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BACKGROUND: We assessed the hemodynamic effects of isometric exercise by an ambulatory radionuclide monitoring device (VEST) that measured left ventricular function in patients who had hypertrophic cardiomyopathy (HCM), with and without significant left ventricular outflow-tract obstruction at rest, compared with control subjects. METHODS AND RESULTS: We studied 10 patients with obstructive HCM, 25 patients with nonobstructive HCM, and 11 control subjects. During VEST monitoring, all patients gripped a dynamometer at 75% of maximal strength for up to 5 minutes. End-diastolic, end-systolic, and stroke volumes; cardiac output; and systemic vascular resistance were expressed as a percentage of baseline. The mean exercise duration was similar among the 3 groups. During handgrip, heart rate, systolic blood pressure, and cardiac output increased significantly and similarly in the 3 groups. There was a significant difference in the lung activity between obstructive and nonobstructive HCM patients and control subjects (P

Electromagnetic interference (EMI) and electromagnetic compatibility (EMC) are problems that increasingly claim the attention of the biomedical industry all over the world. The potential risk of interaction between radiofrequencies of transmitters and medical devices is well documented and frequently reported in the scientific press [1–7]. In a technogically advanced world, radiating EMIs are omnipresent at home, work and other everyday environments (Table 1). They are spread by different modes (Table 2), such as electrical lines or cables, electrostatic induction, electromagnetic radiation, intentional transmitters (radar, radio, TV and satellite transmissions, mobile telecommunication systems, scientific equipment) and unintentional transmitters (induction heaters, electrical equipment, car ignition systems, diathermy generators), and they constitute the main source of disturbance to active medical devices equipped with an electrical circuit prone to detect them.

Coexistence of peripheral arterial disease (PAD) and coronary artery disease (CAD) is common. PAD worsens the prognosis of patients with and without CAD. Thus, patients with PAD should be treated for secondary prevention, regardless of the diagnosis of CAD. PAD should be sought in smokers or diabetics aged between 59 and 69 years, in those older than 70 years, in those with known atherosclerotic disease, and in those with suspicion of PAD. As a screening tool, Doppler measurement of the ratio between ankle and arm pressures offers the best approach. Conversely, pharmacological stress imaging should be employed to rule out CAD in PAD patients. Treatment of PAD implies risk factor modification, especially smoking cessation and lipid profile. Pharmacological treatments include preventive drugs and drugs that affect claudication. Unfortunately, few drugs have been proven effective for the latter. These include cilostazol and propionyll-camitine, which ameliorates symptoms and quality of life. It remains unresolved whether different treatment strategies for coexistent CAD impact favourably on prognosis in these problematic patients.

The regulation of gene expression by cell surface receptors often involves the stimulation of signaling pathways including one or more members of the MAPK superfamily of serine-threonine kinases. Upon their activation in the cytosol, MAPKs can translocate to the nucleus and affect the activity of a variety of transcription factors. Recently, it has been observed that a novel member of the MAPK superfamily, ERK5, can be potently activated by transforming G protein-coupled receptors (GPCRs) and that ERK5 participates in the regulation of c-jun expression through the activation of MEF2 transcription factors. How cell surface receptors, including GPCRs, stimulate ERK5 is still poorly understood. In this study, we have used transiently transfected COS-7 cells to begin delineating the biochemical route linking GPCRs to ERK5. We show that receptors that can couple to the G(q) and G(12/13) families of heterotrimeric G proteins, m1 and thrombin receptors, respectively, but not those coupled to G(i), such as m2 receptors, are able to regulate the activity of ERK5. To investigate which heterotrimeric G proteins signal to ERK5, we used a chimeric system by which Galpha(q)- and Galpha(13)-mediated signaling pathways can be conditionally activated upon ligand stimulation. Using this system, as well as the expression of activated forms of G protein subunits, we show that the Galpha(q) and Galpha(12/13) families of heterotrimeric G proteins, but not the Galpha(i), Galpha(s), and betagamma subunits, are able to regulate ERK5. Furthermore, we provide evidence that the stimulation of ERK5 by GPCRs involves a novel signaling pathway, which is distinct from those regulated by Ras and Rho GTPases.

In the last few years the hypothesis of coronary thrombosis, frequently triggered by plaque ulceration or fissuration, has gained wide acceptance as one of the key events in the pathophysiology of acute coronary syndromes. Plaque ulceration may activate both platelets and the coagulation cascade via exposure of a variety of substances, such as von Willebrand factor and tissue factor. It has been demonstrated that aspirin reduces mortality and improves the prognosis of patients with such syndromes. More recently, newer drugs have been identified for the treatment of acute coronary syndromes; in particular, platelet glycoprotein IIb/IIIa inhibitors have been found to be more effective than aspirin in a variety of clinical conditions, such as unstable angina, acute myocardial infarction, and coronary angioplasty. Other drugs with different mechanisms of action will be soon available for large scale clinical trials.

