Skin cancer in heart transplant recipients: risk factor analysis and relevance of immunosuppressive therapy.

BACKGROUND: The frequency of skin tumors of all types and specifically of squamous cell carcinoma (SCC) is increased in heart transplantation (HT), but the predisposing risk factors are controversial. METHODS AND RESULTS: We studied 300 patients (age 49+/-15 years, 258 men, mean follow-up 4.6 years, follow-up range 1 month to 12 years) who were receiving standard double (cyclosporin plus azathioprine) or triple (cyclosporin plus azathioprine plus prednisone) therapy. The first-year rejection score was calculated for endomyocardial biopsy samples (International Society for Heart and Lung Transplantation grade 0=0, 1A=1, 1B=2, 2=3, 3A=4, 3B=5, and 4=6) and used as an indirect marker of the level of immunosuppression. Multivariate analysis (Cox regression) included age at HT, sex, skin type, first-year rejection score, presence of warts and solar keratosis, lifetime sunlight exposure, and first-year cumulative dose of steroids. The incidence of skin tumors of all types increased from 15% after 5 years to 35% after 10 years after HT according to life-table analysis. Age at HT of >50 years (P:=0.03, RR=5.3), skin type II (P:=0.05, RR=2.6), rejection score of 19 (P:=0.003, RR=5.7), solar keratosis (P:=0.001, RR=6.9), and lifetime sunlight exposure of >30 000 hours (P:=0.0003, RR=7.6) were risk factors for SCC. CONCLUSIONS: Older age at HT, light skin type, solar keratosis, greater sunlight exposure, and high rejection score in the first year were independently associated with an increased risk of SCC. The progressive increase in cancer frequency during follow-up and the association with high rejection scores suggest that both the length and level of immunosuppression may be relevant. Because cumulative immunosuppressive load is cumbersome to calculate, a high rejection score in the first year may provide a useful predictor for patients at risk.

Adrenergic nervous activity in patients after surgical correction of tetralogy of Fallot.

OBJECTIVES: The study was done to define the role of the autonomic nervous system in postoperative tetralogy of Fallot. BACKGROUND: Subsequent to surgical correction of tetralogy of Fallot, patients are at long-term risk of sudden death owing to ventricular electrical instability. The status of the sympathetic nervous system in these patients, known to play an important role in other patients at risk, remains unknown. METHODS: We used (123)I metaiodobenzylguanidine (MIBG) with tomographic imaging, combined with assessment of heart rate variability (HRV), to evaluate the activity of the sympathetic nervous system. We analyzed 22 patients who had undergone total correction of tetralogy of Fallot: 13 with either no or minor ventricular arrhythmias, and 9 with sustained ventricular tachycardia or ventricular fibrillation. RESULTS: Analysis of HRV revealed a reduction in vagal control and sympathetic dominance in all patients compared with a healthy control group of 20 subjects. A significant difference was found in the standard deviation of all the adjacent intervals between normal beats (SDNN) in patients with or without severe ventricular arrhythmias. A significant reduction in uptake of (123)I MIBG was demonstrated 30 min after IV injection, and a trend toward reduction after 5 h, associated with reduced washout indices. These data reflect a decrease in the number of nerve endings in the right and left ventricular walls, and an inhomogeneous distribution of the adrenergic nervous system. The uptake of MIBG was significantly reduced in the patients at risk of ventricular tachycardia or fibrillation. CONCLUSIONS: Subsequent to surgical correction of tetralogy of Fallot, the positive correlation between myocardial uptake of MIBG, SDNN and the QRS dispersion confirmed the usefulness of analysis of the adrenergic nervous system to stratify patients at risk of life-threatening arrhythmias.

Long-term nifedipine unloading therapy in asymptomatic patients with chronic severe aortic regurgitation.

