Pietro Amedeo Modesti

Transient intermittent lymphocyte activation is responsible for the instability of angina.

BackgroundBlood clotting activation is an important component of the inflammatory response; the outbursts of unstable angina are usually associated with increased thrombin formation and coronary mural thrombosis. Methods and ResultsTo investigate 1) whether monocyte activation is responsible for the enhanced thrombin formation during bursts of unstable angina and 2) what mechanism(s) might be responsible for monocyte activation, we studied patients with unstable angina (n=31), stable effort angina (n=23), left endoventricular thrombosis (n=8), and control subjects (n=44), measuring plasma fibrinopeptide A (FPA) levels and the capacity of monocytes to express procoagulant activity (PCA) and of lymphocytes to modulate this expression. Patients with unstable angina and patients with endoventricular thrombosis had significantly (p<0.0001) higher FPA plasma levels than patients with effort angina and control subjects. However, only monocytes from unstable angina patients expressed significantly increased PCA characterized as tissue factor-like activity (units/105 monocytes, median and range; 120, 1.1–463.2 versus 10.8, 0.8–39.1 in control subjects; p<0.0001 versus the other groups). When 14 patients with unstable angina were restudied 8–12 weeks later, they showed neither elevated plasma FPA levels nor monocyte PCA. In unstable angina patients, there was a correlation between FPA and PCA (r=0.56, p<0.001). For expression of PCA by monocytes, both an incubation of at least 2 hours with lymphocytes and direct monocyte-lymphocyte contact were needed. In reconstitution and cross-mixing experiments, only lymphocytes from patients with active unstable angina induced the expression ofPCA by monocytes from both control and patient groups. ConclusionsThe results demonstrate that the increased thrombin formation in unstable angina patients is due to the expression of tissue factor-like activity by activated monocytes. The monocyte activation appears to be a part of a lymphocytic cell-instructed response intermittently triggered by unknown factors.

Weather-Related Changes in 24-Hour Blood Pressure Profile. Effects of Age and Implications for Hypertension Management

A downward titration of antihypertensive drug regimens in summertime is often performed on the basis of seasonal variations of clinic blood pressure (BP). However, little is known about the actual interaction between outdoor air temperature and the effects of antihypertensive treatment on ambulatory BP. The combined effects of aging, treatment, and daily mean temperature on clinic and ambulatory BP were investigated in 6404 subjects referred to our units between October 1999 and December 2003. Office and mean 24-hour systolic BP, as well as morning pressure surge, were significantly lower in hot (>90th percentiles of air temperature; 136±19, 130±14, and 33.3±16.1 mm Hg; P<0.05 for all), and higher in cold (<10th percentiles) days (141±12, 133±11, and 37.3±9.5 mm Hg; at least P<0.05 for all) when compared with intermediate days (138±18, 132±14, and 35.3±15.4 mm Hg). At regression analysis, 24-hour and daytime systolic pressure were inversely related to temperature (P<0.01 for all). Conversely, nighttime systolic pressure was positively related to temperature (P<0.02), with hot days being associated with higher nighttime pressure. Air temperature was identified as an independent predictor of nighttime systolic pressure increase in the group of elderly treated hypertensive subjects only. No significant relationship was found between air temperature and heart rate. Our results show for the first time that hot weather is associated with an increase in systolic pressure at night in treated elderly hypertensive subjects. This may be because of a nocturnal BP escape from the effects of a lighter summertime drug regimen and may have important implications for seasonal modulation of antihypertensive treatment.

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.

Role of Endothelin-1 in Exposure to High Altitude Acute Mountain Sickness and Endothelin-1 (ACME-1) Study

Background— The degree of pulmonary hypertension in healthy subjects exposed to acute hypobaric hypoxia at high altitude was found to be related to increased plasma endothelin (ET)-1. The aim of the present study was to investigate the effects of ET-1 antagonism on pulmonary hypertension, renal water, and sodium balance under acute and prolonged exposure to high-altitude–associated hypoxia. Methods and Results— In a double-blind fashion, healthy volunteers were randomly assigned to receive bosentan (62.5 mg for 1 day and 125 mg for the following 2 days; n=10) or placebo (n=10) at sea level and after rapid ascent to high altitude (4559 m). At sea level, bosentan did not induce any significant changes in hemodynamic or renal parameters. At altitude, bosentan induced a significant reduction of systolic pulmonary artery pressure (21±7 versus 31±7 mm Hg, P<0.03) and a mild increase in arterial oxygen saturation versus placebo after just 1 day of treatment. However, both urinary volume and free water clearance (H2OCl/glomerular filtration rate) were significantly reduced versus placebo after 2 days of ET-1 antagonism (1100±200 versus 1610±590 mL; −6.7±3.5 versus −1.8±4.8 mL/min, P<0.05 versus placebo for both). Sodium clearance and segmental tubular function were not significantly affected by bosentan administration. Conclusions— The present results indicate that the early beneficial effect of ET-1 antagonism on pulmonary blood pressure is followed by an impairment in volume adaptation. These findings must be considered for the prevention and treatment of acute mountain sickness.