Patients with atherosclerosis, valvular, ischemic, and dilatative cardiomyopathies, or atrial fibrillation, and those with a cardiac valvular prothesis, by-pass, pacemaker, or ICD, may be subject to thrombotic or thromboembolic events (TEEs). TEEs associated with the implantation or chronic presence of permanent pacing leads have been described in many case reports but are actually considered a relatively uncommon complication of cardiac pacing [1]. TEEs have traditionally been reported as a late problem (more than 1 month after implantation of a pacemaker or ICD), and embolic complications have been reported as occurring at any time following implantation. However, venous obstruction can also occurr soon after implantation [2, 3]. Venous stenosis and thrombosis after permanent cardiac pacing are probably more common than previously thought because most patients remain asymptomatic and the condition remains undetected. An understanding of the thromboembolic complications of transvenous cardiac pacing is important because prompt diagnosis and therapy may diminish the potential for morbidity and mortality. The pathogenesis of venous thrombosis after implantation of a permanent transvenous pacemaker or ICD has not been clearly determined. Possible causes of early thrombosis include the following: 1. Extrusion of thrombus from the ligated vein (especially with the cephalic vein approach) 2. Lead entry site 3. Lead-induced endothelial trauma, which causes local release of coagulation factors 4. Hypercoagulability induced by the surgical procedure 5. Atrioventricular asynchronism that causes numerous atrial contractions against closed atroventricular valves (this mechanism is even more significant in patients with 1:1 ventricular retrograde conduction) 6. Presence of the lead in the right ventricle 7. Old age in patients with pacemaker or ICD 8. Interventricular and intraventricular asynchronism of contraction. Venous thrombosis that occurs more than 1 year after implantation of a permanent transvenous pacemaker is usually associated with underlying venous stenosis, which may result from fibrosis of preexistent venous thrombi. The long-term residence of a permanent lead in the venous system may also act a continuing nidus for formation of a thrombus [4–6]. The presence of multiple transvenous pacemaker leads, especially if one is severed, also increases the risk of thrombosis [7, 8]. In addition, the pacing lead may produce a foreign-body type of reaction and subsequent inflammation and fibrosis along the course of the lead. In some reports on the evaluation of antiplatelet therapy and platelet aggregability in patients with pacing [9,10], Fazio et al. have shown an increase of TEEs (fatal and nonfatal stroke, fatal and nonfatal myocardial infarction, inferior limb thromboembolism) in patients treated with antiplatelet therapy compared to those not so treated (p < 0.05) [9]; they have shown a significant increase of β-Tromboglobulin (β-Tg) in paced patients with respect to controls. Even if their data do not conclusively demonstrate a precise causal relationship between platelet activation and increase of TEEs in patients with pacemakers or ICDs, they strongly suggest that antiplatelet drugs could represent a pathogenic treatment in these patients.

E-cadherins are surface adhesion molecules localized at the level of adherens junctions, which play a major role in cell adhesiveness by mediating calcium-dependent homophylic interactions at sites of cell-cell contacts. Recently, E-cadherins have been also implicated in a number of biological processes, including cell growth and differentiation, cell recognition, and sorting during developmental morphogenesis, as well as in aggregation-dependent cell survival. As phosphatidylinositol (PI) 3-kinase and Akt play a critical role in survival pathways in response to both growth factors and extracellular stimuli, these observations prompted us to explore whether E-cadherins could affect intracellular molecules regulating the activity of the PI 3-kinase/Akt signaling cascade. Using Madin-Darby canine kidney cells as a model system, we show here that engagement of E-cadherins in homophylic calcium-dependent cell-cell interactions results in a rapid PI 3-kinase-dependent activation of Akt and the subsequent translocation of Akt to the nucleus. Moreover, we demonstrate that the activation of PI 3-kinase in response to cell-cell contact formation involves the phosphorylation of PI 3-kinase in tyrosine residues, and the concomitant recruitment of PI 3-kinase to E-cadherin-containing protein complexes. These findings indicate that E-cadherins can initiate outside-in signal transducing pathways that regulate the activity of PI 3-kinase and Akt, thus providing a novel molecular mechanism whereby the interaction among neighboring cells and their adhesion status may ultimately control the fate of epithelial cells.

The ECG stress test represents the most commonly-used technique to evaluate the occurrence of nitroglycerin tolerance. It acts by increasing cardiac O2 demand with resulting insufficient blood flow through a stenotic coronary artery and development of cardiac ischemia. However, other tests are also potentially suitable, such as the ECG-dipyridamole test. The aim of the present study was to evaluate the acute response of ECG-dipyridamole and ECG-stress tests to nitroglycerin. In particular, the development of nitroglycerin tolerance during chronic therapy was evaluated with both tests in patients with stable angina. Eleven patients (8 men and 3 women) with CAD proven by a previous coronarography, a known history of stable angina within at least six months and a positive response to both the tests were studied. At the end of a seven-day wash-out period, all patients were positive to initial ECG-stress and ECG-dipyridamole tests; after 3 days a new evaluation was carried out (Effort 0 and Dip 0) and this confirmed the previous results. We performed a randomized trial in two phases: acute and chronic therapy. In the acute phase, all patients underwent ECG-stress and ECG-dipyridamole tests (Effort 1 and Dip 1) in a randomized fashion one day apart, four hours after administration of a 10 mg/24 h nitroglycerin patch. The chronic phase consisted of 25 days of continuous treatment with a nitroglycerin patch. The two tests (Effort 2 and Dip 2) were always repeated after four hours of the morning therapy. Nitroglycerin does not modify the hemodynamic response to dipirydamole in either acute or chronic treatment. Lastly, our data confirm the efficacy of nitroglycerin on stress and dipyridamole tests after acute administration. Nitroglycerin tolerance is confirmed by both tests although with different patterns. ECG stress test showed nitroglycerin tolerance because time to ischemia and max ST deteriorated during chronic therapy. Moreover, the ECG-dipyridamole test showed nitroglycerin tolerance because five patients with a negative acute test (Dip 1) became positive during chronic therapy (Dip 2).

In recent years 201thallium scintigraphy at rest has been used for evaluating myocardial viability in patients with chronic ischemic coronary artery disease and left ventricular dysfunction. Based on the assumption that reversible myocardial dysfunction arises from chronic hypoperfusion (hibernation), resting 201thallium scintigraphy is performed by acquiring two sets of images, one early after tracer injection and a second following 3 to 4 hours to allow for the redistribution process to take place. However, redistribution of 201thallium following injection at rest rarely occurs, and in many studies it does not significantly contribute to the identification of reversibly dysfunctional myocardium. In fact, current interpretation of resting 201thallium scintigraphy is based on the measurement of regional tracer uptake on the redistribution images, using a fixed threshold value (most commonly from 50 to 65% of maximal uptake) that arbitrarily identify viable (presumably reversible) and nonviable (presumably irreversible) dysfunctional myocardium. The practical implication of this approach is relevant as it implies that analysis of a single set of images is adequate for viability information. As with other nuclear techniques, sensitivity of 201thallium scintigraphy for predicting functional recovery following revascularization is very high, but specificity is suboptimal, reflecting the identification of substantial residual tracer uptake in territories that will remain dysfunctional at rest following successful revascularization. Inadequate timing of follow-up functional evaluation, ongoing degeneration of hibernating myocytes, admixture of necrotic and normal myocardium in dysfunctional areas are among factors that likely explain this discrepancy. It remains to be evaluated in future studies whether revascularization of these areas that contain viable myocardium but where resting function does not change, may also contribute to the beneficial effects of revascularization in patients with left ventricular dysfunction.