Vasodilating agents acutely reduce regurgitant volume and improve left ventricular performance in aortic regurgitation, but more information is necessary about their long-term efficacy. To evaluate the effects of 12 months of therapy with nifedipine, a randomized, double-blind, placebo-controlled trial was performed in 72 asymptomatic patients with severe aortic regurgitation. At 12 months, patients receiving nifedipine had a significant reduction in left ventricular end-diastolic volume index (110 +/- 19 versus 136 +/- 22 ml/m2, p less than 0.01) and mass (115 +/- 19 versus 142 +/- 16 g/m2, p less than 0.01) measured by two-dimensional echocardiography. They also had a reduction in left ventricular mean wall stress (360 +/- 27 versus 479 +/- 36 kdyne/cm2, p less than 0.001) and an increase in ejection fraction (72 +/- 8% versus 60 +/- 6%, p less than 0.05). These data show that the long-term unloading action of nifedipine is able to reverse left ventricular dilation and hypertrophy and suggest that such therapy has the potential to delay the need for valve replacement in asymptomatic patients.

Myocardial dysfunction and adrenergic cardiac innervation in patients with insulin-dependent diabetes mellitus.

BACKGROUND: Insulin-dependent diabetes mellitus (IDDM) is associated with an increased incidence of heart failure due to several factors, and in some cases a specific cardiomyopathy has been suggested. OBJECTIVES: This study sought to assess the mechanisms of exercise-induced left ventricular (LV) dysfunction in asymptomatic patients with IDDM in the absence of hypertensive or coronary artery disease. METHODS: Fourteen consecutive patients with IDDM were enrolled (10 men, 4 women; mean [+/- SD] age 28.5 +/- 6 years); 10 healthy subjects matched for gender (7 men, 3 women) and age (28.5 +/- 3 years) constituted the control group. LV volume, LV ejection fraction (LVEF) and end-systolic wall stress were calculated by two-dimensional echocardiography at rest and during isometric exercise. LV contractile reserve was assessed by post-extrasystolic potentiation (PESP) obtained by transesophageal cardiac electrical stimulation and dobutamine infusion. Myocardial iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy was performed to assess adrenergic cardiac innervation. RESULTS: Diabetic patients were classified into group A (n = 7), with an abnormal LVEF response to handgrip (42 +/- 7%), and group B (n = 7), with a normal response (72 +/- 8%). Baseline LVEF was normal in both group A and B patients (60 +/- 6% vs. 61 +/- 7%, p = NS). In group A patients, the LV circumferential wall stress-LVEF relation showed an impairment in LVEF disproportionate to the level of LV afterload. No significant changes in LVEF occurred during dobutamine (60 +/- 6% vs. 64 +/- 10%, p = NS), whereas PESP significantly increased LVEF (60 +/- 6% vs. 74 +/- 6%, p < 0.001); PESP at peak handgrip normalized the abnormal LVEF (42 +/- 7% vs. 72 +/- 5%, p < 0.001); and MIBG uptake normalized for body weight or for LV mass was lower than that in normal subjects (1.69 +/- 0.30 vs. 2.98 +/- 0.82 cpm/MBq per g, p = 0.01) and group B diabetic patients (vs. 2.79 +/- 0.94 cpm/MBq per g, p = 0.01). Finally, a strong linear correlation between LVEF at peak handgrip and myocardial MIBG uptake normalized for LV mass was demonstrated in the study patients. CONCLUSIONS: Despite normal contractile reserve, a defective blunted recruitment of myocardial contractility plays an important role in determining exercise LV dysfunction in the early phase of diabetic cardiomyopathy. This abnormal response to exercise is strongly related to an impairment of cardiac sympathetic innervation.

IPO-V2: a prospective, multicenter, randomized, comparative clinical investigation of the effects of sulodexide in preventing cardiovascular accidents in the first year after acute myocardial infarction.

