Guido Perani

Protective Effects of Carvedilol, a Vasodilating β-Adrenoceptor Blocker, Against in vivo Low Density Lipoprotein Oxidation in Essential Hypertension

Low density lipoprotein (LDL) oxidation plays a crucial role in the development and progression of atherosclerosis and is enhanced in patients with essential hypertension. This finding has stimulated a search for antihypertensive drugs with high intrinsic antioxidant properties. We investigated the antihypertensive and antioxidant effects of carvedilol, a new vasodilating beta-adrenoceptor blocking agent in a group of patients with mild to moderate essential hypertension after 4-month treatment. Carvedilol administration markedly increased the resistance to oxidation of LDL isolated from treated patients to values comparable to those of control, nonhypertensive subjects. This effect was achieved despite a significant loss in LDL-associated vitamin E. The increased resistance of LDL to oxidation promoted by carvedilol was not related to the normalization of previously increased blood pressure (BP). Indeed, the administration of other conventional antihypertensive drugs, capable of decreasing arterial BP but without high intrinsic antioxidant properties, to a control group of matched hypertensive patients failed to ameliorate LDL oxidation parameters. Carvedilol treatment also reduced the extent of in vivo LDL oxidation, as reflected by the decrease in antioxidized LDL autoantibody titer. This effect as well was detected only in the group of carvedilol-treated hypertensive patients and not after the simple reduction in BP obtained with antihypertensive drugs different from carvedilol.

Efficacy and Pharmacokinetics of Simvastatin in Heart Transplant Recipients

Objective: To evaluate the efficacy and safety of simvastatin administered to a group of heart transplant patients receiving triple-drug immunosuppressive therapy. We also assessed the potential pharmacokinetic interaction between simvastatin and cyclosporine by comparing mean plasma concentrations of simvastatin beta-hydroxy acid, the major metabolite of the drug, in a group of heart transplant patients treated with cyclosporine and in a control group of patients who had not received heart transplants. Both groups received long-term (>6 wk) simvastatin therapy. Design: We monitored hyperlipidemia in 20 hypercholesterolemic heart transplant patients receiving simvastatin 10 mg/d and triple-drug immunosuppressive therapy. Changes in laboratory results before and after 4 months of simvastatin therapy were considered. The same laboratory data were monitored in a control group of 20 nonhypercholesterolemic heart transplant patients who were not treated with simvastatin but were receiving triple-drug immunosuppressive therapy. Plasma concentrations of simvastatin beta-hydroxy acid were measured in 14 hypercholesterolemic patients, 7 of whom had received heart transplants and 7 who had not. Setting: The Division of Cardiology and the First Medical Clinic for the clinical study, as well as the Department of Pharmacology for the pharmacokinetic analysis. Participants: Forty heart transplant patients and 7 hypercholesterolemic nontransplant patients. Main Outcome Measures: Effectiveness of simvastatin was determined by comparing cholesterol and lipoprotein plasma concentrations in 20 patients who underwent heart transplant and were treated with simvastatin for 4 months. The safety of the drug was determined by analyzing changes in laboratory results in the treated group and in the control group, both those who had received heart transplants and those who had received immunosuppressive therapy. Results: After 4 months of simvastatin therapy, total cholesterol decreased by 12.5% and low-density lipoprotein cholesterol decreased by 21.3%. The only statistically significant laboratory change was an increase of 28.7% in the alanine aminotransferase concentrations. Plasma concentrations of simvastatin beta-hydroxy acid were higher in heart transplant patients than in those who had not received heart transplants, the control group. Conclusions: Low-dosage simvastatin treatment seems to be safe and sufficiently effective to decrease cholesterol concentrations. Concomitant treatment with immunosuppressive therapy (primarily cyclosporine) in heart transplant patients appeared to cause a reduced metabolic clearance of simvastatin from the plasma. More extensive studies on the interaction between simvastatin and cyclosporine are needed to understand the marked variability found in the response to simvastatin.

Left ventricular function after reversal of myocardial hypertrophy in systemic hypertension, and response to acute increase of afterload by cold pressor test

Using digitized M-mode echocardiography, the left ventricular (LV) response to acute increase in blood pressure after regression of myocardial hypertrophy due to an effective antihypertensive treatment was evaluated. Fifteen hypertensive patients with basal LV hypertrophy (LV mass greater than 230 g, and normal LV diastolic diameter) and normal LV mass after 3 to 4 months of treatment with angiotensin-converting enzyme inhibitors were selected for study. Subjects performed a cold pressor test before and after therapy. LV systolic function was normal in all subjects. LV diastolic function (impaired at basal evaluation in 13 subjects) improved after therapy in all subjects, with normalization in 10. Before treatment, the cold pressor test induced significant increases in blood pressure and heart rate without changes in LV parameters. After regression of hypertrophy, the cold pressor test induced increases in hemodynamic parameters comparable to those of the basal test, and LV parameters remained unchanged. Our results indicate that regression of myocardial hypertrophy induced by angiotensin-converting enzyme inhibitors does not impair the ability of the left ventricle to face acute increases in afterload. The improvement in LV diastolic function (found at rest after reversal of hypertrophy) persists during the cold pressor test, which confirms that it is primarily due to LV mass reduction and is not simply a consequence of decrease in afterload induced by treatment.

