Stefano Carugo

Effects of chronic ACE inhibition on sympathetic nerve traffic and baroreflex control of circulation in heart failure

BACKGROUND In congestive heart failure ACE inhibitors chronically reduce plasma norepinephrine. No information exists, however, on whether and to what extent this reduction reflects a true chronic inhibition of sympathetic outflow and which mechanisms may be responsible. METHODS AND RESULTS In 24 patients aged 60.3+/-2.0 years (mean+/-SEM) affected by congestive heart failure (New York Heart Association class II) and treated with diuretics and digitalis, we measured mean arterial pressure (Finapres), plasma renin activity and angiotensin II levels (radioimmunoassay), plasma norepinephrine (high-performance liquid chromatography), and muscle sympathetic nerve activity (microneurography at a peroneal nerve) at rest and during baroreceptor stimulation and deactivation caused by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. In 12 patients measurements were repeated after a 2-month addition of the ACE inhibitor benazepril (10 mg/d P.O.), while in the remaining 12 patients they were performed again after 2 months without any treatment modifications. Benazepril did not alter mean arterial pressure, markedly increased plasma renin activity, reduced plasma angiotensin II, and caused a nonsignificant reduction in plasma norepinephrine. In contrast, muscle sympathetic nerve traffic was significantly reduced (-30.5+/-5.3%, P<.01). This reduction was accompanied by no change in the sympathoexcitatory responses to baroreceptor deactivation but by a marked enhancement of the sympathoinhibitory responses to baroreceptor stimulation (103.5+/-3.4%). CONCLUSIONS These results provide the first direct evidence that in congestive heart failure chronic ACE inhibitor treatment is accompanied by a marked reduction in central sympathetic outflow. This reduction may depend on a persistent restoration of baroreflex restraint on the sympathetic neural drive.

Effects of cigarette smoking on carotid and radial artery distensibility

Objective Cigarette smoking acutely induces a marked increase of blood pressure and heart rate. This is accompanied by a marked reduction of radial artery distensibility. Whether this reflects an alteration of arterial mechanics of large elastic arteries as well is not established, however. Design and methods In this study we addressed the acute effects of smoking on the stiffness of a peripheral medium-sized muscular artery and a large elastic vessel. We studied seven healthy normotensive smokers (age 28 ± 7 years, mean ± SEM), in the absence of smoking for at least 24 h. Radial artery (NIUS 02) and carotid artery diameter (WTS) were concomitantly acquired beat-to-beat in the 5 min before, during and after smoking of a cigarette containing 1.2 mg of nicotine. Blood pressure and heart rate were concomitantly recorded by a Finapres device. Radial and carotid artery distensibility were calculated according to the Langewouters and Reneman formulae, respectively. Data were collected for consecutive 30 s periods. Statistical comparisons were performed between the three different phases and, within each phase, between 30 s periods. In five subjects the protocol was repeated after 1 week using a stran rather than a cigarette to obtain data under sham smoking. Results Smoking increased systolic blood pressure by 14%, diastolic blood pressure by 10% and heart rate by 27%. Radial artery diameter was reduced during smoking (−3.7%) and more so after smoking (−14.8%), while carotid artery diameter did not change significantly either during or after smoking. Radial artery distensibility was also significantly reduced only after smoking (−41.3%, P < 0.01), while carotid artery distensibility was significantly reduced both during (−33.3%) and after smoking (−27.2%) (P < 0.01 versus before). No changes in blood pressure, heart rate and arterial wall mechanics were induced by sham smoking. Conclusions Acute cigarette smoking reduces distensibility not only in medium-sized but also in large elastic arteries, therefore causing a systemic artery stiffening. The mechanisms of these effects remain to be determined. However, it is likely that adrenergic mechanisms are responsible for the arterial distensibility alterations.