OBJECTIVES: This study was conducted to assess the efficacy of sulodexide, a glycosaminoglycan compound with antithrombotic properties, in preventing death and thromboembolic events after acute myocardial infarction. BACKGROUND: Antithrombotic therapy has been found to play an important role in the prevention of cardiovascular events and death after acute myocardial infarction. Glycosaminoglycan-containing compounds, including sulodexide, show profibrinolytic and antithrombotic properties that render them suitable for use in patients after infarction. METHODS: A total of 3,986 patients who had recovered from acute myocardial infarction were randomized to receive either the standard therapy routinely administered at each study center, excluding antiplatelet and anticoagulant drugs (control group, 1,970 patients), or the standard therapy plus sulodexide (treated group, 2,016 patients). Between 7 and 10 days after the episode of acute myocardial infarction, sulodexide was administered as a single daily 600-lipoprotein-lipase-releasing unit (LRU) intramuscular injection for the 1st month, followed by oral capsules of 500 LRU twice daily. Patients were evaluated for > or = 12 months. RESULTS: At the end of the study, 140 deaths (7.1%) were recorded in the control group and 97 (4.8%) in the sulodexide group (32% risk reduction, p = 0.0022, chi-square test). A total of 90 patients (4.6%) in the control group had a further infarction, compared with 66 (3.3%) in the sulodexide group (28% risk reduction, p = 0.035). Furthermore, a reduction in left ventricular thrombus formation (evaluated by echocardiography) was observed in the sulodexide group (n = 12; 0.6%), compared with values in the control group (n = 25; 1.3%) (53% risk reduction, p = 0.027). Sulodexide was well tolerated and devoid of significant adverse events. All significant results were confirmed by "actual treatment" analyses. CONCLUSIONS: The study provides evidence that long-term therapy with sulodexide started early after an episode of acute myocardial infarction is associated with reductions in total mortality, rate of reinfarction and mural thrombus formation.

PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2.

BACKGROUND: The effect of alteplase versus heparin in pulmonary embolism has not been studied extensively with serial pulmonary angiograms. OBJECTIVES: The aim of this randomized, open trial was to evaluate the efficacy and safety of alteplase followed by heparin, versus heparin alone, in 36 patients with angiographically documented pulmonary embolism. METHODS: Twenty patients were allocated randomly to a 2-h infusion of alteplase (10 mg bolus, then 90 mg over 2 h) followed by heparin; the other 16 patients were given intravenous heparin at a continuous infusion rate of 1,750 IU/h. RESULTS: The vascular obstruction, assessed by the Miller index at pulmonary angiography, decreased significantly in alteplase-treated patients (p less than 0.01) from a baseline of 28.3 +/- 2.9 to a value of 24.8 +/- 5.2 2 h after the start of infusion; in the heparin group there was no change (from 25.3 +/- 5.3 to 25.2 +/- 5.4). Mean pulmonary artery pressure decreased significantly from a baseline of 30.2 +/- 7.8 mm Hg to 21.4 +/- 6.7 in the alteplase group and increased in the heparin group (from 22.3 +/- 10.5 to 24.8 +/- 11.2 mm Hg). For a subset of patients, lung scans were performed at baseline and on days 7 and 30. There were no differences between the two groups in the follow-up lung scans, but there were significant decreases from the baseline values. Bleeding occurred in 14 of 20 alteplase-treated patients and in 6 of 16 in the heparin group (p = NS). There were three major bleeding episodes in the alteplase group and two in the heparin group. Two patients died after fibrinolysis (one of acute renal failure after cardiac tamponade and one of cardiac arrest after cerebral hemorrhage) and one patient in the heparin group died of recurrent pulmonary embolism. CONCLUSIONS: Alteplase resulted in a greater and faster improvement of the angiographic and hemodynamic variables compared with heparin. However, the high frequency of bleeding observed with alteplase in this trial suggests that patients should be carefully selected before thrombolytic therapy is given.

Cardiac and respiratory involvement in advanced stage Duchenne muscular dystrophy.

