Morphologic spectrum of primary restrictive cardiomyopathy.

A restrictive hemodynamic profile with left ventricular (LV) end-diastolic volume < 100 ml/m2 and LV end-diastolic pressure > 18 mm Hg, in the absence of endomyocardial, pericardial, and specific cardiomyopathy, is a peculiar feature of primary restrictive cardiomyopathy. From 1985 to 1994, 7 hearts of patients who met the above hemodynamic criteria and underwent endomyocardial biopsy because of heart failure, were studied through gross (5 cardiectomies and 2 autopsies), histologic, and electron microscopic investigations. Ages ranged from 9 to 48 years (mean age 29 +/- 13). Four patients (57%) had a positive family history: 2 for hypertrophic and 2 for restrictive cardiomyopathy. Three patterns were identified in the 7 hearts: (1) pure restrictive form in 4 cases with mass/volume ratio 1.2 +/- 0.5 g/ml, ejection fraction 58 +/- 5%, LV end-diastolic volume 67.5 +/- 12.6 ml/m2, LV end-diastolic pressure 26.7 +/- 3.5 mm Hg; (2) hypertrophic-restrictive form in 2 cases with mass/volume ratio 1.5 +/- 0.07 g/ml, ejection fraction 62 +/- 1%, LV end-diastolic volume 69 +/- 10 ml/m2, LV end-diastolic pressure 30 +/- 7 mm Hg; and (3) mildly dilated restrictive form in 1 case with mass/volume ratio 0.9 g/ml, ejection fraction 25%, LV end-diastolic volume 98 ml/m2, LV end-diastolic pressure 40 mm Hg. Histology and electron microscopy disclosed myocardial and myofibrillar disarray and endoperimysial interstitial fibrosis in each pattern. The familial forms suggest the presence of a genetic abnormality. Primary restrictive cardiomyopathy may present with or without hypertrophy and shares similar microscopic pictures with hypertrophic cardiomyopathy. The 2 entities may represent a different phenotypic expression of the same genetic disease.

Effects of iloprost (ZK 36374) on glutathione status during ischaemia and reperfusion of rabbit isolated hearts.

1. Reperfusion of rabbit isolated hearts after 60 min of ischaemia resulted in poor recovery of mechanical function, release of creatine phosphokinase (CPK) and of reduced (GSH) and oxidized (GSSG) glutathione, reduction of mitochondrial superoxide dismutase (Mn SOD) activity and of tissue GSH/GSSG ratio with a shift of cellular thiol redox state toward oxidation, suggesting the occurrence of oxidative stress. 2. Pretreatment of the isolated heart with the stable prostacyclin analogue (iloprost) at 27 or 270 nM, but not at 2.7 nM, improved the functional recovery of the myocardium, reduced CPK, GSH and GSSG release, maintained Mn SOD activity and attenuated the occurrence of oxidative stress. 3. This effect of iloprost cannot be explained by a decreased demand or an enhanced delivery of oxygen during ischaemia or by a direct effect on glutathione peroxidase and reductase activity.

Donor shortage in heart transplantation. Is extension of donor age limits justified?

Chronic shortage of donor organs for heart transplantation led us to extend donor age limits. To verify the effectiveness of such a policy we have compared the results of heart transplantation in 45 patients with donors more than 40 years of age (group 1) with those of 72 patients older than 50 years of age who had heart transplantation with younger donors (group 2) between November 1985 and December 1992. The two groups were comparable in terms of mean recipient age, recipient and donor sex, and indication for heart transplantation. Mean donor age was 46 +/- 4 years (range 41 to 59 years) in group 1 and 23 +/- 7 years (range 8 to 39 years) in group 2 (p < 0.001). In group 1 cerebrovascular accidents were more common as the cause of donor death (60% versus 16%, p = 0.001), and no difference was found in ischemic time (144 +/- 47 minutes versus 140 +/- 48 minutes, p = not significant). There were 6 early (< 30 days) deaths in group 1 (13%) and 10 in group 2 (14%; p = not significant). Fatal acute graft failure was more prevalent, but not significantly so, in group 1 (10% versus 5.5%, p = not significant). Mean follow-up was 29 +/- 20 months (range 3 to 78 months) in group 1 and 30 +/- 20 months (range 3 to 80 months) in group 2 (p = not significant). At 5 years actuarial survival was 80% +/- 6% in both groups with comparable graft performance at echocardiographic and hemodynamic control studies. A significant difference was found in freedom from any type of coronary artery abnormality between group 1 (49% +/- 13%) and group 2 (77% +/- 8%) at 5 years (p < 0.05); however, freedom from coronary stenotic lesions only was similar. Major conduction disturbances have occurred more frequently in patients of group 1 (37% versus 12%; p = 0.003) without any difference in the need for permanent pacing. Donors older than 40 years of age can be accepted for heart transplantation with early and long-term results comparable with those obtained with younger donors. The impact of a higher incidence of coronary abnormalities on late performance of older grafts must be assessed at longer follow-up. Our results indicate that, because of the current organ shortage, extension of donor age limits is justified, even up to the sixth decade of life in selected cases.

