Maria Boddi

Effect of heparin, aspirin, or alteplase in reduction of myocardial ischaemia in refractory unstable angina

399 out of 474 inpatients with unstable angina were monitored for 48 h and 97 of these were found to be refractory to conventional antianginal treatments and entered a randomised double-blind study. With the initial protocol heparin infusion or bolus were compared with aspirin; with a modified protocol, heparin infusion, the best of these three treatments, was compared with alteplase. Patients were monitored for 3 days after starting treatment and then observed clinically for 4 more days. On the first days of treatment heparin infusion significantly decreased the frequency of angina (by 84-94%), episodes of silent ischaemia (by 71-77%), and the overall duration of ischaemia (by 81-86%). Heparin bolus and aspirin were not effective. Alteplase caused small (non-significant) reductions on the first day only. Only minor bleeding complications occurred.

Cardiac Growth Factors in Human Hypertrophy Relations With Myocardial Contractility and Wall Stress

The aim of the present study was to investigate whether and which cardiac growth factors are involved in human hypertrophy, whether growth factor synthesis is influenced by overload type and/or by the adequacy of the hypertrophy, and the relationships between cardiac growth factor formation and ventricular function. Cardiac growth factor formation was assessed by measuring aorta-coronary sinus concentration gradient in patients with isolated aortic stenosis (n=26) or regurgitation (n=15) and controls (n=12). Gene expression and cellular localization was investigated in ventricular biopsies using reverse transcriptase-polymerase chain reaction and in situ hybridization. Cardiac hypertrophy with end-systolic wall stress <90 kdyne/cm2 was associated with a selective increased formation of insulin-like growth factor (IGF)-I in aortic regurgitation and of IGF-I and endothelin (ET)-1 in aortic stenosis. mRNA levels for IGF-I and preproET-1 were elevated and mainly expressed in cardiomyocytes. At stepwise analysis, IGF-I formation was correlated to the mean velocity of circumferential fiber shortening (r=0.86, P<0.001) and ET-1 formation to relative wall thickness (r=0.82, P<0. 001). When end-systolic wall stress was >90 kdyne/cm2, IGF-I and ET-1 synthesis by cardiomyocytes was no longer detectable, and only angiotensin (Ang) II was generated, regardless of the type of overload. The mRNA level for angiotensinogen was high, and the mRNA was exclusively expressed in the interstitial cells. Ang II formation was positively correlated to end-systolic stress (r=0.89, P<0.001) and end-diastolic stress (r=0.84, P<0.001). Multivariate stepwise analysis selected end-systolic stress as the most predictive variable and left ventricular end-diastolic pressure as the independent variable for Ang II formation (r=0.93, P<0.001). In conclusion, the present results indicate that the course of human left ventricular hypertrophy is characterized by the participation of different cardiac growth factors that are selectively related both to the type of hemodynamic overload and to ventricular function.

Hepatitis C virus RNA localization in human carotid plaques.

BACKGROUND Hepatitis C virus (HCV) infection has certain characteristics that enable it to play an important role in atherosclerosis. Some studies report its association with an increased risk of carotid artery plaque. OBJECTIVES The aim of this study was to evaluate the presence of HCV genomic sequences and replicative intermediates in plaque tissues. STUDY DESIGN A cohort of consecutive, prospectively recruited patients with HCV infection and chronic ischemic heart disease from the Cardiology, Vascular Surgery and Hepatology Units of a University Hospital in Florence, Italy, were studied. RESULTS Positive-strand HCV RNA was detected in seven carotid plaque tissues from anti-HCV-positive patients and was not detected in the nine carotid plaque tissues obtained from anti-HCV-negative patients. In three patients, HCV RNA was found in carotid plaque and not in serum. HCV replicative intermediates were detected in three plaque samples. Direct sequencing of HCV RNA from the plaque and serum showed HCV genotypes 2 (five cases) and 1 (two cases). CONCLUSIONS The novel finding of HCV RNA sequences in plaque tissue strongly suggests an active local infection. This in turn makes it conceivable that the virus may exert local action in carotid atherosclerosis.