This study aimed to describe myocardial involvement, respiratory impairment and pulmonary blood flow abnormalities in advanced-stage Duchenne muscular dystrophy (DMD). Twenty-one wheelchair-bound patients, aged from 10 to 24 yr, underwent electrocardiographic and echocardiographic examination, conventional spirometry, diurnal arterial blood gas analysis, and nocturnal polysomnography (SaO2 monitoring). Diagnosis was confirmed by neurological examination, dystrophin analysis at protein and DNA level. Patients were classified into two groups: group A normoxemic (14 cases) and group B with nocturnal hypoxemia (seven cases). Group A was further split into two subgroups, one without, and one with, left ventricular dilation (A1 = nine patients, end diastolic volume (EDV) = 51 ml m-2, ejection fraction (EF) = 56 per cent; A2 = five patients, EDV = 112 ml m-2, EF = 32 per cent; P < 0.05). Left ventricular regional wall motion abnormalities were found in 55, 40, and 43 per cent of groups A1, A2, and B patients respectively. Analysis of pulsed Doppler pulmonary data highlighted a significant reduction in corrected time to peak velocity in group B patients, when compared with control, A1, and A2 groups respectively. In group A, we observed a direct correlation between ejection fraction and corrected time-to-peak velocity. Two patterns of cardiac involvement may be recognized in advanced-stage DMD: left ventricular wall motion abnormalities and dilated cardiomyopathy. Doppler data which could suggest pulmonary hypertension may be observed in patients with dilated cardiomyopathy, and in patients with nocturnal hypoxemia. Therefore, in the management of advanced-stage DMD, a careful diagnosis of the heart-lung relationship should be performed, and both conventional treatment of heart failure and ventilatory therapy are necessary to improve the quality of life and survival in these patients.

Cardiac transplantation in a Duchenne muscular dystrophy carrier.

We report here for the first time the case of a symptomatic DMD carrier, who had a heart transplant for a severe dilated cardiomyopathy. Dystrophin immunohistochemistry, western blot and analysis of X-chromosome inactivation on leucocytes, and skeletal and cardiac muscle biopsies on the explanted heart were performed. The patient was a heterozygote for exons 50-52 deletion in the dystrophin gene. The number of dystrophin-deficient fibres in the heart was much higher than in skeletal muscle. On the other hand, the explanted heart showed a non-skewed pattern of X-chromosome inactivation, as in leukocytes and skeletal muscle. The adverse cardiac course may be explained by the absence of regeneration among cardiomyocytes.

Enhanced "in vitro" release of platelet alpha-granules after acute myocardial infarction (AMI).

In vivo platelet activity was studied in 58 patients with AMI on admittance to the Coronary Care Unit, in 48 of these patients after 1 week, in 30 after 1 month and in 24 patients after 6 months. Patients were carefully selected and excluded if they had associated diseases known to increase platelet activity. In vivo activation was studied by evaluating the plasma concentration of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) in the same blood sample. On admittance (x = 58.5) and on day 7 (x = 52.9) beta-TG values were significantly higher than those obtained in the control group (x = 29). beta-TG values were moderately elevated after 1 month (x = 37.7) and then returned to values similar to those of the control group after 6 months (x = 27.9). The simultaneous assessment of PF4 shows a beta-TG/PF4 ratio indicative for in vitro release (less than or equal to 2.5) in many patients on days 1 and 7. Moreover, the beta-TG/PF4 ratio in patients with AMI tends towards 2 when beta-TG values are high. These results may indicate a greater tendency to an in vitro platelet release in the acute phase of AMI.

Adenosine diphosphate (ADP)-induced alpha-granules release from platelets of native whole blood is reduced by ticlopidine but not by aspirin or dipyridamole.

A brief contact between native whole blood and ADP promotes a dose-dependent release of platelet alpha-granules without a fall in the platelet number. We assessed the "ex vivo" effect of three widely used antiplatelet drugs, aspirin dipyridamole and ticlopidine, on this system. Aspirin (a single 800 mg dose) and dipyridamole (300 mg/die for four days) had no effect, while ticlopidine (500 mg/die for four days) significantly reduced the alpha-granules release for an ADP stimulation of 0.4 (p less than 0.02), 1.2 (p less than 0.01) and 2 microM (p less than 0.01). No drug, however, completely inhibits this early stage of platelet activation. The platelet release of alpha-granules may be related to platelet shape change of the light transmission aggregometer and may be important "in vivo" by enhancing platelet adhesiveness and by liberating the platelet-derived growth factor.

A comparison of a moderate with moderate-high intensity oral anticoagulant treatment in patients with mechanical heart valve prostheses.