The asynchrony of the left ventricle--i.e., its nonuniform contraction and relaxation--is an important factor for left ventricular function. Heart failure is often related to abnormal systolic function, sometimes associated with a diastolic dysfunction. We studied the relationship of left ventricular asynchrony to left ventricular function in patients with nonischemic heart failure.Radionuclide angiography at rest was performed in 25 patients with nonischemic heart failure and in 26 age and sex matched normal subjects. In addition to ejection fraction and peak filling rate, two indices of left ventricular asynchrony were calculated: the coefficient of variation of regional time to end systole and the coefficient of variation of regional time to peak filling rate. These factors indicate how disperse are the regional values of time to end systole and of time to peak filling rate. In fact, the higher the value, the greater the asynchrony.A significant (r = .46, p.05) inverse correlation was found between the ejection fraction and the coefficient of variation of regional time to end systole in both the normal subjects and the heart failure patients, while the ejection fraction correlated significantly (r = .46, p.05) with the coefficient of variation of regional time to peak filling rate only in the patients. Moreover, the peak filling rate was inversely correlated (r = .57, p.05) with the coefficient of variation of regional time to peak filling rate in the heart failure patients but not in the normal subjects.These results suggest that left ventricular systolic and diastolic asynchrony may contribute to impair left ventricular systolic and diastolic function in patients with nonischemic heart failure.

New effective therapies have been producing longer survival times for HIV-patients. Thus non-infectious complications of late stage of HIV infection (such as the development of left ventricular dysfunction) have emerged; in fact cardiac involvement has been identified frequently at autopsy and is described in 80% of patients with acquired immunodeficiency syndrome (AIDS) as an evidence of the virus cardiotrophism, while clinical findings of left ventricular dysfunction were only detected in about 15% of the patients. It is possible that the development of heart failure had been underestimated in those years; in fact signs and symptoms of cardiac involvement had been often misinterpreted as the results of non cardiac causes (pulmonary failure or infections) also determining a delay in the beginning of cardiac therapy. The aim of this study was to follow 16 human immunodeficiency-virus positive patients during a 3-year period to evaluate the usefulness of early detection of heart failure in order to start a specific therapy as soon as possible. The follow-up consisted of a clinical and electrocardiographic control every 4 months. Echocardiography was carried out when involvement of the cardiac muscle was suspected. During the follow-up we could reveal an early involvement in 5/16 patients (31.2%) and in 2 of them (40%) early therapy caused clinical and echocardiographic regression of left ventricular dysfunction. The present study demonstrates that periodical clinical and echocardiographic controls are useful in patients with HIV infection.

Angioplasty is a principal treatment for occlusive vascular disease but 30-50% of patients show a restenosis of the vessel. There is no clinical effective therapy for this disease. It has been demonstrated, in animal models, that various drugs such as NO-donor, plasminogen inhibitor tranexamic acid and MMP (matrix metalloproteinases) reduce the rate of restenosis. Other therapeutic approaches are cytotoxic therapy, and strategies to inhibit cell cycle progression. Systemic administration of conventional pharmacologic agents inhibit cell cycle kinases and vascular lesion formation in animal models. As cell cycle progression is accompanied by fluctuations in the concentration of adenosine 3',5-monophospate (cAMP) and in the activity of the cAMP dependent protein kinase (PKA), local administration of cAMP and phospodiesterase-inhibitor drugs (aminophylline or amrinone) markedly inhibit neointima formation. The successful use of local radiation therapy to inhibit neointima formation after vascular injury may reflect a similar combination of cell-cycle arrest and vascular cell apoptosis. The most effective therapy for occlusive vascular disease will likely combine intravascular stenting with an antiproliferative therapy.

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease, whose typical pathophysiological features include normal systolic dynamics, impaired diastolic function [1–4], and, in about one fourth of patients, left ventricular (LV) outflow tract obstruction [5–8].

Non-ionizing radiation is emitted by different types of equipment such as microwave ovens, high-voltage electrical lines, cellular phones, etc. This kind of radiation (electromagnetic waves) can also cause interference. Many electronic medical devices such as pacemakers (PM) can malfunction as a consequence of electromagnetic interference (EMI) [1–5].

Although controversial, laparoscopic inguinal hernia repair has become increasingly popular among surgeons. The overall advantages of this procedure over conventional hernia repair have not as yet been substantiated. One hundred and three consecutive laparoscopic, transabdominal, preperitoneal inguinal hernia repairs in 91 patients were evaluated retrospectively. Patients' satisfaction was assessed using the Visick grading system. The mean follow-up was 18.3 months. One case was converted to an open procedure. Eighty-eight patients (91%) were discharged on the day of surgery. Eighty-seven patients (96%) were satisfied with the operation (Visick grades III). Twenty-nine patients who previously underwent a traditional open herniorraphy stated that they would have preferred the laparoscopic method if they had the choice. Early complications included wound infection (n = 1), urinary retention (n = 1) and intestinal obstruction necessitating a laparotomy (n = 1). All patients were ambulating without significant pain after a mean of 7.6 days, and returned to work after 2.4 weeks on average. There was one case of recurrence. In conclusion, patients are satisfied with the laparoscopic hernioplasty technique, which is associated with a low morbidity and short term recurrence rate. Laparoscopic hernioplasty should be considered a viable and valuable alternative to the open method. It appears especially attractive for recurrent or bilateral hernias.