Left ventricular hypertrophy increases cardiovascular risk independently of in-office and out-of-office blood pressure values

Objectives Previous studies have shown that left ventricular hypertrophy (LVH) represents a cardiovascular risk factor independently of clinic blood pressure (BP). The present study was aimed at determining the impact of LVH on the incidence of cardiovascular morbid and fatal events taking into account not only classical risk factors but also home and ambulatory BP values, which have been shown to have an important independent prognostic impact. Methods In 1716 patients belonging to the ‘Pressioni Arteriose Monitorate E Loro Associazioni’ population of Monza, we quantified left ventricular mass index and identified LVH by standard cutoff values. We also measured clinic, home and 24-h ambulatory BPs together with serum glucose and lipids. Results During a follow-up of 148 months, the rate of fatal and nonfatal (hospitalizations) cardiovascular events as well as of all-cause death was markedly greater (four-fold to five-fold) in patients as compared with those without LVH. In LVH individuals, the increased risk remained significant even when data were adjusted for a large number of other confounding factors including home BP, 24-h mean BP and ambulatory BP. Results were similar when left ventricular mass was indexed by height and body surface area. A 10% increase in left ventricular mass index was associated with a significant increase in cardiovascular risk or all-cause deaths. In multivariate analysis, left ventricular mass index was always an independent predictor of cardiovascular events and death for any cause. Conclusion Our data provide evidence that LVH is an important risk factor even when the contribution of different BPs to risk is fully taken into account.

Impaired radial artery compliance in normotensive subjects with familial hypercholesterolemia

Hypercholesterolemia impairs arteriolar dilatation, but whether the vascular abnormalities accompanying this condition include large artery function is unknown. We addressed this issue in 13 normotensive subjects with familial hypercholesterolemia (serum cholesterol 401.6 +/- 16.9 mg/dl, mean +/- S.E., FHC) and no evidence of atherosclerotic lesions, in whom radial artery (RA) diameter and blood pressure (BP) were measured beat to beat by an echotracking and a Finapres device, respectively. RA compliance (RAC) was derived from the diameter/BP relationship and expressed over the systo-diastolic BP range, both at baseline and after a 12-min brachial artery occlusion. RAC was expressed also as the area under the RAC/BP curve divided for pulse BP. Measurements included maximal forearm blood flow (plethysmography) and minimal forearm vascular resistance (FVR) which were obtained from the values following the 12-min brachial arterial occlusion. Data were collected before and after 6- and 24-month lipid lowering treatment (simvastatin 40 mg/day). Ten age-matched normotensive normocholesterolemic healthy subjects (N) served as controls. Compared to N, baseline RAC was strikingly reduced in FHC (-53.5%, P < 0.01). After ischemia RAC increased significantly and markedly in N (+38.7, P < 0.01), while only a modest and non-significant increase was observed in FHC. Minimal FVR was markedly higher in FHC than in N (3.5 +/- 0.9 vs 1.6 +/- 0.1 units, P < 0.01). In FHC (7 subjects) RAC remained unchanged after 6 months of lipid lowering treatment, but increased markedly (+55.2%, p < 0.05) when treatment was prolonged to 24 months. Lipid lowering treatment also reduced minimal FVR, the effect being significant both after 6 and after 24 months. No changes in RAC and minimal FVR were seen after 6 months in controls. Thus, in subjects with a marked increase in serum cholesterol due to FHC, not only arteriolar dilatation, but also RAC and distensibility are markedly impaired. This impairment can be favourably affected by an effective lipid lowering treatment of long duration.

Acute effects of smoking on radial artery compliance in humans.

Objective To clarify whether the acute and marked increase in blood pressure associated with smoking is accompanied by an alteration in arterial compliance. Design Arterial compliance was measured in 13 subjects before and after smoking a cigarette with a nicotine content of 1.2mg, or before and after sham smoking. Measurements were obtained with the subjects at rest and after prolonged brachial artery occlusion (12min). Methods Compliance was measured using an echo-tracking system capable of continuously providing (300 readings/s) radial diameter data and, with the addition of a photoplesythmographic device, blood pressure measurement. Results Acute cigarette smoking caused a pressor and tachycardie response, and decreased markedly both resting radial artery diameter and compliance, at blood pressure values identical to those before smoking. The marked increase in radial artery diameter and compliance brought about by local ischaemia was unaffected by smoking, and no changes were observed both at rest and after ischaemia as a result of sham smoking. Conclusions Smoking causes a marked reduction in radial artery compliance, and the effect is independent of the increase in blood pressure. However, the marked increase in compliance due to ischaemia is not modified by smoking.