Global and regional left ventricular function in heart transplant patients: an angiographic follow-up study.

We studied the global and regional left ventricular function, its determinants and its modification with time, in orthotopic heart transplant recipients. We reviewed the left ventricular cineangiography performed 1 (50 patients), 2 (33 patients), 3 (18 patients), and 4 (seven patients) years after operation. Regional wall motion was quantitatively evaluated by the area method. All patients had angiographically normal coronary arteries and no evidence of acute rejection at the time of the study. One year after heart transplantation, cardiac index and left ventricular ejection fraction were mildly but significantly lower than normal. Cardiac index was more than 2.5 L/min/m2 in all but one patient, and ejection fraction was more than 50% in all patients. Only previous acute cardiac rejection necessitating therapy and arterial hypertension showed some influence on the left ventricular function. Two years after operation, the left ventricular end-diastolic volume was increased, and left ventricular mass-volume ratio decreased compared with year 1. Three years after operation, an increase of left ventricular end-diastolic pressure and of left ventricular ejection fraction was also evident. Four years after operation, the heart rate was higher, compared with previous years. Even if the changes in the parameters of left ventricular function were significant, they were small in terms of absolute value. Regional hypokinesia was detected 1 year after heart transplantation in eight patients, involving one segment in six patients and two segments in two patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Discordance between pre and post cardiac transplant diagnosis: implications for pre- and postoperative decision making.

A correct clinical diagnosis in end-stage patients undergoing cardiac transplantation may have important prognostic and therapeutic implications. A retrospective clinico-pathologic study was carried out in 257 patients who had undergone cardiac transplantation at the University of Padua. A discrepancy between clinical and pathological diagnosis was found in 20 cases (8%). Among 126 patients with the clinical diagnosis of dilated cardiomyopathy, seven were found eventually to have ischemic heart disease (IHD), five myocarditis, one arrhythmogenic right ventricular cardiomyopathy (ARVC), and one non-compacted myocardium. Among the 87 patients with clinical diagnosis of IHD, three turned out to be dilated cardiomyopathy and one granulomatous myocarditis. Among the 10 patients with the clinical diagnosis of hypertrophic-restrictive cardiomyopathy, one had ARVC and one had cardiac fibroma. Altogether, only 24.5% underwent endomyocardial biopsy (EMB) and 75% coronary angiography before transplantation. Missed diagnosis of myocarditis occurred in patients in whom EMB was not carried out. EMB and coronary angiography might be indicated routinely in patients with apparent dilated cardiomyopathy, before proceeding to cardiectomy.

Oxygen free radical-mediated heart injury in animal models and during bypass surgery in humans. Effects of alpha-tocopherol.

There is evidence that oxygen free radicals play a role in myocardial ischemic and reperfusion injury. We investigated the effect of ischemia and reperfusion on glutathione status. Reperfusion after prolonged ischemia (60 min) induced an important release of reduced (GSH) and oxidized (GSSG) glutathione, concomitant with an increase of tissue GSSG and no recovery of mechanical function, indicating that reperfusion results in oxidative stress. These alterations are associated with tissue and mitochondrial calcium accumulation, loss of mitochondrial function, and membrane damage. We also determined the arteriocoronary sinus difference for GSH and GSSG of 16 CAD patients undergoing coronary artery bypass. Patients were divided in two groups according to the length of clamping period: 25 +/- 2 min (group 1), and 55 +/- 6 min (group 2). In group 1, reperfusion resulted in a transient release of GSH, GSSG, CPK, and lactate, with return to preclamping values in 10 minutes. In group 2, reperfusion determined a sustained and pronounced release of GSH, GSSG, CPK, and lactate during declamping, suggesting the occurrence of an oxidative stress. Using an in vitro model, administration of alpha-tocopherol bound with albumin showed protection of mitochondrial function, improved recovery of contraction, and reduced oxidative stress during reperfusion.