Selective Upregulation of Cardiac Endothelin System in Patients With Ischemic but Not Idiopathic Dilated Cardiomyopathy: Endothelin-1 System in the Human Failing Heart

Only scarce information is available on the activity and modifications of the cardiac endothelin (ET)-1 system in heart failure due to ischemic (ICM) or idiopathic dilated (DCM) cardiomyopathy. The activity of the ET-1 system was investigated by measuring cardiac ET-1 and big ET-1 formation and quantifying cardiac mRNA for prepro-ET-1 (ppET-1), ET-converting enzyme-1, and ET(A) and ET(B) receptors both in myocardium and in isolated myocytes using Northern blot, reverse transcription-polymerase chain reaction, and in situ hybridization in 22 patients with DCM and 20 with ICM who underwent cardiac transplantation and in 7 potential heart transplant donors (nonfailing hearts). Notwithstanding a similar increase of plasma ET-1 in the 2 groups, cardiac ET formation, mRNA levels for ppET-1, and ET(A) and ET(B) receptors were higher on both the myocardium and isolated myocytes from ICM than on those from DCM hearts (P<0.001 for all). ppET-1 and ET-converting enzyme-1 mRNAs were expressed on myocytes and endothelial and interstitial cells in ICM, whereas in DCM and nonfailing hearts they were mainly expressed on nonmyocyte cells. In both ICM and DCM, the ET(A) mRNA signal was expressed on both myocytes and nonmyocyte cells, whereas ET(B) mRNA was almost exclusively localized on nonmyocyte cells. ET(A)- and ET(B)-specific receptor binding was increased on both myocytes and cardiac membranes, showing a positive correlation with left ventricular ejection fraction in ICM (r=0.78 and 0.70) but not in DCM patients. The present results show that human ventricular myocytes express all of the components of the ET-1 system, which is selectively upregulated in ICM patients and appears to be functionally important in the maintenance of cardiac function.

Evidence for the Existence of a Functional Cardiac Renin-Angiotensin System in Humans

BACKGROUND The presence of mRNA for the essential components of the renin-angiotensin system (RAS) has been found in animal and human hearts. The present study was designed to provide evidence for the existence of a (functional) cardiac RAS. METHODS AND RESULTS Twenty-four patients with atypical chest pain undergoing coronary angiography for diagnostic purposes were investigated. The cardiac production rate of angiotensins was estimated by measurement of the cardiac extraction of 125I-angiotensin I and 125I-angiotensin II associated with the determination of endogenous angiotensins in aortic and coronary sinus blood in normal, low, or high sodium diets. In a normal sodium diet, angiotensin I and II aorta-coronary sinus gradients were tendentially negative (-1.8 +/- 2.5 and -0.9 +/- 1.7 pg/mL, respectively), and the amounts of angiotensin I and II added by cardiac tissues were 6.5 +/- 3.1 and 2.7 +/- 1.3 pg/mL, respectively. The low sodium diet caused a significant increase in both plasma renin activity (PRA) and angiotensin I concentration in aortic but not in coronary sinus blood, resulting in a more negative aorta-coronary sinus gradient (-9.7 +/- 3.1 pg/mL, P < .01). Angiotensin formation by PRA in blood during transcardiac passage increased (P < .001), whereas angiotensin I formed by cardiac tissues decreased dramatically. Accordingly, in the low sodium diet, 125I-angiotensin II extraction did not change, the cardiac fractional conversion rate of 125I-angiotensin I to 125I-angiotensin II notably decreased (P < .01), and angiotensin II formation by cardiac tissues was undetectable. The high sodium diet caused a decrease in PRA and no changes in cardiac extraction of radiolabeled angiotensins; conversely, angiotensin I formed by cardiac tissues, cardiac Ang I fractional conversion rate, and angiotensin II formed during transcardiac passage significantly (P < .01 for all) increased. CONCLUSIONS These results provide evidence for the existence of a functional cardiac RAS independent of but related to the circulating RAS.