The follow up of pacemaker and defibrillator dependent patients has a significant role for both the evaluation of pacing effectiveness and check of hemodynamic advantages about patient's quality of life. The bulky paper archives are often inaccurate, hampering the consultation. At present the paper card is the only document which can be utilized to record some data concerning the implant and patient clinical story. Therefore, there is the necessity for a card that can include all patient's data, and the implant and programming pacemaker/defibrillator data during follow up. This new pacemaker card has portable file or data-base including shared data with safety mechanism, which can be utilized in several controls by different users (physicians, hospital ward, primary care units, insurance companies). The pacemaker card includes a chip that permits to store a considerable amount of data; it can be update in every further medical control, in observance of laws. The card Chip Operating System (C.O.S.) consists of a microchip with a memory completely managed by the operating system inside the chip itself. The card can be read by means of a GCR-200 modem linked with a PC IBM-compatible computer and the data can be updated during the follow up. The pacemaker-defibrillator card will appear immediately on screen, and it can be printed, updated and/or modified by a Microsoft Windows operating programme. With this pacemaker card we are able to ensure serviceable medical work, particularly in terms of cost/benefit ratio giving to patient more and more reasoning and safe service.

Some evidence indicate that platelets (PLTs) and leukocytes might contribute to the development of neointimal hyperplasia following arterial injury, via release of several growth factors. To study the relative contribution of these cells and of growth factors released in consequence of activation, smooth muscle cells (SMCs), isolated from the aorta of New Zealand White rabbits, were grown in Dulbecco's medium containing 10% fetal calf serum (FCS). At 70% confluence, SMCs were made quiescent by removing FCS from the medium. Twenty-four hours later, the cells were stimulated with activated platelets, neutrophils, lymphocytes+monocytes, whole leukocytes and platelets + whole leukocytes. Then, 1 microCi of O3H-thymidine were added to SMC cultures to evaluate the degree of proliferation. Relative contribution of different PLT-derived mediators to SMC growth was evaluated by adding either ketanserin, a 5-HT2 receptor antagonist, ridogrel, a thromboxane A2 (TxA2) receptor antagonist, BN52021, a platelet activating factor (PAF) receptor antagonist, and trapidil, a platelet-derived growth factor (PDGF) receptor antagonist, or all antagonists together. SMC proliferation was significantly increased by platelet activation. This effect was reduced by adding either ketanserin, ridogrel, BN 52021 or trapidil. Neutrophils, lymphocytes + monocytes and whole leukocytes also increased SMC proliferation. Simultaneous stimulation of SMCs by platelets and whole leukocytes was associated with a significant increase in SMC proliferation as compared to platelets or leukocytes alone. Thus, TxA2, 5-HT, PAF, and PDGF all contribute to SMC proliferation in vitro. Adding all antagonist together resulted in an additive antiproliferative effect. Leukocytes are also important in SMC proliferation. Interaction between platelets and leukocytes may play a pivotal role in the modulation of this phenomenon.

The extrinsic coagulation pathway is activated when tissue factor (TF) is exposed as a consequence of arterial damage. TF binds to factor VII (FVII) or activated FVII (FVIIa), generating a complex that activates both FX and FIX, ultimately leading to thrombin formation. To determine whether inhibition of FVII binding to TF would result in antithrombotic effects, active site-blocked FVIIa (FVIIai) was used in a rabbit model of intravascular thrombus formation. In addition, to study the interaction between extrinsic coagulation pathway activation and platelet aggregation, in the same model of intravascular thrombus formation, recombinant human FVIIa was administered in antiplatelet-treated rabbits. Cyclic flow variations (CFVs), due to recurrent thrombus formation, were initiated by placing an external constrictor around the endothelially-injured rabbit carotid arteries (Folt's model). Carotid blood flow was measured continuously by a Doppler flow probe placed proximally to the constrictor. CFVs were induced in 29 New Zealand White rabbits. After CFVs were observed for 30 min, the animals were randomly divided in four groups: 5 animals received via a small catheter (26G) placed proximally to the stenosis, an intra-arterial infusion of human recombinant FVIIai (0.1 mg/kg/min for 10 min); 9 animals received AP-1, a monoclonal antibody against rabbit TF (0.1 mg/kg i.v. bolus); 7 animals received ridogrel, a dual thromboxane A2 synthetase inhibitor and thromboxane A2 receptor antagonist (10 mg/kg i.v. bolus); finally, 8 rabbits received aurintrycarboxilic acid (ATA), an inhibitor of platelet glycoprotein Ib/von Willebrand factor interaction (10 mg/kg i.v. bolus). FVIIai abolished CFVs in 5 of 5 animals (CFV frequency minutes 0 cycles/hour; p0.05; carotid blood flow velocity minutes 106 +/- 9% of the baseline values; NS vs baseline). AP-1 abolished CFVs in 7 of 9 animals (CFV frequency minutes 0 cycles/hour; p0.05; carotid blood flow velocity minutes 58 +/- 35% of the baseline values; NS vs baseline). Finally, in all the animals receiving ridogrel or ATA CFVs were abolished (CFV frequency 0 cycles/hour; p0.05 in both groups; carotid blood flow velocity, respectively 62 +/- 32 and 66 +/- 40% of the baseline values; NS vs baseline in both groups). Thirty minutes following inhibition of CFVs, in the FVIIai treated rabbits, human recombinant FVIIa was infused, via the small catheter placed proximally to the stenosis, at the dose of 0.1 mg/kg/min for 10 min. In the other three groups, FVIIa, at the same dose, was infused i.v. Infusion of FVIIa restored CFVs in all FVIIai treated animals and in 6 of 7 AP-1 treated animals, thus indicating that AP-1 and FVIIai bindings to TF was competitive and was replaced by FVIIa. Infusion of FVIIa failed to restore CFVs in ridogrel e ATA treated rabbits (1 of 7 and 0 of 8 rabbits, respectively), showing that activation of extrinsic coagulation by FVIIa was overcome by inhibition of platelet function. Activated partial thromboplastin time, and ex vivo platelet aggregation in response to ADP and thrombin, were not different after FVIIai infusion, while prothrombin time was slightly but significantly prolonged as compared to baseline values. Thus, FVII-VIIa plays an important role in initiating thrombus formation in vivo. Administration of FVIIai exerts a potent antithrombotic effects in this model without affecting systemic coagulation. In addition, in this model platelets exert an important role in arterial thrombosis, since in the presence of inhibition of platelet function, activation of the extrinsic coagulation pathway failed to restore thrombus formation.