Clinical results of steroid-free induction immunosuppression after heart transplantation.

Between January 1987 and September 1991, 112 operative survivors of heart transplantation were initially immunosuppressed with cyclosporin A and azathioprine without prednisone. Eighty-eight patients (79%) remained on a regimen of double therapy for a mean follow-up of 25 +/- 15 months (range, 1 to 54 months), whereas 24 patients (21%) had oral prednisone, 5 mg/day, added to maintenance therapy for persistent or repeated rejection. There were 5 early deaths (4%) because of acute rejection (4 patients) or infection (1 patient). Only 1 patient died late after heart transplantation of chronic rejection. Actuarial survival was 95% +/- 2% and 94% +/- 3% at 12 and 48 months, respectively. Mean rate of acute rejection was 1.7 +/- 1.0 episodes per patient, with a 5% +/- 2% freedom from rejection at 48 months. Ten patients (9%) required in-hospital treatment for infection; the actuarial freedom from infectious episodes was 85% +/- 4% at 48 months. Actuarial freedom from hypertension was 43% +/- 7% at 48 months. At annual catheterization, mean left ventricular ejection fraction was 0.64 +/- 0.08 and 0.62 +/- 0.05 at 1 year and 4 years, respectively, with evidence of coronary lesions in 9 patients (8%). In conclusion, steroid-free immunosuppression after heart transplantation is associated with a high incidence of acute rejection. However, the excellent medium-term survival and the low incidence of both infection and chronic rejection seem to justify a wider use of such treatment.

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.

Angiographic presentation of coronary artery spasm in heart transplant recipients.

We describe the angiographic characteristics of coronary artery spasm observed in 12 out of 247 (4.9%) patients who underwent 808 coronary angiographies after heart transplantation. Coronary artery spasm was diagnosed when localized and reversible narrowing of the coronary lumen was identified. After coronary artery spasm identification all patients were followed-up clinically for a mean period of 5.1 years. Coronary artery spasm was documented 1-3 years after heart transplant. Coronary artery spasm affected 1 main coronary artery in 10 patients and 2 in 2 patients; in 3 patients 1 or more secondary branches were also affected. The right coronary artery was affected by coronary artery spasm in 8 patients and the anterior descending coronary artery in 6 patients. In 6 patients coronary artery spasm was mechanically induced by the catheter tip. The degree of luminal narrowing due to coronary artery spasm ranged from mild to almost complete occlusion. Coronary artery spasm appeared as a single tubular smooth and concentric stenosis in 8 patients, was discrete in 2 patients and multiple on the same vessel in 2 patients. In 1 patient coronary artery spasm was erroneously interpreted as an organic lesion and percutaneous transluminal coronary angioplasty was planned. During follow-up 3 patients out of 4 who had shown multiple coronary artery spasm died and 2 patients developed critical organic stenosis. In conclusion coronary artery spasm after heart transplant is less rare than commonly believed. Although it usually has a peculiar appearance, it can be misinterpreted as an organic lesion. Multiple coronary artery spasm appears to carry a poor prognosis.

Endomyocardial biopsy in right ventricular cardiomyopathy.

