C. Monteduro

Cardiovascular Status of Carriers of the Apolipoprotein A-IMilano Mutant The Limone sul Garda Study

BackgroundCarriers of the apolipoprotein A-IMilano (apoA-IM) mutant present with very low plasma HDL cholesterol and moderate hypertriglyceridemia, apparently not leading to premature coronary heart disease. The objective of this study was to establish whether this high-risk lipid/lipoprotein profile is associated with structural changes in the carotid arteries and heart, indicative of preclinical atherosclerosis. Methods and ResultsTwenty-one A-IM carriers were compared with age- and sex-matched control subjects from the same kindred and with 2 series of matched subjects with primary hypoalphalipoproteinemia (HA). Structural changes in the carotid arteries were defined as the intima-media thickness (IMT) measured by B-mode ultrasound. HA subjects, both recruited among patients attending our Lipid Clinic and blood donors, showed significant thickening of the carotids (average IMT, 0.86±0.25 and 0.88±0.29 mm, respectively) compared with control subjects (average IMT, 0.64±0.12 mm); the apoA-IM carriers instead showed normal arterial thickness (average IMT, 0.63±0.10 mm). Moreover, a significantly higher prevalence of atherosclerotic plaques was found in patients and blood donors with HA (both 57%) compared with apoA-IM carriers (33%) and control subjects (21%). Echocardiographic findings and maximal treadmill ECG did not differ significantly between apoA-IM carriers and control subjects, apart from a slight increase in left ventricular end-diastolic dimension in the carriers. ConclusionsDespite severe HA, carriers of the apoA-IM mutant do not show structural changes in the arteries and heart, in contrast to HA subjects, who are characterized by a marked increase in carotid IMT and increased prevalence of atherosclerotic plaques.

Left Ventricular Concentric Geometry During Treatment Adversely Affects Cardiovascular Prognosis in Hypertensive Patients

Abstract—Left ventricular (LV) mass and geometry predict risk for cardiovascular events in hypertension. Regression of LV hypertrophy (LVH) may imply an important prognostic significance. The relation between changes in LV geometry during antihypertensive treatment and subsequent prognosis has not yet been determined. A total of 436 prospectively identified uncomplicated hypertensive subjects with a baseline and follow-up echocardiogram (last examination 72±38 months apart) were followed for an additional 42±16 months. Their family doctor gave antihypertensive treatment. After the last follow-up echocardiogram, a first cardiovascular event occurred in 71 patients. Persistence of LVH from baseline to follow-up was confirmed as an independent predictor of cardiovascular events. Cardiovascular morbidity and mortality were significantly greater in patients with concentric (relative wall thickness ≥0.44) than in those with eccentric geometry (relative wall thickness <0.44) in patients presenting with LVH (P =0.002) and in those without LVH (P =0.002) at the follow-up echocardiogram. The incidence of cardiovascular events progressively increased from the first to the third tertile of LV mass index at follow-up (partition values 91 and 117 g/m2), but for a similar value of LV mass index it was significantly greater in those with concentric geometry (OR: 4.07; 95% CI: 1.49 to 11.14; P =0.004 in the second tertile; OR: 3.45; 95% CI: 1.62 to 7.32; P =0.001 in the third tertile; P <0.0001 in concentric versus eccentric geometry). Persistence or development of concentric geometry during follow-up may have additional prognostic significance in hypertensive patients with and without LVH.

Effects of long-term antihypertensive treatment with lisinopril on resistance arteries in hypertensive patients with left ventricular hypertrophy.

Objective To evaluate the effects of long-term antihypertensive therapy with the angiotensin converting enzyme inhibitor lisinopril on structural alterations and the endothelial function of small resistance arteries in hypertensive patients with left ventricular hypertrophy. Methods Fourteen patients with left ventricular hypertrophy were treated for 3 years with a lisinoprilbased regimen. Patients underwent an echocardiographic evaluation of left ventricular mass index at baseline, during the first and third years of treatment. At the end of the treatment period, subcutaneous small resistance arteries (obtained by biopsy of the subcutaneous fat from the gluteal region) were dissected and mounted on a micromyograph (Mulvanys technique); the media: lumen ratio was then calculated. Data obtained were compared with those observed for 14 untreated essential hypertensive patients and 14 normotensive subjects, ageand sex-matched. Results In the present study, a significantly lower media: lumen ratio was observed in treated compared with untreated hypertensive patients, although it remained significantly higher than that in normotensive subjects. In treated hypertensive patients a significant reduction in clinic blood pressure was observed. However, their blood pressure remained significantly higher than that in normotensive subjects. Significant correlations between the media: lumen ratio and blood pressure, left ventricular mass index or changes in left ventricular mass index during treatment were observed. The response to acetylcholine administration was reduced in untreated hypertensives compared with that in normotensives. In patients treated with lisinopril, the vasodilatation obtained with the two higher doses of acetylcholine was greater than that in untreated hypertensives, thus suggesting an improvement of endothelial function. Conclusions Long-term therapy based on lisinopril was associated with a smaller media: lumen ratio in the subcutaneous small resistance arteries of hypertensive patients with left ventricular hypertrophy. Our retrospective study confirms previous findings obtained in prospective studies with other angiotensin converting enzyme inhibitors. Endothelial function was probably improved by lisinopril therapy.