Plasminogen activator inhibitor-1 and carotid intima-media thickening in patients with newly detected primary hypertension.

Objective To investigate the correlation between ultrasonographically evaluated intima-media thickness (IMT) of common carotid artery (CCA) and cardiovascular risk factors for subjects with newly detected, uncomplicated and untreated primary hypertension. Methods The study population consisted of 200 subjects (123 men and 77 women, aged 46±7.5 years). Blood pressure was measured in the clinical setting and by 24 h noninvasive ambulatory monitoring. Fasting levels of blood glucose, plasma lipids and lipoproteins, fibrinogen and plasminogen activator inhibitor (PAI)-1 were measured. Ultrasound examination included measurement of far-wall intima-media complex of CCA and morphologic evaluation of occurrence of plaques in carotid and femoral bifurcations. Results The prevalence of greater than normal IMT (mean IMT ≥ 0.80 mm) was 22%. Significant univariate correlations to the dichotomy between normal and greater than normal mean IMT were detected for age, smoking, level of LDL cholesterol, level of PAI-1 and total ultrasonographic score. Multivariate logistic regression analysis confirmed the associations between greater than normal mean IMT and plasma concentrations of LDL cholesterol and PAI-1 as well as total ultrasonographic score. Conclusion Greater than normal IMT of CCA was more strictly related to other cardiovascular risk factors than it was to blood pressure and was strongly associated with the occurrence of atherosclerotic plaques in carotid and femoral arteries. The role of PAI-1 in intima-media thickening that is emerging suggests that fibrinolytic balance is an important determinant of vessel-wall homeostasis in hypertensive patients.

Metabolic effects of the combination of captopril and hydrochlorothiazide in hypertensive subjects

The medium‐term (16 weeks) effects of the combination of captopril and hydrochlorothiazide (HCTZ) on some metabolic indexes, particularly on plasma lipoproteins, were evaluated in 20 mild to moderate hypertensive outpatients.

Correlation of the controlled attenuation parameter with indices of liver steatosis in overweight or obese individuals: A pilot study

Objective The aim of this study was to assess the clinical relevance of the controlled attenuation parameter (CAP) by analyzing the correlations between CAP and indirect indices of liver steatosis in obese or overweight individuals. Methods Consecutive participants were prospectively enrolled. BMI, waist circumference, hepatic steatosis index, fatty liver index, percent fat mass and regional fat masses as assessed by dual-energy X-ray absorptiometry (DXA), fat signal fraction as assessed by MRI, and CAP were obtained. Pearson’s r coefficient was used to test the correlation between two study variables. Results A total of 88 individuals were studied. They included 31 men [age, 50.4 years (12.9 years); BMI, 30.7 kg/m2 (4.8 kg/m2)] and 57 women [age, 49.0 years (12.6 years); BMI, 31.4 kg/m2 (5.6 kg/m2)]. DXA, anthropometric parameters, and fatty liver index were moderately correlated with CAP in men. In women, there was a moderate correlation of CAP with the hepatic steatosis index and anthropometric parameters and only a slight or fair correlation of CAP with DXA parameters. CAP and fat signal fraction showed a good correlation (r=0.65 in men, P=0.002; r=0.68 in women, P=0.0009). Conclusion Measurement of CAP is a reliable method for noninvasive assessment of liver steatosis, showing a correlation with other indirect markers of central obesity and a good correlation with MRI results.

La beta2-microglobulina come marcatore bioumorale di malattia aterosclerotica nelle dislipidemie familiari

Recenti aneddotiche osservazioni hanno posto in relazione le concentrazioni sieriche di beta2-microglobulina (MG) con le malattie vascolari in alcuni gruppi di popolazione. Questo studio si e proposto di indagare i rapporti fra beta2-MG e la malattia aterosclerotica clinica e preclinica in un gruppo di pazienti con dislipidemia di natura genetica. Sono stati arruolati 68 soggetti (M 44, eta media 639 anni) portatori di ipercolesterolemia familiare eterozigote (n=36) o di iperlipidemia familiare combinata (n=32) in trattamento cronico con statine. La presenza di cardiopatia ischemica e stata valutata sulla base della storia clinica, quella di arteriopatia periferica mediante misurazione dell’indice caviglia-braccio (ABI); l’aterosclerosi preclinica e stata indagata tramite misurazione dello spessore intima media (IMT) della parete distale della carotide comune (3 misurazioni per ciascun lato) con ecocolor Doppler. Nove pazienti avevano una storia positiva per cardiopatia ischemica, 6 erano affetti da arteriopatia periferica (ABI 1.30) e 8 presentavano sia cardiopatia ischemica che arteriopatia periferica. Rispetto ai soggetti non vasculopatici, i pazienti con cardiopatia ischemica (p=0.015) e quelli con cardiopatia ischemica associata ad arteriopatia periferica (p<0.001), ma non quelli con arteriopatia periferica isolata, mostravano concentrazioni sieriche di beta2-MG significativamente superiori. La prevalenza sia di malattia coronarica che di arteriopatia periferica mostrava un andamento crescente con i terzili di beta2-MG. I valori individuali di beta2-MG erano significativamente correlati in senso positivo sia con l’IMT medio (r=0.357, p<0.01) che con l’IMT massimo (r=0.350, p<0.01). Nei pazienti con dislipidemia familiare trattati con statine le concentrazioni sieriche di beta2-MG possono essere considerate un marcatore bioumorale di malattia aterosclerotica clinica e preclinica, anche se l’associazione della beta2-MG con l’arteriopatia periferica e dipendente dalla contemporanea presenza di cardiopatia ischemica.