Right ventricular cardiomyopathy is characterized by a progressive myocyte loss and fibro-fatty substitution of the right ventricle. The aim of our study was to assess the diagnostic accuracy of right ventricular endomyocardial biopsy. Using an imaging analyser system, histomorphometric parameters of myocytes, interstitium, fibrous tissue and fatty tissue were evaluated on endomyocardial biopsy from 30 patients with arrhythmogenic right ventricular cardiomyopathy, 29 patients with dilated cardiomyopathy and 30 control patients. The percent area of myocytes decreased from 78.10 +/- 7.34 in control to 63.39 +/- 9.22 in dilated cardiomyopathy (P < 0.05) and to 47.28 +/- 15.01 in arrhythmogenic right ventricular cardiomyopathy (P < 0.01). Fibrous tissue increased from 8.10 +/- 3.89 in control to 21.80 +/- 9.29 in dilated cardiomyopathy (P < 0.05) and to 24.60 +/- 11.37 in arrhythmogenic right ventricular cardiomyopathy (P < 0.05). Fatty tissue varied from 0.33 +/- 1.44 in control and 0.07 +/- 0.31 in dilated cardiomyopathy to 13.30 +/- 17.30 in arrhythmogenic right ventricular cardiomyopathy (P < 0.05). Fatty tissue was a feature of arrhythmogenic right ventricular cardiomyopathy (67% of patients vs. 6% of control and dilated cardiomyopathy patients). Diagnostic values typifying arrhythmogenic right ventricular cardiomyopathy, obtained by excluding any overlapping between confidence intervals in the three groups, were: myocytes < 44.95%; fibrous tissue > 40.38%, and fatty tissue > 3.21%, with 67% sensitivity and 91.53% specificity for at least one parameter. In conclusion, a significant difference between arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy and control exists in terms of amount of myocytes, fibrous tissue and fatty tissue. Presence of fatty tissue and fibrous tissue exceeding 3.21% and 40.38%, respectively should be considered highly suspect for arrhythmogenic right ventricular cardiomyopathy in right ventricular endomyocardial biopsy.

Mid-term results of heart transplantation for end-stage valvular disease.

The results of heart transplantation in a consecutive series of 19 end-stage valvular disease patients (15 male, aged 48 +/- 8 years) were analysed retrospectively. The indication for heart transplantation was heart failure due to left and/or right ventricular dysfunction; 16 patients had undergone previous valve surgery, but prosthetic dysfunction was present in only one patient. All patients were in NYHA class IV, 15 were on oral anticoagulants and 5 on i.v. catecholamine support. There were four in-hospital deaths (21%) and one late death (5%), resulting in a 1-year mortality rate slightly, but not significantly, higher than that of patients transplanted for other indications (16%). Mean follow-up of the survivors was 48 +/- 33 months (range 9-95); 5-year actuarial survival was similar to that observed among the other heart transplantation patients (74 +/- 10% vs 77 +/- 3%, P = NS). The incidence of acute rejection and infection was also similar in valvular disease and non-valvular disease patients. Kidney and liver function at 1 year post-heart transplantation was preserved in all cases; cardiac catheterization revealed normal graft function in all patients and the absence of coronary lesions in all but two. In conclusion, in our limited experience morbidity and mortality in patients transplanted for end-stage valvular disease seem to be similar to those of patients undergoing heart transplantation for other etiologies.

Mid-term results of heart transplantation in diabetic patients.

BACKGROUND: Diabetes mellitus (DM) has been considered a relative contraindication to heart transplantation (HTx) because of possible increased infection rates and worsening DM with prednisone immunosuppression. The introduction of cyclosporine has allowed us to reduce the dosage of oral steroids and to accept DM patients (pts) for HTx. We reviewed the mid-term outcome of our DM pts who had undergone HTx. MATERIALS AND METHODS: Out of 257 HTx recipients, 19 males and 3 females, aged 53 +/- 8 years, were diabetic. Prior to HTx, DM was controlled with insulin in 5, with oral hypoglycemic agents in 7 and with diet in the remaining patients. Immunosuppression consisted of cyclosporine and azathioprine; low-dose prednisone was added in 10 patients because of repeated rejections. RESULTS: All patients survived HTx and were followed 2 to 75 (mean 38 +/- 21) months. There were 4 late deaths, with actuarial survival of 84% at 5 years. DM was more difficult to control after HTx (12 patients requiring insulin vs 5 pre-HTx), but comparison of diabetic vs non diabetic patients following HTx showed no significant difference in frequency of rejection or infection during the 1st year (2.6 +/- 1.6 vs 2.1 +/- 1.5; 0.5 +/- 0.4 vs 0.4 +/- 0.3 episode/patient respectively) and in 5-year actuarial survival (84% vs 77%). Renal function is preserved in all DM patients, hypertension has developed in 11/18 (61%); annual post-HTx cardiac catheterisation has shown normal graft function and coronary arteries in all but 2 patients. CONCLUSIONS: Mid-term results indicate that HTx can be safely performed in diabetic patients; a longer follow-up is required to determine whether DM is no longer a contraindication to HTx.