Effect of Treatment on Flow-Dependent Vasodilation of the Brachial Artery in Essential Hypertension

off aim of our study was to evaluate the effect of antihypertensive treatment on flow-mediated dilation (FMD)of a large artery, a noninvasive estimate of endothelial function, in hypertensive patients. In 78 consecutive hypertensive patients (40%men; age range, 42 to 67 years) we measured by a high-resolution ultrasound system the changes of brachial artery diameter during reactive hyperemia and after sublingual glyceryl trinitrate (400 microg); brachial artery flow velocity was measured by pulsed Doppler. The results of 2 studies are reported. In the first study, this procedure was repeated in 58 patients after 6 and 12 months of treatment with a combination of antihypertensive drugs; in a second study, the FMD was assessed in 20 patients after 2 months of monotherapy with either nifedipine or hydrochlorothiazide. In the first study, FMD was significantly increased after treatment compared with baseline (from 3.1+/-3% at baseline to 6.5+/-4.5% at 6 months and to 8.12+/-4. 6% at 12 months; P<0.001 by ANOVA), concomitant with blood pressure reduction (from 162+/-24/102+/-13 mm Hg to 141+/-12/89+/-6 mm Hg and to 141+/-9/89+/-6 mm Hg; P<0.001 by ANOVA); significant changes of endothelium-independent dilation were also observed, but only after 12 months of treatment (from 14.2+/-4.8 at baseline to 15.5+/-4.7 at 6 months and 16.8+/-5.9% at 12 months; P=0.03 by ANOVA). In the second study, FMD was significantly increased during nifedipine treatment as compared with baseline (from 5+/-6.18% at baseline to 9. 45+/-3.94%, P<0.001), while it did not change in patients receiving hydrochlorothiazide (from 5.15+/-5.28% at baseline to 4.69+/-4.34%, NS). No significant changes of endothelium-independent dilation were observed with both drugs (from 17.10+/-2.4% to 18.14+/-3.76% and from 18.73+/-4.07% to 17.46+/-4.27% during nifedipine and hydrochlorothiazide, respectively, NS). Thus, in essential hypertensive patients an improvement of the impaired FMD of the brachial artery, evaluated by noninvasive ultrasound, may be observed after long-term, effective blood pressure reduction, suggesting a beneficial effect of antihypertensive treatment on endothelial function. It seems that beyond blood pressure control, a calcium antagonist may be more effective than a diuretic in this respect.

Relations Between Cardiac and Vascular Structure in Patients With Primary and Secondary Hypertension

BACKGROUND Data on cardiac and vascular structure in secondary hypertension are generally scarce, and no data on the interrelations between cardiac mass and structural characteristics of the vessel wall, both in large and in small resistance arteries, are presently available. OBJECTIVES The aim of this study was to investigate the relation between structural changes in subcutaneous small arteries, left ventricular mass and wall thickness of the common carotid artery in patients with primary and secondary hypertension. METHODS Seventy-four subjects were included in the study: 11 patients with pheochromocytoma, 14 with primary aldosteronism (PA), 19 with renovascular hypertension (RVH), 18 with essential hypertension (EH) and 12 normotensive (NT) control subjects. All subjects were submitted to a biopsy of subcutaneous fat. Morphologic characteristics of subcutaneous small resistance arteries (relaxed diameter <300 microm) were directly evaluated using a micromyographic technique. All subjects were submitted to calculation of left ventricular mass index (LVMI) and common carotid artery intima-media thickness (CCIMT), using ultrasound technique. RESULTS The correlation coefficients between the media to lumen ratio in subcutaneous small arteries (M/L) and LVMI or between M/L and CCIMT were closer in RVH than in pheochromocytoma, EH or NT; in PA the correlation coefficients were slightly less close than those in RVH. An excess prevalence of carotid plaques in RVH was observed. CONCLUSIONS A close relation between small resistance artery morphology and cardiac or carotid artery structure may be observed in those hypertensive patients in whom the renin-angiotensin-aldosterone system is activated. In constrast, in NT, EH and pheochromocytoma no significant correlation between M/L and LVMI or CCIMT was observed.