BACKGROUND: The long-term administration of oral anticoagulants to patients with mechanical heart valve prostheses is generally accepted. However, the appropriate intensity of oral anticoagulant treatment in these patients is still controversial. METHODS AND RESULTS: From March 1991 to March 1994, patients referred to the Padova Thrombosis Center who had undergone mechanical heart valve substitution at least 6 months earlier were randomly assigned to receive oral anticoagulants at moderate intensity (target INR = 3) or moderate-high intensity (target INR = 4). Principal end points were major bleeding, thromboembolism and vascular death. Minor bleeding was a secondary end-point. A total of 104 patients were assigned to the target 3 group and 101 to the target 4 group; they were followed for from 1.5 years to up 4.5 years (mean, 3 years). Principal end-points occurred in 13 patients in the target 3 group (4 per 100 patient-years) and in 20 patients in the target 4 group (6.9 per 100 patient-years). Major hemorrhagic events occurred in 15 patients, 4 in the target 3 group (1.2 per 100 patient-years) and 11 in the target 4 group (3.8 per 100 patient-years) (p = 0.019). The 12 recorded episodes of thromboembolism, 4 of which consisted of a visual deficit, were all transient ischemic attacks, 6 in the target 3 group (1.8 per 100 patient-years) and 6 in the target 4 group (2.1 per 100 patient-years). There were 3 vascular deaths in each group (0.9 and 1 per 100 patient-years for target 3 and target 4 groups, respectively). Minor bleeding episodes occurred 85 times (26 per 100 patient-years) in the target 3 group and 123 times (43 per 100 patient-years) in the target 4 group (p = 0.001). CONCLUSIONS: Mechanical heart valve patients on anticoagulant treatment who had been operated on at least 6 months earlier experienced fewer bleeding complications when maintained on a moderate intensity regimen (target INR = 3) than those on a moderate-high intensity regimen (target INR = 4). The number of thromboembolic events and vascular deaths did not differ between the two groups.

Safety and efficacy study of delapril versus enalapril in patients with congestive heart failure.

The results after the first 6 months of the 1-year treatment of this multicenter, randomized, open, parallel-group design study of delapril versus enalapril in patients with congestive heart failure (CHF), New York Heart Association (NYHA) classes II and III, are presented. The initial dose of delapril (7.5 mg twice daily) and enalapril (2.5 mg twice daily) could be doubled on a 2-weekly basis (from the beginning of the study) to a maximum of 30 mg twice daily and 10 mg twice daily, respectively. The evaluation of the efficacy was based on the changes of NYHA class, results of exercise testing involving bicycle ergometry (duration of exercise, workload, work performed, double product) performed before and after 3 months' treatment, echocardiography (left ventricular end-diastolic volume and end-systolic volume, ejection fraction, and left ventricular wall stress) at baseline and after 3 and 6 months of treatment and changes in cardiothoracic ratio, electrocardiography, and NYHA class, and patient's opinion of efficacy. Safety was evaluated by monitoring the adverse reactions, laboratory tests, and blood pressure. At 3 months, both treatments had produced a significant improvement compared with baseline in the duration of exercise, workload, and work performed in the bicycle ergometry test as well as in the ejection fraction and in left ventricular wall stress after 6 months of treatment. In addition, after 3 and 6 months of treatment, delapril produced a significant decrease in left ventricular end-systolic volume. Improvement of at least one NYHA class was observed in 20% of delapril patients and 14% of enalapril patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnostic accuracy of right ventriculography in arrhythmogenic right ventricular cardiomyopathy.

