Active versus borderline myocarditis: clinicopathological correlates and prognostic implications.

OBJECTIVE: To compare active (AM) with borderline (BM) myocarditis to verify whether the pathological distinction between the two forms may help to identify patients with different clinical and haemodynamic characteristics and to aid prognosis. MATERIALS: Myocarditis was diagnosed in 56 patients on endomyocardial biopsy (EMB) within one year from clinical onset of the disease between 1991 and 1998. Fourteen patients were excluded because of a lack of adequate and complete information. EMBs and clinical records of the 42 remaining patients were reviewed. Immunohistochemistry on bioptic samples was regularly performed. Polymerase chain reaction (PCR) for a panel of viruses was performed in 23 patients (55%). Clinicopathological correlations were calculated. RESULTS: The histological diagnosis was AM in 26 patients (62%) and BM in 16 (38%). Significant differences were found in the following parameters: presence of left bundle branch block on ECG (AM 2 (8%) v BM 5 (31%), p = 0.05); left ventricular volume on echocardiogram (mean (SD) AM 90 (42) ml/m(2) v BM 128 (50) ml/m(2), p = 0.002); mass to volume ratio (AM 1.0 (0) v BM 0.8 (0.1), p = 0.03); time interval between clinical onset of the disease and EMB (AM 40 (55) v BM 90 (93) days, p = 0.04); and degree of inflammatory infiltrates, scored on a scale of 0 to 3 (AM 1.65 (0.8) v BM 0.85 (0.3), p = 0.004). In 6 of 15 patients (40%) with AM and in 2 of 8 (25%) with BM, a viral genome was detected by PCR (NS). At follow up, no differences in death or heart transplantation were detected between the two forms (AM 4 patients (15%) v BM 2 patients (12.5%)). Three of eight PCR positive patients (37.5%) and 1 of 15 virus negative patients (7%) died or underwent heart transplantation. CONCLUSIONS: BM seems to encompass inflammatory forms with a less aggressive inflammatory infiltrate evolving towards left ventricular dilatation. The term "chronic myocarditis" seems to be more appropriate. The absence of myocyte necrosis does not predict a more favourable prognosis, whereas the absence of a viral genome seems to predict it.

[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.

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.

Myocarditis mimicking acute myocardial infarction: role of endomyocardial biopsy in the differential diagnosis.

OBJECTIVE: To test the hypothesis, using endomyocardial biopsies, that unexplained cases of apparent acute myocardial infarction were caused by myocarditis. MATERIAL: Between 1992 and 1998, 12 patients were admitted to the coronary care unit with severe chest pain, ST segment elevation, increased serum creatine kinase and MB isoenzyme, and with wall motion abnormalities on echocardiogram highly suggestive of acute myocardial infarction. These patients were further investigated by endomyocardial biopsy, as their coronary angiograms were normal. A diagnosis of myocarditis was made according to the Dallas criteria. A panel of antibodies was used for immunohistochemical characterisation of inflammatory cell infiltrate. Polymerase chain reaction (PCR) was used to detect viral genomes in seven cases. RESULTS: Haematoxylin and eosin staining of the endomyocardial biopsy showed active myocarditis in six patients and borderline myocarditis in one. Immunohistochemistry was positive for inflammatory cell infiltrates in 11 patients, including all the seven who were positive on haematoxylin and eosin staining according to the Dallas criteria. Only one patient had no evidence of inflammation. PCR was positive in two patients, both for Epstein-Barr virus. Follow up showed complete resolution of echocardiographic abnormalities in all patients except one. CONCLUSIONS: Myocarditis can mimic acute myocardial infarction in patients with angiographically normal coronary arteries, leading to errors of treatment. In patients with apparent myocardial infarction and a normal coronary angiogram, endomyocardial biopsy may help in the diagnosis of myocarditis. The sensitivity of endomyocardial biopsy was enhanced by using immunohistochemical and molecular biological techniques.

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.

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.

[Improvement of short-term prognosis in patients with refractory heart failure]. / Miglioramento della prognosi a breve termine dei pazienti con scompenso cardiaco refrattario.