Inappropriate Left Ventricular Mass in Patients With Primary Aldosteronism

Assessment of appropriateness of left ventricular mass (LVM) for a given workload may better stratify hypertensive patients. Inappropriate LVM may reflect the interaction of genetic and neurohumoral factors other than blood pressure playing a significant role in myocardial growth. Primary aldosteronism (PA) represents a clinical model useful in assessing the effect of aldosterone increase on LVM. The aim of this study was to evaluate the inappropriateness of LVM in patients with PA. In 125 patients with PA (54 females; adrenal hyperplasia in 73 and adenoma in 52 patients) and in 125 age-, sex-, and blood pressure–matched, essential hypertensive patients, echocardiography was performed. The appropriateness of LVM was calculated by the ratio of observed LVM to the predicted value using a reference equation. In all of the subjects plasma renin activity and aldosterone, as well as clinic and 24-hour blood pressure, were measured. The prevalence of inappropriate LVM was greater in patients with traditionally defined left ventricular hypertrophy (70% and 44%, respectively; P=0.02) but also in patients without left ventricular hypertrophy (17% and 9%, respectively; P=0.085). In PA patients, a correlation was observed between the ratio of observed:predicted LVM and the ratio of aldosterone:plasma renin activity levels (r=0.29; P=0.003) or the postinfusion aldosterone concentration (r=0.44; P=0.004; n=42). In conclusion, in patients with PA, the prevalence of inappropriate LVM is increased, even in the absence of traditionally defined left ventricular hypertrophy. The increase in aldosterone levels could contribute to the increase of LV mass exceeding the amount needed to compensate hemodynamic load.

Prognostic role of flow-mediated dilatation of the brachial artery in hypertensive patients.

Background The prognostic role of endothelial dysfunction, as evaluated by flow-mediated vasodilatation of the brachial artery, has been demonstrated in patients at very high risk. We aimed to investigate whether flow-mediated vasodilatation predicts cardiovascular events in uncomplicated hypertensive patients. Methods and results A total of 172 prospectively identified uncomplicated hypertensive patients (age 56 ± 8 years, 41% women, 48 with diabetes mellitus type 2) were studied. At baseline all patients were untreated and underwent baseline standard laboratory examination. A standard echocardiogram was performed for the evaluation of left ventricular anatomy and function and patients with systolic dysfunction or left ventricular wall motion abnormalities were excluded. Endothelial function was measured as flow-mediated vasodilatation of the brachial artery using high-resolution ultrasound. Patients were followed for 95 ± 37 months (range 2–136 months). A first nonfatal or fatal cardiovascular event occurred in 32 patients. The incidence of cardiovascular events was 1.4 and 3.1 per 100 patient-years in patients with a flow-mediated vasodilatation below and above the median value (4.7%), respectively (P < 0.005 by the log-rank test). In Cox analysis, controlling for age, sex, glycemia, cholesterol, smoking, BMI, systolic and diastolic blood pressure at baseline and left ventricular mass index, a low flow-mediated vasodilatation conferred an increased risk of cardiovascular events (odds ratio 2.67, 95% confidence interval 1.17 to 6.1, P = 0.02). Conclusion The presence of endothelial dysfunction, as evaluated by flow-mediated vasodilatation of the brachial artery, identifies hypertensive patients at increased risk of nonfatal and fatal cardiovascular events.

