Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review.

OBJECTIVE: Peripartum cardiomyopathy (PPCM) is a rare life-threatening cardiomyopathy of unknown cause that occurs in the peripartum period in previously healthy women. In April 1997, the National Heart, Lung, and Blood Institute (NHLBI) and the Office of Rare Diseases of the National Institutes of Health (NIH) convened a Workshop on Peripartum Cardiomyopathy to foster a systematic review of information and to develop recommendations for research and education. PARTICIPANTS: Fourteen workshop participants were selected by NHLBI staff and represented cardiovascular medicine, obstetrics, immunology, and pathology. A representative subgroup of 8 participants and NHLBI staff formed the writing group for this article and updated the literature on which the conclusions were based. The workshop was an open meeting, consistent with NIH policy. EVIDENCE: Data presented at the workshop were augmented by a MEDLINE search for English-language articles published from 1966 to July 1999, using the terms peripartum cardiomyopathy, cardiomyopathy, and pregnancy. Articles on the epidemiology, pathogenesis, pathophysiology, diagnosis, treatment, and prognosis of PPCM were included. RECOMMENDATION PROCESS: After discussion of data presented, workshop participants agreed on a standardized definition of PPCM, a general clinical approach, and the need for a registry to provide an infrastructure for future research. CONCLUSIONS: Peripartum cardiomyopathy is a rare lethal disease about which little is known. Diagnosis is confined to a narrow period and requires echocardiographic evidence of left ventricular systolic dysfunction. Symptomatic patients should receive standard therapy for heart failure, managed by a multidisciplinary team. If subsequent pregnancies occur, they should be managed in collaboration with a high-risk perinatal center. Systematic data collection is required to answer important questions about incidence, treatment, and prognosis.

Comparison of usefulness between exercise capacity and echocardiographic indexes of left ventricular function in cardiac amyloidosis.

In patients with primary systemic amyloidosis (AL), the echocardiographic assessment of ventricular function alone does not always correspond to patients' symptoms and functional status. Peak oxygen uptake and anaerobic threshold (AT), in contrast, constitute 2 objective, reliable and reproducible indicators of functional status in patients with circulatory failure. Thirty-two consecutive patients (mean age 50 +/- 13 years) with histologic evidence of systemic primary AL were studied (29 AL, 3 hereditary). There were 16 with echocardiographic features of cardiac infiltration (group I) and 16 without (group II). Twenty age- and gender-matched healthy subjects were also studied for comparison. Of the 32 patients, 12 were in New York Heart Association functional class I, 9 were in class II, and 11 were in class III. Each subject underwent 2-dimensional and Doppler echocardiography and cardiopulmonary exercise testing using a modified Bruce protocol. Left atrial (LA), left ventricular (LV) dimensions, wall thickness, and LV fractional shortening, as well as transmitral flow velocities and their E/A ratio were measured. Peak oxygen consumption (VO2max [ml/kg/min]), AT (ml/kg/min), and exercise duration (seconds) were also measured. VO2max and AT were lower in patients with AL than in controls (20.8 +/- 7.0 vs 35.0 +/- 8.5, p <0.001 and 13.1 +/- 3.7 vs 27.0 +/- 4.2, p <0.001, respectively). As a group, symptomatic patients had lower VO2max, AT, and exercise duration than those without symptoms (17.1 +/- 3.6 vs 27.0 +/- 6.9, p = 0.0001, 11.1 +/- 2.1 vs 16.2 +/- 3.6, p = 0.0001, and 489 +/- 235 vs 843 +/- 197, p = 0.0001, respectively), whereas LV dimensions only showed a small difference (p = 0.03). VO2max, AT, and exercise duration of patients in functional class I were higher than those in functional classes II and III (p = 0.01, p <0.05, and p = 0.007, respectively). Asymptomatic patients had lower VO2max, AT, and exercise duration than controls (p <0.0001). VO2max, AT, and exercise duration were poorly related to LA diameter, LV dimensions, fractional shortening, wall thickness, peak velocities of E and A waveforms, and E/A ratio. Patients with VO2max > 15 ml/kg/min had a better survival than patients with VO2max < 15 ml/kg/min. Thus, in patients with primary systemic AL, cardiorespiratory exercise testing is the preferred way of assessing functional capacity. Echocardiographic Doppler indexes at rest are not predictive of a patient's symptoms and exercise capacity. Furthermore, VO2max is a strong independent predictor of survival in these patients.