Human Vascular Renin-Angiotensin System and Its Functional Changes in Relation to Different Sodium Intakes

A growing body of evidence supports the existence of a tissue-based renin-angiotensin system (RAS) in the vasculature, but the functional capacity of vascular RAS was not investigated in humans. In 28 normotensive healthy control subjects, the metabolism of angiotensins through vascular tissue was investigated in normal, low, and high sodium diets by the measurement of arterial-venous gradient of endogenous angiotensin (Ang) I and Ang II in two different vascular beds (forearm and leg), combined with the study of 125I-Ang I and 125I-Ang II kinetics. In normal sodium diet subjects, forearm vascular tissue extracted 36+/-6% of 125I-Ang I and 30+/-5% of 125I-Ang II and added 14.9+/-5.1 fmol x 100 mL(-1) x min(-1) of de novo formed Ang I and 6.2+/-2.8 fmol x 100 mL(-1) x min(-1) of Ang II to antecubital venous blood. Fractional conversion of 125I-Ang I through forearm vascular tissue was about 12%. Low sodium diet increased (P<.01) plasma renin activity, whereas de novo Ang I and Ang II formation by forearm vascular tissue became undetectable. Angiotensin degradation (33+/-7% for Ang I and 30+/-7% for Ang II) was unchanged, and vascular fractional conversion of 125I-Ang I decreased from 12% to 6% (P<.01). In high sodium diet subjects, plasma renin activity decreased, and de novo Ang I and Ang II formation by forearm vascular tissue increased to 22 and 14 fmol x 100 mL(-1) x min(-1), respectively (P<.01). Angiotensin degradation did not significantly change, whereas fractional conversion of 125I-Ang I increased from 12% to 20% (P<.01). Leg vascular tissue functional activities of RAS paralleled those of forearm vascular tissue both at baseline and during different sodium intake. These results provide consistent evidence for the existence of a functional tissue-based RAS in vascular tissue of humans. The opposite changes of plasma renin activity and vascular angiotensin formation indicate that vascular RAS is independent from but related to circulating RAS.

Age-related changes in the hemostatic system

SummaryThe increased incidence of arterial thromboembolism in the elderly has prompted investigation of age-related changes in the hemostatic system. Aging is associated with increased plasma levels of fibrinogen, factor VII and factor VIII, which have been shown to be risk factors for thrombotic disease in five large epidemiological studies. An increased responsiveness to different aggregating stimuli, elevated levels of β-thromboglobulin and an increased production of thromboxane A2 were reported in the platelets of the elderly. These alterations are associated with modifications of platelet membrane lipid composition (namely an increase in the cholesterol/phospholipid ratio and a decrease in linoleic acid) with possible related changes in membrane fluidity. Moreover, a decrease in the number of platelet prostacyclin and thromboxane A2 receptors was observed with aging. Fibrinolytic activity is impaired in the elderly, probably due to an increase in plasminogen activator inhibitor 1. Interestingly, hypercoagulability has been demonstrated by an increase in the activation markers of the coagulation cascade (mainly fibrinopeptide A and prothrombin activation fragment F 1+2). Finally, clinical and experimental evidence suggests that endothelium could play a central role in hemostatic alterations which determine a thrombophilic state in the elderly.

Age-related and vasomotor stimuli-induced changes in renal vascular resistance detected by Doppler ultrasound

Indirect measurement of renal vascular resistance by duplex Doppler waveform analysis was evaluated in relation to aging and some pathophysiological conditions. Baseline renal resistive index (RRI) (peak systolic frequency shift - lowest diastolic frequency shift/peak systolic frequency shift) was measured in healthy controls aged 20 to 85 years by analyzing the blood flow velocity waveform of interlobar arteries. RRI changes induced by sympathetic activation (cold pressor test and handgrip test) or by fluid load were evaluated. Both repeatability and reproducibility were very good, as the intra and interoperator variations were all less than their reproducibility coefficients. RRI showed a significant increase with aging (ANOVA P < .001), particularly evident in subjects older than 50 years. Both the cold pressor test and handgrip test induced in all the subjects (n = 16) a significant increase in RRI (P < .001), from 0.59 +/- 0.04 to 0.69 +/- 0.04 (12 +/- 6%) for the cold pressor test and from 0.57 +/- 0.03 to 0.66 +/- 0.03 (15 +/- 2%) for the handgrip test. In eight subjects intravenous fluid load (0.25 mL/kg/min of 0.9% NaCl for 120 min) caused a significant decrease in RRI (P < .001), from 0.62 +/- 0.02 to 0.53 +/- 0.01 (17 +/- 2%), which was inversely related to mean blood pressure rise (r = 0.71, P < .001). These data show that pulsed wave Doppler analysis is an accurate method for an indirect evaluation of changes in renal vascular resistance induced by common vasomotor stimuli.