Prevalence and incidence of the metabolic syndrome in the European Lacidipine Study on Atherosclerosis (ELSA) and its relation with carotid intima-media thickness

Background The European Lacidipine Study on Atherosclerosis (ELSA) randomized 2334 hypertensive patients to either the lipophilic calcium antagonist lacidipine or the β-blocker atenolol for 4 years. About 35% of subjects in both groups received additional hydrochlorothiazide (12.5–25 mg/day). The patients were followed up for carotid intima–media thickness (IMT) changes for 3.7 years. Objectives The present post-hoc analyses were aimed at: describing the prevalence of the metabolic syndrome (MS) at baseline; investigating the effect of long-term antihypertensive therapy (and separately of atenolol and lacidipine) on MS prevalence; exploring whether MS at baseline influenced changes in carotid IMT and incidence of cardiovascular events during treatment; and describing the relations between MS and new cases of diabetes developing during treatment. Methods At baseline 2034 patients had, in addition to blood pressure (BP), measurements of blood glucose, serum high-density lipoprotein (HDL)-cholesterol, triglycerides and body mass index (BMI > 28.8 for men and > 26.2 for women were taken to correspond to waist circumference > 102 and > 88 cm, respectively). These measurements were repeated after 4 years of treatment in 1444 patients. MS was defined according to Adults Treatment Panel III (ATP III). Results A high proportion of ELSA patients (33.3%) had MS at baseline, with no difference between atenolol and lacidipine. Baseline IMT was slightly greater in MS patients, but only the difference in mean maximum IMT at common carotids and bifurcations (CBMmax) achieved significance (P = 0.0325). Progression of CBMmax was also slightly greater in MS patients (P = 0.0241), but significance was lost when adjusted for covariates. No significant difference was found in the incidence of new cardiovascular events between patients with and without MS. The incidence of new MS was 21.4%, and significantly greater in patients under atenolol (25.2%) than lacidipine (17.7%; P = 0.0045). New-onset diabetes occurred in 5.54% of ELSA patients, and was three times higher among patients with than those without MS (10.28 versus 3.43%, P > 0.0001). Conclusions Our analyses show a high prevalence of MS in ELSA hypertensives, a substantial incidence of new cases of MS and diabetes, the latter mostly among patients with MS. These analyses also show that in ELSA lacidipine was superior to atenolol, not only in showing a lower progression of carotid atherosclerosis, but also in causing a significantly lower incidence of new MS.

Impact of Body Mass Index and Waist Circumference on the Long-Term Risk of Diabetes Mellitus, Hypertension, and Cardiac Organ Damage

Obesity is associated with a higher risk of developing diabetes mellitus (DM), hypertension (HT), and left ventricular hypertrophy (LVH). The present study assessed in the general population the impact of body weight and visceral obesity on the development of alterations in glucose metabolism and cardiac structure, as well as of elevation in blood pressure. In 1412 subjects randomly selected and representative of the general population of Monza, we assessed twice (in 1990/1991 and 2000/2001) body mass index (BMI); waist circumference; office, home, and 24-hour ambulatory (24-hour) blood pressure, fasting glycemia, and left ventricular mass (echocardiography). New-onset high-risk conditions were DM; impaired fasting glucose; office, home, and 24-hour HT; and LVH. The incidence of new-onset DM; impaired fasting glucose; office, home, and 24-hour HT; and LVH increased progressively from the quintile with the lowest to the quintile with the highest BMI values. Adjusting for confounders, the risk of developing new-onset DM; impaired fasting glucose; office, home, and 24-hour HT; and LVH increased significantly for an increase of 1 kg/m2 of BMI and 1 cm of waist circumference (respectively, 8.4% [P<0.01], 9.5% [P<0.0001], 4.2% [P<0.0001], 3.9% [P<0.001], 2.5% [P<0.05], and 5.1% [P<0.001] for BMI and 3.2% [P<0.001], 3.5% [P<0.0001], 1.8% [P<0.0001], 1.5% [P<0.0001], 1.4% [P<0.001], and 2.6% [P<0.0001]). These data provide evidence that an increase in BMI and waist circumference is associated with a linearly increased adjusted risk of developing conditions with high cardiovascular risk, such as DM, impaired fasting glucose, in- and out-of-office HT, and LVH.

Long-term follow-up of 111 patients with angiotensin-converting enzyme inhibitor-related angioedema.