La sindrome metabolica è un fattore di rischio cardiovascolare anche nell’ipercolesterolemia familiare?

Questo studio si e proposto di indagare l’importanza della sindrome metabolica nell’espressione fenotipica dell’ipercolesterolemia familiare eterozigote per quanto riguarda la cardiopatia ischemica clinicamente espressa e le manifestazioni precliniche di malattia aterosclerotica a livello dei distretti carotideo e periferico. Sono stati studiati 186 pazienti (85 uomini) di eta media 54.9 +/- 11.5 anni, affetti da ipercolesterolemia familiare eterozigote definita o probabile secondo i criteri NICE. La sindrome metabolica era presente in 41 soggetti (22%). Rispetto ai pazienti senza sindrome metabolica, quelli con sindrome metabolica associata mostravano eta, BMI, circonferenza addominale, trigliceridemia, glicemia, pressione sistolica e diastolica (p<0.001 per tutte le variabili) significativamente superiori e concentrazioni di C-HDL significativamente inferiori (p<0.001). La prevalenza di cardiopatia ischemica era significativamente superiore nei soggetti con sindrome metabolica (p=0.009 negli uomini e p=0.043 nelle donne); l’analisi stratificata per l’eta ha mostrato che tale differenza era significativa solo per i soggetti appartenenti al terzile inferiore di eta. Nessuna differenza e stata osservata nella prevalenza di placche carotidee all’esame ultrasonografico e di ABI <0.90 in rapporto alla presenza di sindrome metabolica. I risultati ottenuti indicano che la sindrome metabolica gioca un ruolo importante nell’estrinsecazione clinica della cardiopatia ischemica nell’ipercolesterolemia familiare eterozigote, anche se gia in trattamento con statine, specie nei soggetti piu giovani.

Significato clinico e prognostico degli xantomi tendinei nell’ipercolesterolemia familiare

Gli xantomi tendinei sono un reperto obiettivo di frequente riscontro nell’ipercolesterolemia familiare eterozigote, tanto da fungere da importante criterio diagnostico; non e chiaro tuttavia se la loro presenza si associ ad un rischio cardiovascolare particolarmente elevato. Lo scopo di questo studio e stato quello di verificare l’associazione degli xantomi tendinei con la malattia aterosclerotica clinica e preclinica in un gruppo di 242 pazienti (110 uomini e 142 donne, eta media 52.2 +/- 14.2 anni) affetti da ipercolesterolemia familiare eterozigote, diagnosticata secondo i criteri del NICE inglese. La prevalenza di xantomi tendinei e stata del 44.4%, senza differenze fra i due generi, superiore nei pazienti di eta >50 rispetto a quelli di eta >50 anni (52.4% vs 36.7%, p=0.012). La presenza di xantomi si e significativamente associata alla presenza di cardiopatia ischemica clinicamente manifesta (p<0.001 negli uomini, p=0.003 nelle donne) e di placche carotidee all’esame ultrasonografico dei tronchi sopraaortici nel genere maschile (p=0.004). La prevalenza di ABI patologico e stata superiore, ma non significativamente, nei pazienti con xantomi. All’epoca della diagnosi, i pazienti con xantomi erano piu anziani (p=0.009 negli uomini, p=0.049 nelle donne) e mostravano concentrazioni di colesterolo totale (p=0.025 negli uomini e p<0.001 nelle donne) e C-LDL (p=0.003 e p<0.001) significativamente superiori rispetto ai pazienti senza xantomi. Le donne con xantomi avevano anche livelli inferiori di C-HDL (p=0.028). Alla piu recente osservazione, i pazienti con xantomi tendinei differivano da quelli senza xantomi per eta superiore (p=0.006 negli uomini e p=0.015 nelle donne), maggior prevalenza di ipertensione arteriosa fra le donne (p=0.024), livelli di C-HDL inferiori (p=0.031 e p=0.018 nei due generi). Nel complesso i risultati depongono per un ruolo preminente del carico di C-LDL lungo l’arco della vita nel condizionare lo sviluppo sia di aterosclerosi che di xantomi tendinei nei pazienti con FH eterozigote. Gli xantomi tendinei possono quindi aiutare a identificare i soggetti a rischio particolarmente elevato.