Endothelial dysfunction in small resistance arteries of patients with non-insulin-dependent diabetes mellitus

Objective Arterial hypertension is frequently associated with the presence of endothelial dysfunction in human subcutaneous small resistance arteries, as evaluated by responses to acetylcholine or bradykinin; however it is not known whether patients with diabetes mellitus show similar alterations. Therefore, we have investigated endothelial function in subcutaneous arteries of normotensive subjects (NT), of patients with essential hypertension (EH), of patients with non-insulin-dependent diabetes mellitus (NIDDM), as well as of patients with both essential hypertension and non-insulin-dependent diabetes mellitus (NIDDM + EH). Patients and methods All subjects were submitted to a biopsy of the subcutaneous fat. Small arteries were dissected and mounted on a micromyograph. The media to lumen ratio (M/L) was calculated. A concentration-response curve to acetylcholine, to bradykinin as well as to the endothelium-independent vasodilator sodium nitroprusside were performed. We also evaluated the contractile response to endothelin-1. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) plasma levels were also measured. Results The vasodilatation to acetylcholine and bradykinin (but not to sodium nitroprusside) was significantly and similarly reduced in EH, in NIDDM, and in NIDDM + EH compared with NT. The contractile response to endothelin-1 was similarly reduced in EH, in NIDDM and in NIDDM + EH. Plasma ICAM-1 and VCAM-1 concentrations were higher in EH, NIDDM and NIDDM + EH than in NT. Conclusions An evident endothelial dysfunction was detected in patients with NIDDM, and the simultaneous presence of EH did not seem to exert an additive effect. The contractile responses to endothelin-1 were reduced possibly as a consequence of ETA receptor down-regulation.

Inappropriate Left Ventricular Mass Changes During Treatment Adversely Affects Cardiovascular Prognosis in Hypertensive Patients

Inappropriate left ventricular mass (LVM; ie, the value of LVM exceeding individual needs to compensate hemodynamic load) predicts the risk of cardiovascular (CV) events, independent of risk factors, either in the presence or in the absence of traditionally defined LV hypertrophy. The relation between changes in appropriateness of LVM during antihypertensive treatment and subsequent prognosis was evaluated in 436 prospectively identified uncomplicated hypertensive subjects, with a baseline and follow-up standard clinical evaluation, laboratory examinations, and echocardiogram (last examination: 6±3 years apart), followed for additional 4.5±2.5 years. The appropriateness of LVM to cardiac workload was calculated by the ratio of observed LVM to the value predicted for individual sex, height, and stroke work at rest. At baseline, low or appropriate LVM (≤128% of predicted) was found in 178 patients, and 258 had inappropriate LVM. A first CV event occurred in 82 patients. Event rate (×100 patient-years) was 3.18 among patients with inappropriate LVM persistence (n=152), 0.97 among patients with inappropriate LVM regression (n=104), 1.87 among patients with inappropriate LVM development (n=75), and 0.81 among patients with persistence of appropriate LVM from baseline to the follow-up (n=105; log-rank test: P=0.0001). Coxs proportional hazard model, considering all of the known CV risk factors, indicated that age, male sex, persistence, or development of inappropriate LVM, in addition to persistence and development of LVH, were independently associated with the occurrence of CV events (P<0.001). The presence of inappropriate LVM during antihypertensive treatment may adversely influence subsequent CV prognosis.

Structural changes in small resistance arteries and left ventricular geometry in patients with primary and secondary hypertension.

Objective To prospectively evaluate the interrelationships between left ventricular (LV) geometry and structural characteristics of the vessel wall in small resistance arteries in patients with consecutive primary and secondary hypertension. Methods In 14 patients with phaeochromocytoma, 12 with primary aldosteronism, 25 with renovascular, 25 with essential hypertension and 12 normotensive controls, an echocardiographic study for the measurement of LV mass index and relative wall thickness (RWT) was performed. Morphological characteristics of small resistance arteries (relaxed diameter < 300 μm) were directly evaluated by a micromyographic technique. Results A total of 25 patients had normal LV mass and geometry, 28 patients had normal RWT (< 0.45) and 23 patients had a RWT ⩾ 0.45; all normotensive subjects had normal LV mass and geometry. Media to lumen ratio (M/L) in subcutaneous small arteries was greater in hypertensive patients with concentric LV hypertrophy in respect to normotensives (ANOVA P = 0.01) and hypertensives with normal LV geometry (ANOVA P = 0.05). In the whole group of hypertensive patients the correlation coefficient between M/L and LV mass index was 0.33 (P < 0.05); the correlation coefficient between M/L and RWT was 0.46 (P < 0.01) and it was higher in primary aldosteronism (r = 0.67) and renovascular hypertension patients (r = 0.46). Conclusions A close relation between morphology of subcutaneous small resistance arteries and LV geometric patterns may be observed in hypertensive patients; this relationship is more evident when the renin–angiotensin–aldosterone system is activated.