Diagnostic sensitivity and specificity of cineangiography were evaluated by multivariate logistic discriminant analysis in 32 patients with arrhythmogenic right ventricular (RV) cardiomyopathy, 27 patients with biventricular dilated cardiomyopathy, 28 patients with atrial septal defect and 18 normal subjects. In patients with arrhythmogenic RV cardiomyopathy and biventricular dilated cardiomyopathy, the diagnosis was confirmed by endomyocardial biopsy. All RV values overlapped for the diagnosis of atrial septal defect and arrhythmogenic RV cardiomyopathy; overlapping extended to dilated cardiomyopathy for end-diastolic volume and infundibular dimensions. RV ejection fraction appeared reduced in all the diseases; in particular, mean values in dilated cardiomyopathy and arrhythmogenic RV cardiomyopathy were 38 and 53%, respectively (p less than 0.05). Left ventricular quantitative studies showed a significant difference between dilated and arrhythmogenic RV cardiomyopathy, both in terms of pumping indexes (mean end-diastolic volumes 180 vs 91 ml/m2 and mean ejection fraction 33 vs 60%), and indexes of contractility (stress/end-diastolic volume 3.7 vs 6.7). Multivariate analysis disclosed that transversally arranged hypertrophic trabeculae, separated by deep fissures, were associated with the highest probability of arrhythmogenic RV cardiomyopathy (p less than 0.001). Posterior subtricuspid and anterior infundibular wall bulgings were the only other independently significant variables. Coexistence of these signs was associated with 96% specificity and 87.5% sensitivity. Thus, arrhythmogenic RV cardiomyopathy presents quantitative volumetric and hemodynamic as well as qualitative features that clearly distinguish it from dilated cardiomyopathy and confirm its nosographic autonomy among the primary diseases of the myocardium.

Postextrasystolic potentiation echocardiography in predicting reversible myocardial dysfunction by surgical coronary revascularization.

Sustained inotropic stimulation, such as dobutamine infusion, has the potential to cause an additional contractile deterioration in viable but chronically hypoperfused and dysfunctioning myocardium, by inducing ischemia. Postextrasystolic potentiation (PESP) represents a potent inotropic stimulus without risk of provoking ischemia, as it is instantaneous. In this study, we assessed the role of PESP-echocardiographic examination in predicting the recovery of regional contractility after coronary revascularization. We examined 105 consecutive patients with multivessel coronary artery disease who were candidates for bypass surgery; 79 were included in this prospective study. Preoperative reversibility of contractile dysfunction in asynergic myocardial regions was determined by PESP, with a coupling interval of 500 msec decreasing to 300 msec, with a progressive decrease by 10 msec. The examination was accompanied by continuous 2-dimensional (2D) echocardiographic monitoring. The assessed sensitivity and specificity were 92% and 87%, respectively; the predictive accuracy was 90%. These results demonstrated that PESP echocardiography is a useful and cost-effective method for identifying viable myocardium in patients undergoing myocardial revascularization.

A polymorphic form of familial arrhythmogenic right ventricular dysplasia.

Thirty-two members of a family were studied. Three of them died in their youth and had evidence of arrhythmogenic right ventricular (RV) dysplasia. The other 29 members underwent clinical examination, electrocardiography, chest x-ray and M-mode and 2-dimensional echocardiography. Fourteen patients found to have structural abnormalities of the right ventricle underwent 24-hour ambulatory electrocardiographic recording and symptom-limited bicycle stress testing. Hemodynamic and angiographic studies were performed in 6 of these patients. In this family the arrhythmogenic RV dysplasia showed a wide variation of abnormalities, ranging from mild, local alterations to generalized involvement of the right ventricle. The patients were separated into 3 groups on the basis of both the clinical profile and noninvasive/invasive studies: 3 subjects who died suddenly; 3 subjects who had severe ventricular arrhythmias; and 8 subjects in whom RV impairment was not associated with any significant arrhythmias. There was no close relation between the severity of the RV abnormality and presence of ventricular arrhythmias. The variability of the RV abnormality and the high prevalence of this condition in this family is consistent with a genetic pattern of autosomal dominance with incomplete penetrance.

Long-term echocardiographic Doppler monitoring of Hancock bioprostheses in the mitral valve position.

