis (DHD). Conversely, the burden of these major independent risk factors is only marginally reduced by the initiation of standard thrice-weekly dialysis (SHD), and cardiovascular events still represent the most common cause of death in hemodialysis patients. Therefore, we performed a randomized two-period crossover study to compare the effect of short DHD versus SHD on BP and LVM in hypertensive patients with end-stage renal disease. We studied 12 hypertensive patients who had been stable on SHD treatment for more than 6 months. At the end of 6 months of SHD and 6 months of DHD in a sequence of randomly assigned 24-hour ambulatory BP monitoring, echocardiography and bioimpedance were performed. Throughout the study, patients maintained the same Kt/V. A significant reduction in 24-hour BP during DHD was reported (systolic BP [lsqb ]SBP[rsqb ]: DHD, 128 [plusmn] 11.6 mm Hg; SHD, 148 [plusmn] 19.2 mm Hg; P [lt ] 0.01; diastolic BP: DHD, 67 [plusmn] 8.3mm Hg; SHD, 73 [plusmn] 5.4 mm Hg; P [equals] 0.01). The decrease in BP was accompanied by the withdrawal of antihypertensive therapy in 7 of 8 patients during DHD (P [lt ] 0.01). LVM index (LVMI) decreased significantly during DHD (DHD, 120.1 [plusmn] 60.4 g/m2; SHD, 148.7 [plusmn] 59.7 g/m2; P [equals] 0.01). Extracellular water (ECW) content decreased from 52.7% [plusmn] 11.4% to 47.6% [plusmn] 7.5% (P [equals] 0.02) and correlated with 24-hour SBP (r [equals] 0.63; P [lt ] 0.01) and LVMI (r [equals] 0.66; P [lt ] 0.01). In conclusion, this prospective crossover study confirms that DHD allows optimal control of BP, reduction in LVMI, and withdrawal of antihypertensive treatment. These effects seem to be related to reduction in ECW content. [copy ] 2001 by the National Kidney Foundation, Inc.
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American Journal of Hypertension, 2007
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American Journal of Cardiology, 1996
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Journal of Hypertension, 2004
Clinicians are often confronted with the incidental finding of isolated minor, non-specific repol... more Clinicians are often confronted with the incidental finding of isolated minor, non-specific repolarization changes on the electrocardiogram (ECG) in hypertensive patients. The aim of this study was to investigate the prognostic significance of such changes. Prospective, observational study. A total of 1970 hypertensive patients without prevalent cardiovascular disease were followed for up to 9.1 years (mean 4.7 years). Patients with ECG abnormalities including ischaemia, previous infarction, bundle branch block, atrial fibrillation and ventricular pre-excitation were excluded. Patients were divided into three groups: normal left ventricular (LV) repolarization (n = 1355); minor repolarization changes (n = 504); and typical LV strain (n = 111). During follow-up, 78 patients developed new-onset ischaemic heart disease. The event rates were 0.50, 1.28 and 3.08 per 100 patient-years in the groups with normal repolarization, minor changes, and typical LV strain, respectively (P < 0.001). After adjustment for the effect of age, sex, diabetes, serum cholesterol, smoking, LV hypertrophy and 24-h pulse pressure, the risk for developing coronary events was higher in patients with minor repolarization changes (hazard ratio 2.07, 95% confidence interval 1.23-3.47; P < 0.01) or LV strain (hazard ratio 4.00, 95% confidence interval 2.09-7.65; P < 0.001) than in patients with normal repolarization (reference category). Population-attributable risks were 21 and 14%, respectively. Minor ST-T changes also retained an adverse prognostic value among patients without LV hypertrophy (hazard ratio 1.90, 95% confidence interval 1.08-3.33; P = 0.026). We have identified minor, non-specific LV repolarization changes as a novel, independent risk factor for ischaemic heart disease in patients with uncomplicated hypertension.