Marked variation in the cardiomyopathy associated with Friedreich's ataxia.

OBJECTIVE: To document the cardiac phenotype associated with Friedreich's ataxia, a recessively inherited disorder characterised by spinocerebellar degeneration. SETTING: Individuals with Friedreich's ataxia who accepted the invitation to participate in the study. HYPOTHESIS: The cardiomyopathy associated with Friedreich's ataxia may offer a human model for the study of factors modulating cardiac hypertrophy. METHODS: 55 patients (mean (SD) age 30 (9) years) with a clinical diagnosis of Friedreich's ataxia were studied by clinical examination, electrocardiography, cross sectional and Doppler echocardiography, and analysis of the GAA repeat in the first intron of the frataxin gene. RESULTS: A wide variety of cardiac morphology was documented. Subjects with normal frataxin alleles had no evidence of cardiomyopathy. In homozygous subjects, a relation was found between the thickness of the interventricular septum (r = 0.53, p < 0.005), left ventricular mass (r = 0.48, p < 0.01), and the number of GAA repeats on the smaller allele of the frataxin gene. No relation was shown between the presence of electrocardiographic abnormalities (mainly repolarisation changes) and either the pattern of ventricular hypertrophy (if present) and degree of neurological disability or the length of time since diagnosis. No tendency to ventricular thinning or dilatation with age was found. Although ventricular systolic function appeared impaired in some cases, Doppler studies of ventricular filling were within the normal range for age. CONCLUSIONS: The cardiomyopathy associated with Friedreich's ataxia shows a variable phenotype which is not concordant with the presence of ECG abnormalities or the neurological features of the condition. As the genetic basis for Friedreich's ataxia has been established, further studies will help to clarify the molecular mechanisms of the cardiac hypertrophy.

Primary pulmonary hypertension: pathologist as patient.

We describe the case of Julia Polak, an internationally known pathologist with an interest in primary pulmonary hypertension, a condition which she was subsequently diagnosed to have. This was successfully treated by heart/lung transplantation and she was then in the unique position to study and present her own pulmonary pathology. Professor Polak's case illustrates the difficulty in diagnosis, the frequent failure of medical treatment and an excellent outcome from heart/lung transplantation. Based on a presentation to a clinico-pathological conference at Hammersmith Hospital.

Echocardiographic assessment of cardiac involvement in systemic AL amyloidosis in relation to whole body amyloid load measured by serum amyloid P component (SAP) clearance.

The severity of cardiac infiltration in AL amyloidosis is unrelated to whole body amyloid load as measured by serum amyloid P (SAP) tracer studies. Radiolabeled SAP and echocardiography permit identification of patients with severe cardiac disease with a low whole body load who may be the best candidates for transplantation.

Myocardial beta adrenoceptor density in primary and secondary left ventricular hypertrophy.