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease whose typical pathophysiologic features include normal systolic dynamics, impaired diastolic function (1–7), and, in about one fourth of patients, left ventricular (LV) outflow tract obstruction (8–11).

It is known that intravenous administration of dipyridamole can induce chest pain and ECG signs of ischemia in patients with coronary artery disease. In the present study we evaluated ECG and hemodynamic changes in response to dipyridamole (0.56 mg/kg in 10 min) under basal conditions and 3 hours after administration of nitroglycerin (10 mg/24 h patch) in 14 patients with coronary artery disease. The effects of nitroglycerin were also compared to those induced by the same drug on a bicycle stress test in the same patients. Exercise stress test induced specific ST changes in all patients when performed off-drug. Nitroglycerin administration completely prevented exercise-induced ischemia in 2 patients, and significantly prolonged exercise time in the remaining patients (p0.01). This effect was accompanied by a significant increase in heart rate (HR) and rate-pressure product at the threshold of ischemia (HRBP, p0.01); furthermore we observed a significant increase in HR at the maximal work load (p0.05). In the absence of treatment, dipyridamole infusion induced ST segment changes and/or typical chest pain in 12/14 patients. Moreover we observed a significant increase (p0.05) in HR, BP and HRBP during the test with respect to basal conditions. Following nitroglycerin administration, dipyridamole infusion failed to induce ischemia in 4 patients, and the time to ST depression in the remaining 8 patients (459 +/- 69 vs 610 +/- 127 s; p0.05) was significantly prolonged.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular hypertrophy is accompanied by the remodeling of the collagen network. We have studied collagen network in left ventricular hypertrophy secondary to aortic stenosis by cardiac catheterization and endomyocardial biopsies. We have demonstrated that collagen architecture is abnormal in 2/3 of patients with aortic stenosis and is more important than collagen concentration in influencing myocardial stiffness and ejection fraction. Furthermore, we observed that relaxation and asynchrony were influenced by the degree of hypertrophy instead of by the collagen network. The postoperative regression of left ventricular hypertrophy and the changes in interstitial tissue after valve replacement have been studied in a subgroup of patients. The major finding is that the regression of myocardial hypertrophy is a process that occurs over many years after correction of primary hemodynamic abnormality. Six to 7 years after valve replacement we observed, together with the normalization of diastolic stiffness, the complete normalization of interstitial fibrosis that was primarily increased (both pre and early postoperatively).

Accumulation and proliferation of vascular smooth muscle cells are associated with atherosclerosis and hypertension. Proliferation of smooth muscle cells constitutes a major pathological event responsible for long-term failure of coronary and peripheral arterial bypass graft as well as the development of restenosis after percutaneous transluminal coronary angioplasty (PTCA). The incidence of restenosis after PTCA has been reported to be as high as 40-45% within 3-6 months. Major advantages in recombinant deoxyribonucleic acid (DNA) technology and eukaryotic gene regulation allow to hypothesize gene therapy as a potential treatment for inherited and acquired diseases. Gene therapy is the introduction of genes into somatic cells to correct an inherited or acquired disorder through the synthesis of missing or defective protein. Although no disease has yet been treated by gene therapy, several gene transfer protocols have recently been undertaken. We have studied the expression of foreign DNA that has been introduced into smooth muscle cells after balloon carotid injury in a rat model of angioplasty. The effects of different degree of balloon injury on neointima formation and c-fos expression was also assessed. Our data demonstrate that site-specific gene expression can be achieved by direct gene transfer in vivo and could be applied to the treatment of restenosis after PTCA.

The purpose of this study was to evaluate left ventricular (LV) structure-function interplay in aortic stenosis. LV structure was assessed from endomyocardial biopsies obtained in 27 patients with aortic stenosis. Total collagen volume fraction, orthogonal collagen fiber meshwork (cross-hatching) and endocardial fibrosis were determined by morphologic-morphometric evaluation. Control biopsy data were obtained from 6 pre-transplantation donor hearts whereas other 11 patients with normal cardiac function served as hemodynamic controls. LV biplane cineangiography and high-fidelity LV pressure measurement were carried out in all patients. Systolic function was assessed by LV biplane ejection fraction, diastolic function by time constant of relaxation, peak filling rates and passive elastic properties. Total collagen volume fraction (7.3 versus 1.6%, p0.01) as well as the degree of cross-hatching (1.7 versus 0.8 grade, p0.01) were significantly increased in patients with aortic stenosis with respect to controls. Endocardial fibrosis was present in 11/27 patients with aortic stenosis and in no patients of control group. In aortic stenosis in presence of increased total collagen volume fraction there were no changes in systolic and diastolic function, whereas in presence of changes in collagen architecture ejection fraction was depressed and passive elastic properties increased. In conclusion, in aortic stenosis, changes in collagen architecture are associated with altered systolic function and passive diastolic properties. The sole increase in total collagen volume fraction without a change in architecture leaves systolic and passive diastolic function unaltered. A prolongation of relaxation was present in aortic stenosis and appears to be mediated by muscle hypertrophy per se.