Ischemic cardiomyopathy: lack of clinical applicability of the WHO/ISFC classification of cardiomyopathies.

BACKGROUND: The classification of cardiomyopathies proposed by the WHO/ISFC Task Force defines ischemic cardiomyopathy as "a dilated cardiomyopathy with impaired contractile performance not explained by the extent of coronary disease or ischemic damage". The aim of this study was to verify the clinical applicability of the WHO/ISFC definition of ischemic cardiomyopathy. METHODS: Retrospective analysis of the clinical characteristics of patients with a left ventricular ejection fraction < 40%, in whom coronary angiography showed a) stenosis < or = 50% of a main coronary artery and/or b) stenosis > 50% of a distal portion of a main coronary artery or of a secondary branch. The patients with a clinical diagnosis of previous myocardial infarction were excluded. RESULTS: Fourteen patients with the angiographic characteristics listed above were identified. Twelve patients were males, mean age 59 years. They represented 3.8% of all the patients with left systolic ventricular dysfunction who underwent coronary angiography in the same period. The left ventricular end-diastolic volume was 170 +/- 45 ml/m2 and the ejection fraction was 27 +/- 6%. The cause of systolic left ventricular dysfunction was systemic arterial hypertension in 3 patients, diabetes mellitus in 2, a combination of these diseases in 4, chronic alcohol abuse in 1, a previous clinically silent myocardial infarction in 1, and idiopathic dilated cardiomyopathy in 3. CONCLUSIONS: In conclusion, in all our patients with severe left ventricular dysfunction which was not explained by the extent of coronary artery disease, at least one possible cause of impaired contractile performance could be identified. Thus the definition of ischemic cardiomyopathy according to the new WHO/ISFC classification of cardiomyopathies appears to be of scarce utility on clinical grounds and should be redefined and if necessary reclassified.

[Treatment of heart failure at a hospital in the north-east of Italy]. / Il trattamento dello scompenso cardiaco in un'Azienda Ospedaliera del Nord-Est.

Because the number of patients who require hospitalization for heart failure is increasing, their treatment is often entrusted to physicians operating in Departments of General Medicine. Published data on the in-hospital treatment of heart failure in Italy have not been available up to now, as they are limited only to patients admitted to Department of Cardiology. This study concerns the patients who were discharged from our Hospital after a diagnosis of heart failure (International Classification of Disease--9th Edition, code 428) from January 1 to February 28, 1998. Information collected from patient hospital records included: age, sex, department to which the patient was referred (General Medicine or Cardiology), cause of heart failure, New York Heart Association (NYHA) functional class, symptoms and signs of heart failure, therapy, length of hospitalization and in-hospital mortality. Of the 178 patients identified (82 males--46.1%, 96 females--53.9%, mean age 78 +/- 11 years) 163 (91.6%) were referred to Departments of General Medicine. The cause of heart failure was coronary artery disease in 88 (49.4%) patients, arterial hypertension in 40 (22.4%), primary cardiomyopathy in 28 (15.7%), valvular heart disease in 22 (12.3%). NYHA functional class was reported or deducible from the severity of dyspnea in 57 (32%) patients. In 8 (4.6%) patients symptoms or signs of heart failure were not reported. Chest X-ray was performed in 77.6% of cases, echocardiography in 41%, ambulatory electrocardiography in 10% and coronary arteriography in 5%. Left ventricular ejection fraction was known in 90 (51.6%) patients, in 44 (48.9%) of these it was > or = 45%. ACE-inhibitors were used in 99 (55.6%) patients, but this percentage rose to 63% when considering only patients with left ventricular ejection fraction < 45%. Eighty-five patients were treated with captopril or enalapril; in 52 patients (61.4%) the daily dose of captopril was < 75 mg and that of enalapril was < 20 mg. Diuretics were utilized in 155 (87%) patients, digoxin in 123 (69%), beta-blocker agents in 5 (2.8%) and other vasodilators in 95 (53%). The mean length of hospitalization was 13 +/- 9 days and the overall in-hospital mortality was 18%. In conclusion, the results of this study demonstrate that the patients who are discharged from our hospital with a diagnosis of heart failure are, on the average, very old. The vast majority of these patients are admitted to the Departments of General Medicine. The advanced age of our patients can explain the limited use of ACE-inhibitors and, especially, of beta-blockers.