BACKGROUND: Prognosis of patients with severe heart failure is poor, despite improved results in medical therapy. Heart transplantation is the only treatment possible in end-stage heart failure. The aim of this study was to evaluate the variation in prognosis over the past six years in the patients admitted to Intensive Care Unit for heart failure in spite of optimal oral therapy. STUDY POPULATION AND METHOD: Between January 1990 and December 1995, 133 patients with heart failure were admitted to the Intensive Care Unit, despite the fact that they were on optimal oral therapy. All patients were in New York Heart Association (NYHA) functional class III to IV and required intravenous administration of sympathomimetic amines, in addition to standard heart failure treatment procedures. Cumulative survival at six months of patients observed between 1990-1992 (group A) was compared with the survival rate of patients observed from 1993 to 1995 (group B). RESULTS: Clinical and haemodynamic parameters were similar in groups A and B, but ACE-inhibitors were used more frequently in group B (75 vs 31% respectively, p < 0.05). During the follow-up period, heart transplantation was indicated in a similar percentage of patients (A 53% vs B 58%). However, mortality on the waiting list (58% group A vs 21% group B; p < 0.05) and the percentage of patients who underwent heart transplantation (41% group A vs 78% group B; p < 0.05) differed. Moreover, all patients in group A and 50% of group B were operated on as "status one" patients. The total six-month mortality rate decreased from 69% before 1992 to 48% thereafter (p < 0.05). CONCLUSION: The short-term prognosis of patients with refractory heart failure improved over time. In the latter period, ACE-inhibitors were used more frequently and the number of heart transplantations was greater. Nevertheless, our results do not allow us to identify the causes of the improved survival rate.

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.

Autoimmunity in myocarditis and dilated cardiomyopathy: cardiac autoantibody frequency and clinical correlates in a patient series from Italy.

BACKGROUND: Organ- and disease-specific cardiac autoantibodies, detected by indirect immunofluorescence, represent markers of autoimmunity in a subgroup (25-35%) of patients with dilated cardiomyopathy or myocarditis from Northern Europe and the United States of America. Autoantibody frequencies, as well as associations between clinical and immunological features, may vary in patients from different countries, due to ethnically related differences in genetic susceptibility to autoimmune disease. METHODS: We assessed the frequency of cardiac autoantibodies in a series from Italy, including 91 subjects with idiopathic dilated cardiomyopathy (61 male, aged 49 +/- 11 years) and 11 with biopsy-proven (Dallas criteria) myocarditis (7 male, aged 23 +/- 16), including 2 cases of giant cell myocarditis. Controls were 160 patients with other cardiac disease, 141 with ischemic heart failure and 270 normals Cardiac antibody test was performed blindly by indirect immunofluorescence on normal human myocardium and skeletal muscle. RESULTS: The frequency of organ-specific cardiac autoantibodies was higher (p = 0.0001) in myocarditis (45%) and in dilated cardiomyopathy (20%) than in other cardiac disease (1%), in ischemic heart failure (1%), or in normals (2.5%). Cross-reactive antibodies were detected in similar proportions of study patients and controls. Both patients with giant cell myocarditis were antibody positive. Myocarditis patients with cardiac antibodies had shorter duration of symptoms compared to those who were antibody negative (0.4 +/- 0.3 vs 4 +/- 1 months, p = 0.004). In dilated cardiomyopathy, antibody status was not associated with any clinical or diagnostic feature. CONCLUSIONS: Autoimmunity is involved in a subset of patients with myocarditis and with dilated cardiomyopathy, regardless of their geographical origin or immunogenetic background. The antibody frequency in our dilated cardiomyopathy series from Italy tended to be lower than in other countries. This may reflect reduced antibody levels with disease progression and/or the recognised feature that Mediterranean populations are often less susceptible to autoimmune disease.

[Analysis of risk factors in a group of patients referred for heart transplantation for refractory heart failure: multivariate analysis]. / Analisi dei fattori di rischio in un gruppo di soggetti riferiti per trapianto cardiaco a causa di uno scompenso cardiaco refrattario: analisi multivariata.

BACKGROUND: In the absence of evident clinical controindication heart transplantation can be performed in patients with critical degree of cardiac failure. The choice of adequate candidates for transplantation is frequently based on clinical severness but also influenced by factors as body size, blood group and so on. METHODS: To identify the presence of prognostic factors for patients with high risk of death, clinical, hemodynamic and therapeutic features of 70 patients (mean age 44.8 +/- 13.8) with critical cardiac failure (64 patients in IV class N.Y.H.A.) have been reviewed. Most of them were affected by dilated or ischemic cardiomyopathy. RESULTS: All patients were admitted to Cardiac Intensive Care Unit, 13 patients received transplantation, 24 were discharged and 33 died. Univariate analysis evidenced, that in the group of patients who died, sepsis (p = 0.0003), renal (p = 0.04) and liver function impairment (P = 0.007) occurred significantly more frequent. The differentiated use of catecholamines (P = 0.0007) and of vasodilators (P = 0.007), the need of mechanical ventilation (P = 0.0001) and the need of hemodialysis (P = 0.02) resulted significantly higher in the group of dead patients where mean arterial pressure (p = 0.01) and mean systemic resistances (P = 0.04) resulted significantly lower. With multivariate analysis were identified following independent risk factors of death: male sex, infections, mechanical ventilation, differentiated use of vasodilators, mean arterial pressure and mean pressure in pulmonary artery. CONCLUSIONS: As predictive risk factors of death in patients with critical cardiac failure and awaiting transplantation resulted: sex, the presence of infection, mechanical ventilation and differentiated use of vasodilators whereas hemodynamic parameters did not result of important predictive value.

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.

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.