Low-density lipoproteins (LDL) oxidized by oxygen radicals are a potent atherogenic stimulus. Chemically modified LDL are internalized by macrophages via a specific cell surface receptor that was termed the scavenger receptor, and could induce foam cell transformation. Post-translational nonenzymatic glycosylation of low density lipoprotein (LDL) occurs in vivo in diabetic patients. Glycosylated LDL (glcLDL) is degraded by macrophages in part by the classic LDL-receptor and in part by the scavenger receptor. This latter mechanism may contribute to the formation of foam cells and acceleration of atherosclerosis in diabetes mellitus. Oxygen free radicals (ORs) could induce LDL peroxidation and subsequent formation of foam cells. Glycosylation may alter protein conformation. A free radical is any chemical species that has an unpaired electron. This property renders it highly chemically reactive. When a radical reacts with a non radical another free radical is generated. This characteristic enables radicals to trigger chain reactions. Oxygen radicals are: superoxide anion (.O2-), hydroxyl radical (.OH) and hydrogen peroxide (H2O2). Thus, the aim of this study was to investigate whether glcLDL are susceptible to peroxidative modification by ORs. GlcLDL was prepared incubating LDL with 40 mM glucose in sterile phosphate-buffer-EDTA 1 mM for 10 days at 37 degrees C. Control LDL (cLDL) was similarly incubated with buffer but without glucose. After this preparation both forms of LDL were oxidized by CuSO4 (15 microM for 20 hours at 37 degrees C) or by xanthine/xanthine oxidase (X:2 mM/XO: 100 mU for 20 hours at 37 degrees C).(ABSTRACT TRUNCATED AT 250 WORDS)

Previous studies in other systems have shown that beta-receptor blockers may effectively inhibit oxygen radical-induced lipid peroxidation. On the other hand, it has been recently proposed that oxygen free radicals can induce peroxidation of human low density lipoproteins (LDL), and that peroxidized LDL may be an atherogenic stimulus. Chemically modified LDL are internalized by macrophages via a specific cell surface receptor that was termed the scavenger receptor. This phenomenon may induce foam cells transformation in vivo. In the present study we investigated whether beta-blockers may reduce oxygen radical-mediated LDL peroxidation. Purified human LDL were oxidized by exposure to oxygen free radicals generated by xanthine (0.2 mM) and xanthine oxidase (100 mU) at 37 degrees C after a pre-incubation (30 min) in presence of different concentrations (from 1 to 30 microM) of acebutolol, metoprolol or propranolol, three agents with a different degree of lipophilicity. Peroxidation was measured from malonyldihaldehyde (MDA) production. Data have shown a significant percent inhibition of MDA formation in presence of beta-blockers (from 33 to 85%). Thus, beta-blockers reduced peroxidation of human LDL in vitro at clinically relevant concentrations. The order of potency appears to follow the degree of lipophilicity. These data suggest that, although beta-blockers are known to adversely effect lipid metabolism, these agents might on the other hand prevent atherogenesis via a mechanism of inhibition of LDL peroxidation in vivo and reduced foam cells formation.

Recently, a new class of drugs has been developed with unique properties with regard to cardiovascular pharmacology: K(+)-channel openers. The increased K+ efflux from smooth muscle cells induced by these drugs is accompanied by a reduced intracellular availability of free Ca++, which in turn induces vascular relaxation. This property is currently being exploited to achieve peripheral and coronary artery dilatation in patients with ischemic heart disease. Cromakalim, pinacidil, and nicorandil, are the most extensively investigated agents in this class. Nicorandil, in addition to its K(+)-channel opener property, also shows a nitrate-like activity on guanylate cyclase of vascular smooth muscle cells. Clinical trials demonstrate that chronic administration of nicorandil can significantly increase exercise tolerance in patients with coronary artery disease. In experimental studies, this drug has also shown protective effects against myocardial injury induced by ischemia and reperfusion, by mechanisms partly independent of its vasodilating properties. These results suggest that K(+)-channel openers may have a relevant place in the pharmacological treatment of patients with ischemic heart disease.

Eighteen patients with isolated stenosis of left anterior descending artery, were randomly given 0.2 mg of nifedipine (Group II) or its solvent (Group I) via balloon catheter positioned across the lesion immediately prior balloon occlusion. Peak velocity of early (E peak) and late (A peak) filling, velocity flow integral at early (E area) and late (A area) filling and their ratios (by echo-Doppler) and heart rate, mean aortic and wedge (W) pressures were measured at baseline, 15 and 30 s during balloon occlusion and 10 min after balloon deflation. In Group I we observed a significant decrease in either E peak at 15 and 30 s (-24.7%, -29.3% respectively) and E area (-32.8%, -40.0% respectively) with a non significant increase in both A peak and A area. Accordingly, either E/A peak ratio and E/A area ratio decreased significantly. In Group II no significant changes were observed in the echo-Doppler parameters of left ventricular filling. Wedge pressure also significantly increased in Group I at 15 and 30 s (68.7% and 97.9% respectively), while a significant increase in Group II occurred only at 30 s (32.5%). Heart rate significantly increased only in Group I at 15 and 30 s (10.3% and 11% respectively), while aortic pressure remained unchanged in both groups. Thus, nifedipine given intracoronary in the post-stenotic area just before balloon occlusion prevents left ventricular filling dynamic alteration by preserving early filling.