Different Growth Factor Activation in the Right and Left Ventricles in Experimental Volume Overload

Abstract—Mechanical factors play a key role in activation of cardiac growth factor response in hemodynamic overload, and both cooperate in myocardial remodeling. The present study was performed to investigate whether a different growth factor response is activated in the right and left ventricles in aortocaval fistula and its effects on regional myocardial adaptation. Relations between regional growth factor expression (angiotensin II, insulin-like growth factor-I, and endothelin-1), myocyte shape changes, and collagen deposition were investigated at mRNA and peptide levels in adult pigs after the creation of an aortocaval fistula distal to the renal arteries (n=15) and in sham-operated animals (n=15). The role of angiotensin II was investigated by the administration of angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist. In the left ventricle, pure volume overload was accompanied by persistent increase of insulin-like growth factor-I mRNA expression, peptide concentration (2.2-fold versus sham at 3 months, P <0.05), and significant increase of myocyte length (+29% at 3 months, P <0.05). Conversely, the mixed pressure-volume overload faced by the right ventricle resulted in significant regional overexpression of all growth factors investigated (angiotensin II, insulin-like growth factor-I, and endothelin-1), with corresponding increase of myocyte diameter and length and collagen deposition (+117% at 3 months). Collagen accumulation in the right ventricle as well as the increase in right ventricular end-diastolic pressure at the 3-month observation were inhibited by angiotensin II antagonism. The left and right ventricles respond differently to aortocaval fistula, and local growth factor expression is closely related to the regional myocardial adaptation.

HCV infection facilitates asymptomatic carotid atherosclerosis: preliminary report of HCV RNA localization in human carotid plaques

BACKGROUND Clinical and experimental evidence suggests that hepatitis C virus (HCV) infection shows peculiar characteristics that strongly support a role in the development of atherosclerosis. We aimed to investigate whether (a) HCV infection can facilitate asymptomatic carotid lesions and (b) the presence of HCV RNA sequences can be shown in plaque tissues. METHODS The status of carotid arteries, studied as intima-media thickness (IMT) in carotid bifurcation and prevalence and severity of plaques in internal carotid artery, was investigated by high-resolution B-mode ultrasonography in 31 HCV seropositive (HCV+) and in 120 age-matched HCV seronegative (HCV-) subjects evaluated for cardiovascular risk factors. The atherosclerotic risk profile, inflammation markers and main liver function tests were also studied in all patients. HCV RNA sequences were investigated by highly sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) in plaque tissues and serum of 2 HCV+ patients who underwent carotid revascularization. RESULTS Genomic and antigenomic HCV RNA strands were evidenced within both the carotid plaque tissues examined. The prevalence of an IMT > 1 mm, but not the prevalence and severity of internal carotid plaques, was significantly higher (P < 0.001) in HCV+ than in HCV patients. The atherosclerotic risk profile for traditional and inflammatory factors did not differ between the HCV+ and HCV- groups. Main liver function tests did not differ between the two groups. HCV positivity was significantly associated with >1 mm IMT (P < 0.01) according to univariate analysis, and this association remained significant in multivariate regression analysis. CONCLUSIONS The novel finding of HCV RNA sequences within carotid plaques suggests a local pro-atherogenetic action of the virus inside the plaque. On the whole our data strongly support that HCV infection facilitates the occurrence of carotid atherosclerotic lesions.