Echocardiographic and Doppler studies were performed in 134 patients with a Hancock bioprosthesis in the mitral valve position during a follow-up period of 1 to 216 months. Among the xenografts, 57% were clinically normal and 43% had severe dysfunction. Among the normal bioprostheses, 35% had echocardiographically thickened mitral cusps (> or = 3 mm) with normal hemodynamic function; by setting the lower 95% confidence limit of valve area at 1.7 cm2 these patients had a significantly (p < 0.01) smaller valve area than that of normal control subjects. Evaluation of all thickened normal mitral valves showed the highest incidence of thickening at 9 years after implantation. Valve replacement surgery was subsequently performed in 33 patients with dysfunctioning bioprosthetic and echocardiographic diagnosis was confirmed in 91% of explanted valves (bioprosthetic stenosis 21%, incompetence 46%, and combined stenosis and regurgitation 33%). In 2 valves that were found to be stenotic on echocardiographic examination, a calcium-related commissural tear was also observed at reoperation, and in another, a paravalvular leak was found. Dystrophic calcification, isolated (64%) or occasionally associated with fibrous tissue overgrowth (21%), was the main cause of failure. Pannus was present in prostheses with longer satisfactory function (168 +/- 31 vs 124 +/- 21 months; p < 0.001). Long-term performance was evaluated by the Kaplan-Meier method for up to 18 years of follow-up. Freedom from structural valvular disfunction after mitral replacement was 89% at 6 years, 77% at 8 years, 56% at 10 years, 31% at 12 years, 16% at 15 years, and 15% at 18 years.

Effectiveness of fixed minidose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation.

Adjusted-dose warfarin is effective for stroke prevention in patients with nonrheumatic atrial fibrillation (AF), but the risk of bleeding is high, especially among the elderly. Fixed minidose warfarin is effective in preventing venous thromboembolism with low risk of bleeding and no need for frequent clinical monitoring. Patients > 60 years with nonrheumatic AF were randomized in an open-labeled trial to receive fixed minidose warfarin (1.25 mg/day) or standard adjusted-dose warfarin (International Normalized Ratio [INR] between 2.0 and 3.0). Primary outcome events were ischemic stroke, peripheral or visceral embolism, cerebral or fatal bleeding, and vascular death. Secondary end points were major bleeding, myocardial infarction, and death. This study was discontinued before completion in light of publication of the Stroke Prevention in Atrial Fibrillation III trial, which indicated that low-intensity fixed-dose warfarin treatment (i.e., INR < 1.5) was insufficient for stroke prevention in high-risk patients with nonrheumatic AF. From a total of 1,209 considered patients, 303 were randomized to be studied (150 in the minidose group and 153 in the adjusted-dose group). Mean follow-up was 14.5 months. The rate of cumulative primary events was 11.1% (95% confidence intervals [CI] 4.0 to 18.2) in the fixed minidose group and 6.1% (95% CI 1.1 to 11.1) in the adjusted-dose group (p = 0.29). The rate of ischemic stroke was significantly higher in the minidose group (3.7% vs 0% per year, p = 0.025). Major bleedings were more frequent in standard treatment group (2.6% vs 1% per year, p = 0.19). Most thromboembolic complications occurred at INRs < 1.2, whereas the majority of hemorrhages occurred at INRs > 3.0. No significant difference in primary outcome events was observed in the abbreviated study. However, the significantly increased occurrence of ischemic stroke in the fixed minidose warfarin group suggests that this regimen does not protect patients with nonrheumatic AF.

Sulfinpyrazone reduces cyclosporine levels: a new drug interaction in heart transplant recipients.