This study evaluated the effects of digoxin infusion (0.014 mg/kg in 10 min i.v.) on large coronary arteries measured by quantitative digital angiography. Twenty-two patients (aged 47 +/- 12), divided in 3 groups were studied. The effects of digoxin infusion (after 10 and 20 min) and sublingual administration of isosorbide dinitrate were investigated in Group I (patients with angiographically normal coronary arteries, n = 9) and in Group II (patients with atherosclerotic coronary arteries, n = 8). In Group III (n = 5) to determine whether or not the effects of digoxin were mediated by activation of alpha-adrenergic receptors, coronary angiographies were performed after alpha-adrenoceptor blockade (phentolamine 0.11 mg/kg, i.v.). In Group I, 10 min after the end of digoxin infusion, cross-sectional area decreased from 7.7 +/- 4.1 mm2 to 6.0 +/- 2.2 mm2, and after 20 min to 5.6 +/- 2.6 mm2 (p0.05). Isosorbide dinitrate reverted digoxin-induced vasoconstriction as cross-sectional area increased to 8.5 +/- 3.4 mm2 (NS versus baseline). By 20 min after digoxin infusion heart rate was significantly reduced from 79 +/- 16 to 74 +/- 13 b/min (p0.01). Peripheral vascular resistances increased significantly 10 min after digoxin infusion (from 1396 +/- 693 to 1693 +/- 984 dyne*s*cm-5, p0.05), whereas cardiac output did not change. In Group II, minimal stenosis diameter decreased significantly 20 min after digoxin infusion from 1.6 +/- 0.5 mm to 1.4 +/- 0.5 mm (p0.05). Again, isosorbide dinitrate reverted digoxin-induced vasoconstriction as minimal stenosis diameter increased (NS versus control).(ABSTRACT TRUNCATED AT 250 WORDS)

Central sympathetic stimulation results in direct vascular vasoconstriction mediated by activation of alpha-adrenergic receptors. However, it is unknown whether this vasoconstriction is mediated by alpha 1 or alpha 2-adrenoceptor subtypes. In patients with congestive heart failure (CHF), both circulating and neuronally released catecholamines produces vasoconstriction via alpha-adrenergic stimulation. This vasoconstriction produces detrimental hemodynamic effect in CHF patients since it increases right and left ventricular filling pressures and pulmonary and systemic vascular resistances. While the myocardial alpha 1-adrenoceptors seems not to be down-regulated in heart failure, the functional integrity of vascular alpha 1 and alpha 2-adrenoceptors in CHF remains to be elucidated. Accordingly, the present study was designed to assess whether the limb vascular response to alpha 1 or alpha 2-adrenoceptor stimulation is impaired in patients with CHF. We studied 25 control subjects and 19 patients with CHF due to primary dilated cardiomyopathy. Forearm blood flow was measured by venous occlusion plethysmography. Sympathetic stimulation was produced by cold. The intraarterial pump-infusions of BHT 933 (a selective alpha 2-adrenoceptors agonist agent, 0.1, 1, 10 micrograms/kg/min for 5 min) produced the same peripheral vasoconstriction in CHF and in control subjects: 32 +/- 23.9%, 47.3 +/- 20% and 55 +/- 26.1% respectively at I, II, and III dose in CHF and 28.7 +/- 38.6%, 36 +/- 14.5%, and 57 +/- 13.8% respectively at I, II, and III dose in control subjects. The dose response to BHT 933 was not different in the 2 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Previous studies have shown that calcium-antagonists may reduce the development of experimental atherosclerosis, and that nifedipine may slow progression of coronary atherosclerosis in man. The mechanisms responsible for this effect are still unclear. It has been recently proposed that oxygen-free radicals can induce peroxidation of human low-density lipoproteins (LDL), and that peroxidized LDL may be an atherogenic stimulus. Chemical modified LDL are internalized by macrophages via specific cell surface receptor that was termed the scavenger receptor, and could induce foam cells transformation in vivo. Previous studies on other systems have shown that calcium-antagonists may effectively inhibit oxygen radical-induced lipid peroxidation. These drugs, though differing widely in their chemical structure, are lipophilic to various degrees and presumably would concentrate in the lipid domain of the phospholipid-rich membranes. Therefore, the aim of the present study was to investigate whether calcium-channel blockers may reduce human LDL peroxidation. Purified human LDL were exposed to oxygen radicals generated by xanthine-xanthine oxidase (18 hours) after a pre-incubation (30 min) in presence of different concentrations of nifedipine, diltiazem and verapamil. Peroxidation was measured from malonyldialdehyde production. The results show that calcium-antagonists prevent LDL peroxidation. Thus, calcium-antagonists may reduce peroxidation of human LDL in vitro, at clinically relevant concentrations. These data suggest that reduced formation of atherogenic peroxidized LDL may be an additional mechanism for the anti-atherosclerotic effects of calcium-antagonists in vivo.

Pravastatin is a new drug that inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the key enzyme in cholesterol synthesis. It prevents mevalonate synthesis, thus reducing cholesterol. Pravastatin also stimulates the expression of LDL receptors, leading to an activation of this specific pathway of LDL catabolism. Gemfibrozil is a fibrate drug. Although the mechanism of hypolipidemic action of fibrates is not conclusively elucidated, it seems to involve reduction of LDL cholesterol secondary to decreased VLDL production and increased VLDL catabolism. Therefore, it might be hypothesized that combination therapy with both agents could afford greater reduction of cholesterol levels as compared to pravastatin alone. This study compared the efficacy and safety of pravastatin in monotherapy or in combination with gemfibrozil in the treatment of primary hypercholesterolemia with moderate hypertriglyceridemia. Thirty-eight subjects (aged 57 +/- 15 years, 25 M and 13 F) with baseline cholesterol levels220 mg/dl, were included in the study. Serum triglyceride levels were greater than 170 mg/dl and lower than 250 mg/dl. All patients initially followed 4 weeks of hypolipidemic diet. The patients were there assigned to receive either 20 mg once a day of pravastatin alone (n 13) or 20 mg of pravastatin in association with 600 mg of gemfibrozil daily (n 11). Fourteen additional patient, treated with diet only, served as a control group. The treatment plan provided 18 months of active treatment with clinical and laboratory controls every month. Both groups of treated patients showed a reduction of total and LDL-cholesterol levels. The HDL-cholesterol levels increased significantly both with pravastatin and with gemfibrozil.(ABSTRACT TRUNCATED AT 250 WORDS)