Objective To investigate, for the first time, the frequency of recurrences of angiotensin-converting enzyme inhibitor (ACE-I)-related angioedema after the discontinuation of ACE-I. Methods This retrospective study was conducted in an outpatient tertiary-level centre for a total period of 173 months (about 14 years). Consecutive patients with recurrent angioedema symptoms, initiated during treatment with an ACE-I, who had been followed for at least 12 months after discontinuation of the drug were eligible. The primary study variable was the incidence of recurrences of angioedema after ACE-I discontinuation. Angioedema location, type of ACE-I and indication for this treatment and the drugs prescribed after the discontinuation of ACE-I were also evaluated. Results In total, 111 patients were followed; 54 of them (49%) were on enalapril. After discontinuation from ACE-I, 51 patients (46%) had further recurrences of angioedema; in 18 relapsers (16% of the total), the frequency of angioedema recurrences remained unchanged when compared with that reported during ACE-I treatment. The large majority of relapsers (88%) had the first recurrence of angioedema within the first month since ACE-I discontinuation. The switch to a different antihypertensive therapy did not seem associated with a reduction in the frequency of angioedema attacks. Conclusion Even with all the limitations on any observational analysis, this long-term study suggests for the first time that patients with angioedema started while on ACE-I treatment seem to have a condition predisposing to angioedema that is elicited by the treatment with these drugs. Further studies in this field appear advocated due to the potential severity of angioedema attacks.

Alterations of radial artery compliance in patients with congestive heart failure

Congestive heart failure is accompanied by several hemodynamic alterations. To investigate whether these alterations include reduced arterial compliance, we studied 25 patients (age 57 +/- 2 years, mean +/- SE) with a mild or severe congestive heart failure based on clinical symptoms (New York Heart Association class II vs III or IV) and on echocardiographic alterations of left ventricular diastolic diameter and ejection fraction. Radial artery diameter and blood pressure were continuously measured by Doppler ultrasonography and a finger pressure device, respectively. Compliance was calculated by the Langewouters formula, and compliance values were derived throughout the systolic-diastolic pressure range. The area under the compliance-pressure curve normalized for pulse pressure was used to compare compliance values in the various groups. Data were obtained both in baseline condition and at the release from a 12-minute brachial artery occlusion. Fourteen healthy, age-matched subjects served as controls. Compared with the control group, patients with severe congestive heart failure showed a reduction of baseline compliance index (-48%, p < 0.01). Furthermore, while in control subjects compliance markedly increased after brachial artery occlusion (+43%, p < 0.01), in patients with severe congestive heart failure no increase occurred. No baseline compliance alteration was seen in patients with mild congestive heart failure in whom, however, the postischemic increase in compliance was also significantly blunted (-50% vs controls, p < 0.05). Thus, arterial compliance and arterial compliance modulation are impaired in congestive heart failure. Although more marked in severe congestive heart failure, the impairment is manifest in mild congestive heart failure as well.

Prevalence and clinical significance of a greater ambulatory versus office blood pressure ('reversed white coat' condition) in a general population

Background Attention has recently been directed to a condition termed ‘reversed white coat’ because of an average 24 h ambulatory blood pressure (BP) uncharacteristically greater than office BP. No data are available, however, on the prevalence of this condition in the general population, as well as on its relationship to BP, age, gender, antihypertensive treatment and cardiac organ damage. Methods In 3200 individuals (participation rate 64%), randomly selected to be representative of the residents of Monza (Milan, Italy) for sex and decades of age (25 to 74 years), we measured office BP (average of three measurements, sphygmomanometry), ambulatory BP (automatic readings every 20 min, Spacelabs 90207) and left ventricular mass (echocardiography). Results A ‘reversed white coat’ condition (identified when 24-h average ambulatory systolic, diastolic or mean were higher than the corresponding office values) was seen in 15% (diastolic) to 26% (systolic) of the population as a whole. Prevalence was greater (34–40%) when the difference between office and daytime BP was considered but in both instances it remained less than the prevalence of the white-coat phenomenon. A reversed white-coat condition was similarly frequent in males and females and showed a steep reduction with age and increasing office BP values. Prevalence was greater in hypertensive subjects in whom treatment achieved BP control than in untreated or unsatisfactorily treated individuals. Within each quartile of 24-h or office BP, left ventricular mass index adjusted for demographic and biochemical values was similar in reversed white coat versus the remaining subjects. The absence of any association with left ventricular hypertrophy scores against the clinical significance of this phenomenon.