BACKGROUND: Management of cyclosporine (CsA)-associated hyperuricemia in heart transplantation (HT) is difficult. Because of the myelotoxicity of combined allopurinol and azathioprine, we tested sulfinpyrazone. METHODS: We studied 120 HT recipients (109 men; mean age at HT, 52+/-10 years). All had received allopurinol for at least 6 months, which was stopped for 1 month before initiation of sulfinpyrazone. Mean follow-up from HT to onset of sulfinpyrazone (200 mg/day) was 59+/-41 months. We stopped the drug after 6+/-2 months. We compared CsA level and daily dose, serum creatinine, blood urea, and uric acid at onset and before interruption of sulfinpyrazone and, as control, in the last 6 months of allopurinol. RESULTS: Mean uricemia decreased with allopurinol (0.58+/-0.12 vs. 0.41+/-0.07 mmol/liter, p = 0.0001) as well as with sulfinpyrazone (0.51+/-0.13 vs. 0.40+/-0.12 mmol/liter, p = 0.0001). Mean creatinine increased (171+/-42 and 164+/-35 micromol/liter, p = 0.01) with allopurinol, whereas it tended to decrease with sulfinpyrazone (160+/-35 and 154+/-48 micromol/liter, p = NS). Mean urea did not change with allopurinol (14+/-5 vs. 15+/-7 mmol/liter, p = NS), but fell with sulfinpyrazone (14.01+/-5 vs. 12.60 +/-5 mmol/liter, p = 0.0004). Mean CsA levels were constant with allopurinol (193+/-73 vs. 188+/-65 ng/ml, p = NS), although CsA dose was slightly reduced (2.7+/-0.8 vs. 2.6+/-0.8 mg/kg/day, p = 0.007). Conversely, CsA levels dropped with sulfinpyrazone (183+/-89 vs. 121 +/-63 ng/ml, p = 0.0001) despite an increase in CsA daily dose (2.6 +/-0.9 vs. 2.8+/-0.9 mg/kg/day, p = 0.0001). Two subjects were treated for acute rejection. We observed no other side effects. In HT recipients sulfinpyrazone, as an alternative to allopurinol, is effective in achieving metabolic control of hyperuricemia. However, this drug reduced CsA levels, thus the risk of rejection is present.

Accuracy of electrocardiographic and echocardiographic indices in predicting life threatening ventricular arrhythmias in patients operated for tetralogy of Fallot.

OBJECTIVE: To validate the accuracy of the prognostic significance of non-invasive clinical diagnostic indices as predictors of sustained ventricular tachycardia (sVT) or fibrillation (VF) in patients undergoing repair for tetralogy of Fallot. METHODS: One way analysis of variance and pairwise comparison of the values with the Bonferroni correction, logistic multivariate analysis, and ordinal logistic analysis were used to study quantitative electrocardiographic and echocardiographic variables in 66 patients who had undergone surgery for tetralogy of Fallot by ventriculotomy at a mean (SD) age of 11.8 (9.5) years. The mean (SD) period of follow up was 16.1 (5.7) years after surgery. RESULTS: Four groups of patients were identified by ECG and 24 hour Holter monitoring: 19 (28.7%) without ventricular arrhythmias, 34 (51.5%) with minor ventricular arrhythmias, seven (10.6%) with non-sustained ventricular tachycardia (nsVT), and six (9.0%) with sVT or VF. One way analysis indicated significant differences in QT dispersion (QTd) and end diastolic volume of the right ventricle (EDVRV) among the groups. Univariate logistic analysis showed EDVRV, QTd, and QRS duration to be significantly associated with sVT or VF. Stepwise multivariate analysis and ordinal logistic analysis showed QTd to be preferable to QRS duration as an indicator, because it was unrelated to EDVRV, and was capable of separating different probability curves for nsVT as opposed to sVT or VF. CONCLUSIONS: Stratification of patients undergoing corrective surgery for tetralogy of Fallot and at risk of life threatening arrhythmias is possible by simple and inexpensive means, which provide sensitive and specific indices.

Cardiomyopathy: a necessary revision of the WHO classification.

The classification of myocardial disease proposed by the WHO/ISFC task force in 1980 distinguishes specific heart muscle diseases from myocardial diseases of unknown origin, termed cardiomyopathies, and differentiated into the dilated, hypertrophic and restrictive forms. This last group includes endomyocardiofibrosis and fibroblastic parietal endocarditis. In more recent years, two new forms of heart muscle disease have been recognized: so-called "primary" restrictive cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Primary restrictive cardiomyopathy is characterized anatomically by normally sized, non-hypertrophic ventricles with dilated atria, and functionally by impaired diastolic compliance due to myocardial stiffness. The clinical picture is that of chronic congestive heart failure; histology shows interstitial fibrosis and myocardial disarray, but not hypereosinophilia. In arrhythmogenic right ventricular cardiomyopathy, the myocardium of the right ventricular free wall is substituted by fibrous and/or adipose tissue, which results in regional dynamic alterations and ominous ventricular arrhythmias. The left ventricle is usually spared. Both forms should be classified as heart muscle diseases of unknown origin, and kept clearly distinct from the other cardiomyopathies listed in the WHO classification.