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.

The onset of symptomatic atrial fibrillation and paroxysmal supraventricular tachycardia is characterized by different circadian rhythms

Abstract Circadian patterns have been demonstrated for several biologic phenomena including cardiovascular diseases such as acute myocardial infarction and sudden death.1 Diurnal distribution of paroxysmal supraventricular arrhythmias has been less extensively investigated,2,3 but only data on hospitalized patients are available. The aim of this study was to find if a diurnal distribution could be identified in the occurrence of the different types of symptomatic supraventricular arrhythmias in patients rescued at home by the Florence Mobile Coronary Care Unit.

Season, temperature and blood pressure: a complex interaction.

An increase in blood pressure values measured during winter either in the office, at home, or at ambulatory blood pressure monitoring was consistently observed. Besides potentially contributing to increase the risk for cardiovascular events during the cold season, long term blood pressure variations can influence results of clinical trials, epidemiological surveys, and require personalized management of antihypertensive medications in the single patient. Those variations are often considered as an effect of climate, due to the close correlation observed in various countries and in different settings between temperature and blood pressure among children, adults, and specially the elderly. However, obtaining true measurements of exposition is a main problem when investigating the effects of climate on human health especially when the aim is to disentangle the effects of climate from those of seasonality. The aim of the present note is not to provide a complete review of the literature demonstrating the implications of seasonal blood pressure changes in the clinical and experimental setting; rather it is to consider methodological aspects useful to investigate the interaction between seasonality and temperature on blood pressure and to make health care providers aware of the implications of environmental factors on blood pressure in clinical and research settings.

Seasonal blood pressure changes: an independent relationship with temperature and daylight hours.

Seasonal blood pressure (BP) changes have been found to be related to either outdoor or indoor temperature. No information regarding the independent effects of temperature measured proximally to the patient, the personal-level environmental temperature (PET), is available. Inclusion of daylight hours in multivariate analysis might allow exploring the independent interaction of BP with seasonality. To investigate whether ambulatory BP monitoring is affected by PET or by seasonality, 1897 patients referred to our hypertension units underwent ambulatory BP monitoring with a battery-powered temperature data logger fitted to the carrying pouch of the monitor. Predictors of 24-hour daytime and nighttime BP and of morning BP surge were investigated with a multivariate stepwise regression model, including age, sex, body mass index, antihypertensive treatment, office BP, ambulatory heart rate, PET, relative humidity, atmospheric pressure, and daylight hours as independent variables. At adjusted regression analysis, daytime systolic BP was negatively related to PET (−0.14; 95% confidence interval, −0.25 to −0.02); nighttime BP was positively related to daylight hours (0.63; 0.37–0.90); and morning BP surge was negatively related to daylight hours (−0.54; −0.87 to −0.21). These results provide new evidence that PET and seasonality (daylight hours) are 2 independent predictors of ambulatory BP monitoring.Seasonal blood pressure (BP) changes have been found to be related to either outdoor or indoor temperature. No information regarding the independent effects of temperature measured proximally to the patient, the personal-level environmental temperature (PET), is available. Inclusion of daylight hours in multivariate analysis might allow exploring the independent interaction of BP with seasonality. To investigate whether ambulatory BP monitoring is affected by PET or by seasonality, 1897 patients referred to our hypertension units underwent ambulatory BP monitoring with a battery-powered temperature data logger fitted to the carrying pouch of the monitor. Predictors of 24-hour daytime and nighttime BP and of morning BP surge were investigated with a multivariate stepwise regression model, including age, sex, body mass index, antihypertensive treatment, office BP, ambulatory heart rate, PET, relative humidity, atmospheric pressure, and daylight hours as independent variables. At adjusted regression analysis, daytime systolic BP was negatively related to PET (−0.14; 95% confidence interval, −0.25 to −0.02); nighttime BP was positively related to daylight hours (0.63; 0.37–0.90); and morning BP surge was negatively related to daylight hours (−0.54; −0.87 to −0.21). These results provide new evidence that PET and seasonality (daylight hours) are 2 independent predictors of ambulatory BP monitoring. # Novelty and Significance {#article-title-25}

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.