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Hypertension, 2007
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Determination of serum creatinine concentration is recommended in all patients with hypertension ... more Determination of serum creatinine concentration is recommended in all patients with hypertension as a marker of target organ damage. However, the possibility that creatinine values within the reference range might contribute to stratification of cardiovascular risk in essential hypertension has never been tested. In the setting of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale Study, for up to 11 years (mean, 4 years) we followed up 1829 white patients with hypertension (mean +/- SD age, 51 +/- 12 years; 53% men; office blood pressure, 157/98 mm Hg) free of cardiovascular events and with normal pretreatment creatinine levels (men, <136 micromol/L [<1.5 mg/dL]; women, <120 micromol/L [<1.4 mg/dL]) who also underwent 24-hour blood pressure monitoring and electrocardiography before therapy. During follow-up, there were 175 fatal or nonfatal major cardiovascular morbid events (2.4 per 100 patient-years). Event rate increased progressively from the first to the fourth sex-specific quartiles of creatinine distribution (1.5, 2.3, 2.3, and 3.5 per 100 patient-years; P =.003 by log-rank test). After adjustment (in a multivariate Cox model) for age, sex, diabetes, cholesterol, smoking, left ventricular hypertrophy, and 24-hour pulse and mean blood pressures (P<.05 for all), creatinine concentration was an independent adverse predictor of cardiovascular morbid events (P =.01). The observed excess risk was 1.30 (95% confidence interval, 1.07-1.59) for a 20-micromol/L (0.23-mg/dL) increase in creatinine concentration. A serum creatinine value within the reference range is a predictor of cardiovascular morbidity in white patients with essential hypertension. Its prognostic value persists after adjustment for several powerful confounders, including average 24-hour blood pressure and left ventricular hypertrophy.
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Circulation, 2001
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Diabetes, 1993
ABSTRACT
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American Journal of Hypertension, 2003
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Papers by Gianpaolo Reboldi
Aliskiren, a drug which inhibits the initial and rate-limiting step of the renin angiotensin aldosterone system (RAAS), recently approved for the treatment of hypertension, may become a reasonable therapeutic choice in a broad number of clinical conditions sharing an increased cardiovascular risk, where the inhibition of the RAAS has been shown to be beneficial.
AREAS COVERED IN THIS REVIEW:
The present review summarizes the pharmacokinetic and pharmacodynamic properties of aliskiren along with the clinical trials that took into account the effects of aliskiren on blood pressure control and on a number of renal and cardiovascular end points. The specific effects of aliskiren on different populations (e.g., elderly hypertensives, patients with diabetes and hypertension, patients with hypertension and renal impairment) are discussed.
WHAT THE READER WILL GAIN:
The review discusses the most recent discoveries of the cardiovascular and renal effects of aliskiren, including a comprehensive discussion of the ongoing trials and of the areas of remaining uncertainty.
TAKE HOME MESSAGE:
Aliskiren is a promising drug that may become a convenient choice in several clinical conditions. The full spectrum of the beneficial effects of aliskiren will be fully elucidated when the results of the large ongoing trials become available.
Aliskiren, a drug which inhibits the initial and rate-limiting step of the renin angiotensin aldosterone system (RAAS), recently approved for the treatment of hypertension, may become a reasonable therapeutic choice in a broad number of clinical conditions sharing an increased cardiovascular risk, where the inhibition of the RAAS has been shown to be beneficial.
AREAS COVERED IN THIS REVIEW:
The present review summarizes the pharmacokinetic and pharmacodynamic properties of aliskiren along with the clinical trials that took into account the effects of aliskiren on blood pressure control and on a number of renal and cardiovascular end points. The specific effects of aliskiren on different populations (e.g., elderly hypertensives, patients with diabetes and hypertension, patients with hypertension and renal impairment) are discussed.
WHAT THE READER WILL GAIN:
The review discusses the most recent discoveries of the cardiovascular and renal effects of aliskiren, including a comprehensive discussion of the ongoing trials and of the areas of remaining uncertainty.
TAKE HOME MESSAGE:
Aliskiren is a promising drug that may become a convenient choice in several clinical conditions. The full spectrum of the beneficial effects of aliskiren will be fully elucidated when the results of the large ongoing trials become available.