OBJECTIVES: Myocardial beta-adrenoceptor density has been found to be reduced in hypertrophic cardiomyopathy, even when systolic function is preserved. Our purpose in the current study was to investigate whether beta-adrenoceptor down-regulation was unique to hypertrophic cardiomyopathy, or is also present in secondary myocardial hypertrophy. METHODS: Myocardial beta-adrenoceptor density was measured in 11 patients with hypertrophic cardiomyopathy, eight patients with left ventricular hypertrophy secondary to arterial hypertension or aortic valve disease and 18 normal control subjects, using positron emission tomography with 11C-CGP-12177 as the myocardial beta-adrenoceptor ligand. RESULTS: Reflecting the natural incidence of the conditions, the age of the hypertrophic cardiomyopathy patients was 37 (10) [mean (SD), range 20-51] years and that of the secondary hypertrophy patients 64 (18), [range 26-80] years; P < 0.01. The controls' ages were 50 (13), [range 21-65] years; however, since beta-adrenoceptor density is known to be influenced by age, the controls' data was split into groups matched to the hypertrophic cardiomyopathy and secondary hypertrophy patient sets. For the hypertrophic cardiomyopathy patients, mean left ventricular beta-adrenoceptor was 7.70 (1.86) pmol.g-1 compared to 10.17 (2.44) pmol.g-1 for a matched set of 15 controls; P < 0.01. In secondary left ventricular hypertrophy, beta-adrenoceptor was 6.35 (1.70) pmol.g-1 compared to 9.16 (2.00) pmol.g-1 for a matched set of 10 controls; P < 0.01. Plasma noradrenaline was 5.5 (2.2) nmol.l-1 in hypertrophic cardiomyopathy and 2.5 (1.0) nmol.l-1 for the matched controls; P < 0.01. The results for adrenaline were 2.2 (1.1) vs 0.4 (0.3) nmol.l-1 respectively; P < 0.001. For the secondary hypertrophy patients, the corresponding figures were 2.5 (1.2) vs 2.5 (1.0) nmol.l-1 for noradrenaline for patients and controls respectively (P = ns); and for adrenaline 0.2 (0.1) and 0.3 (0.2) nmol.l-1 respectively, P = ns. On multiple regression analysis, no relationships could be demonstrated amongst plasma catecholamines, beta-adrenoceptor, myocardial blood flow and echocardiographic E/A ratio and fractional shortening. CONCLUSION: Myocardial beta-adrenoceptor density appears to be comparably decreased in both primary and secondary left ventricular hypertrophy in the presence of preserved left ventricular systolic function.

Effects of aging on neuroendocrine activation in subjects and patients in the presence and absence of heart failure with left ventricular systolic dysfunction.

The neuroendocrine profile and echocardiographic features of 40 patients (81 +/- 1 years, means +/- standard error) with heart failure and impaired left ventricular systolic function were compared with those of an age-matched group of healthy subjects, 20 younger patients with heart failure (aged 58 +/- 1 years) and 15 younger healthy subjects. Normal elderly subjects had a neuroendocrine profile similar to that of healthy younger subjects apart from elevated plasma norepinephrine (958 +/- 84 vs 302 +/- 118 pg/ml; p< 0.001) and atrial natriuretic peptide ( 40 +/- 6 vs 28 +/- 5 pg/ml; p<0.05). Despite a similar severity of heart failure, elderly patients had smaller ventricular dimensions (left ventricular internal dimension in diastole 51 +/- 2 vs 69 +/- 3 mm;p<0.0001 and greater impairment of ventricular compliance using Doppler indexes. Plasma norepinephrine was higher (1,191 +/- 80 vs 620 +/- 67 ppg/ml; p<0.01), and plasma atrial natriuretic peptide, plasma active renin, and angiotensin II were lower in elderly patients than in the younger patients with heart failure. As functional capacity declines with age, elderly patients may have less severe cardiac dysfunction for any given level of functional impairment, and this may account for most of the differences in neuroendocrine activity with age. Age appears to be an important determinant of plasma norepinephrine and may be a confounding factor in interpreting the prognostic significance of this hormone.

Symptoms of hypertrophic cardiomyopathy, with special emphasis on syncope and postprandial exacerbation of symptoms.