The recent development of an ambulatory radionuclide detector (VEST) to assess left ventricular (LV) function may enhance the detection of ischemia during routine daily activities in patients with coronary artery disease (CAD). The aim of this study was to evaluate the usefulness of VEST in monitoring LV ejection fraction (EF) responses to daily activities and sustained handgrip test (HG) in patients with CAD.13 patients (12 men and 1 woman) with angiographically proven coronary artery disease were studied by VEST (mean 162 min, range 120 to 250 min). LV responses to different daily activities (walking and climbing stairs) and to HG were evaluated.Walking on a level surface and climbing stairs did not induce significant change in mean LVEF. However, a transient decrease in EF was observed in 4 (31%) and in 5 (38%) of the 13 patients during walking and climbing stairs, respectively. HG induced a significant (p0.01) reduction in mean EF. In particular, during HG, EF decreasedor = 5% in 11 (85%) of the 13 patients. A transient spontaneous decrease in LVEF lastingor = 1 min was observed on 18 occasions in 11 patients with CAD; 5 episodes were symptomatic and 13 asymptomatic. ECG ST segment depression was recorded in 4 of the 5 symptomatic and in 5 of the 13 asymptomatic episodes.These results suggest that simultaneous monitoring of LV function and ECG may permit a better understanding of the incidence and severity of ischemic symptomatic and asymptomatic episodes.

We compared the results of 201Tl reinjection and those of 99mTc-methoxyisobutyl isonitrile (MIBI) in identifying viable myocardium in 20 male patients with angiographically proven coronary artery disease (CAD) and left ventricular dysfunction (ejection fraction 30% +/- 8%). All patients had irreversible defects on standard exercise-redistribution thallium imaging. Thallium was reinjected immediately after the redistribution study, and images were reacquired. The patients also underwent stress and rest 99mTc-MIBI myocardial scintigraphy (2-day protocol). A total of 300 myocardial regions were analyzed, of which 122 (41%) had irreversible thallium defects on redistribution images before reinjection. Of the 122 myocardial regions with irreversible defects on standard stress-redistribution thallium cardiac imaging, 65 (53%) did not change at reinjection and 57 (47%) demonstrated enhanced uptake of thallium after reinjection. Of the same 122 irreversible defects on stress-redistribution thallium, 100 (82%) appeared as fixed defects and 22 (18%) were reversible on 99mTc-MIBI myocardial scintigraphy. These data indicate that 201Tl cardiac imaging with rest reinjection is superior to 99mTc-MIBI myocardial scintigraphy in identifying viable myocardium in patients with chronic CAD, suggesting that regions with severe reduction of 99mTc-MIBI uptake both on stress and rest images may contain viable myocardium.

Although left ventricular hypertrophy is an adaptative mechanism to increased load, its development represents a pathological state which can affect patients' health in many ways. Systemic hypertension is often associated to left ventricular hypertrophy; a correlation exists between ambulatory blood pressure monitoring daytime mean blood pressure values and left ventricular mass. Left ventricular hypertrophy is an independent risk factor for cardiovascular events, and the pattern of concentric left ventricular hypertrophy is associated with higher morbidity and mortality. The mechanism by which left ventricular hypertrophy impair life expectancy is not completely known; arrhythmias and ischemia may often develop in patients with secondary left ventricular hypertrophy and can contribute to worsen prognosis. Left ventricular mechanics is also affected by hypertrophy. Systolic function is usually normal at rest, but its response to exercise can be blunted when hypertrophy develops. Diastolic dysfunction is often present in patients with hypertension, even before left ventricular hypertrophy occurs, and it can impair systolic function by hampering filling resulting mostly in an impairment in the adjustment to exercise. Effective antihypertensive therapy leads to a decrease in left ventricular hypertrophy and an improvement in diastolic mechanics.

Animal experiments and clinical observation in humans have established a window of opportunity during which reperfusion after acute myocardial infarction may salvage myocardium. This time window was initially thought to be 3 to 4 hours from the onset of coronary occlusion, but it has been recently recognized in humans to be longer, at least 6 hours and possibly even longer. The longer time span for effective intervention was determined in several studies showing an increased survival rate as a consequence of the improvement in left ventricular function and the reduction of infarct sequels with late thrombolysis. Main mechanism by which late thrombolysis may lead to survival benefit seems to be infarct-related artery patency. However, other mechanisms have been postulated such as the positive influence on remodeling, electric stability and different effects due to the breakdown of systemic fibrinogen and the anticoagulant effect that this can produce. Regardless of which of these proposed mechanisms is responsible for reducing mortality in patients treated with late thrombolysis after myocardial infarction, the limitation of treating patients only within the 4- to 6-hour time window must be seriously reconsidered.

The recent advances in cardiovascular pathophysiology have changed our interpretation of the interplay between myocardial metabolism and contractile function which takes place during acute ischemia. For instance, the use of nuclear magnetic resonance (NMR) spectroscopy has allowed to document that the rapid impairment in contractility seen during acute myocardial ischemia is not directly related to depletion of high energy phosphate levels, nor to decreased availability of intracellular calcium. Rather, acidosis and inorganic phosphate accumulation cooperate to decrease myofilament sensitivity to calcium. Marked alterations of cardiac function and metabolism may also accompany the postischemic period. Positron emission tomography studies have shown that myocardial uptake of glucose remains disproportionately elevated in areas of myocardium which have been rendered transiently ischemic by an episode of stress-induced angina in patients with coronary artery disease. This phenomenon may have important practical applications, as it may be used as a metabolic marker to detect areas of myocardium which is viable, but potentially at risk for ischemic episodes. Reduced ATP levels are another biochemical alteration which can be typically found in postischemic hearts. Again, NMR spectroscopy has allowed to establish that these hearts often display near-normal mitochondrial function, and that the delayed resynthesis of ATP is due to lack of purine nucleotide precursors. A most interesting functional peculiarity of postischemic hearts is represented by the prolonged impairment of contractility, which largely outlasts the duration of the period of flow deprivation. This phenomenon, which eventually subsides over the course of hours or days, has been termed myocardial stunning, to underline its occurrence despite the absence of ultrastructural signs of irreversible damage.(ABSTRACT TRUNCATED AT 250 WORDS)