We undertook a prospective study of the symptoms of hypertrophic cardiomyopathy with the aim of profiling symptomatic morbidity in detail, determining the prevalence of anxiety and depression, and describing the prevalence and associations of syncope and postprandial symptom exacerbation. A questionnaire was administered to consecutive outpatients; 70 with hypertrophic cardiomyopathy, 43 with coronary artery disease, 32 with idiopathic dilated cardiomyopathy, and to 40 normal subjects. Hypertrophic cardiomyopathy patients underwent exercise testing, echocardiography, and Holter monitoring. Hypertrophic cardiomyopathy patients had a high frequency of cardiac symptoms and, on average, had a level of symptomatic morbidity equivalent to that of chronic stable angina and dilated cardiomyopathy. There was no evidence for an excess of anxiety (14%) or depression (6%) in patients with hypertrophic cardiomyopathy. Syncope and presyncope, especially provoked by exertion or posture change, were characteristic and common symptoms in hypertrophic cardiomyopathy. A history of syncope was associated with an abnormal blood pressure response to exercise in over 50% of cases that may be the mechanism of syncope in some. Postprandial exacerbation of symptoms occurred in over one-third of hypertrophic cardiomyopathy patients, half of coronary disease patients, and infrequently in dilated cardiomyopathy. Hypertrophic cardiomyopathy patients with postprandial symptoms had a greater frequency of angina, were more symptomatic, and had a reduced exercise capacity, suggesting that postprandial symptoms are a marker for more severe disease.

Tumour necrosis factor and inducible nitric oxide synthase in dilated cardiomyopathy.

BACKGROUND: Two important features of dilated cardiomyopathy (DCM) are low myocardial contractility and risk of thromboembolism. Nitric oxide (NO) exerts a negative inotropic effect on the myocardium and is produced by NO-synthase, an inducible form of which (iNOS) is stimulated by tumour necrosis factor (TNF-alpha). Accordingly, we hypothesized that locally produced TNF-alpha might contribute to the pathogenesis and complications of DCM by inducing iNOS in the heart. METHODS: iNOS and TNF-alpha were quantified by histochemistry and computerised image analysis in explanted heart tissues or myocardial biopsy material from patients with DCM (n = 21) or ischaemic heart disease (HD; n = 10) and from normal donor hearts (n = 9). FINDINGS: Immunoreactivity for iNOS was strong in myocytes of DCM hearts, particularly in areas adjacent to the endocardium, and moderately intense in blood vessels of DCM and IHD hearts. The median optical density of the immunostaining for iNOS was greater in cardiac myocytes of patients with DCM (0.86, range 0.21 to 1.29) than in those from patients with IHD (0.20, range 0.095 to 0.26) (p < 0.01) or controls (0.01, range 0.001 to 0.02) (p < 0.001). Staining for TNF-alpha was observed in the vascular endothelium and smooth muscle cells of patients with DCM but not in IHD or control tissues. INTERPRETATION: The localisation of iNOS and TNF-alpha within cardiac tissues in DCM suggests that TNF-alpha contributes to both the low contractility and the tendency to thromboembolism in these patients.

Valvular disease in pregnancy.

Previously asymptomatic mitral stenosis can lead to remarkably sudden development of life-threatening pulmonary edema in pregnancy and the patients, often immigrants from the developing world, may be unaware that they have heart disease. Diagnosis and treatment need to be rapid and effective. Left ventricular outflow tract obstruction may also lead to trouble in pregnancy with the development of angina and left ventricular failure. Regurgitant valve disease is much better tolerated in pregnancy than valvular stenosis, but mitral valve repair, usually feasible for nonrheumatic prolapsing mitral valves, should be carried out before pregnancy if regurgitation is severe. The treatment of women with Marfan's syndrome who already have aortic root widening but desire children remains very difficult, both with regard to the mother's safety and in relation to the dominant inheritance of the condition. Advice to women with artificial valves desiring pregnancy remains controversial, with continuation of warfarin increasingly favored over transfer to heparin in Europe. The use of bioprostheses in young women anticipating future pregnancy is also fading due to mounting evidence of accelerated deterioration of such bioprostheses during pregnancy.