Natural History Of Dilated Cardiomyopathy Research Articles

P3169Clinical characteristics and natural history of dilated cardiomyopathy due to BAG3 mutations

P3169Clinical characteristics and natural history of dilated cardiomyopathy due to BAG3 mutations

The natural history of dilated cardiomyopathy: how has it changed?

The natural history of dilated cardiomyopathy: how has it changed?

Plasma profiling determinants of matrix homeostasis in paediatric dilated cardiomyopathy

Dilated cardiomyopathy is an important cause of cardiac failure in both children and adults, but is more progressive in children. In adult dilated cardiomyopathy, left ventricular remodelling is associated with changes in the plasma levels of matrix metalloproteinases and tissue inhibitor of metalloproteinases. Plasma matrix metalloproteinases and tissue inhibitors of metalloproteinase changes in paediatric dilated cardiomyopathy have not been examined. This study developed a low blood volume, high-sensitivity assay to test the hypothesis that unique and differential plasma matrix metalloproteinases and tissue inhibitors of metalloproteinase profile exist in patients with paediatric dilated cardiomyopathy. A systemic blood sample (1 millilitre) was obtained from seven children aged 8 plus or minus 7 years with dilated cardiomyopathy and 26 age-matched normal volunteers. Using a high-throughput multiplex suspension immunoassay, plasma levels were quantified for collagenases (matrix metalloproteinase-8), gelatinases (matrix metalloproteinase-2 and -9), lysins (matrix metalloproteinase-3 and -7), and tissue inhibitor of metalloproteinases-1, -2, and -4. The matrix metalloproteinase to tissue inhibitors of metalloproteinases ratios were also calculated. The plasma matrix metalloproteinase-2, -7, -8, and -9 levels were increased by greater than twofold in patients with dilated cardiomyopathy than normal patients (with p less than 0.05). Patients with dilated cardiomyopathy also had significantly higher tissue inhibitors of metalloproteinases-1 and -4 (298% and 230%; with p less than 0.05). These unique findings show that a specific plasma matrix metalloproteinase/tissue inhibitor of metalloproteinase profile occurs in paediatric dilated cardiomyopathy when compared to the cases of normal children. These distinct differences in the determinants of myocardial matrix structure and function may contribute to the natural history of dilated cardiomyopathy in children and may provide a novel biomarker platform in paediatric dilated cardiomyopathy.

Natural history of dilated cardiomyopathy: from asymptomatic left ventricular dysfunction to heart failure – a subgroup analysis from the Trieste Cardiomyopathy Registry

Few data are available in the literature regarding the characteristics and prognosis of asymptomatic patients with idiopathic dilated cardiomyopathy (DCM). To determine the frequency with which patients affected by DCM are diagnosed in the asymptomatic state as well as to evaluate the natural history of such patients and the factors influencing their outcome. Moreover, we sought to compare the outcome of asymptomatic patients with that of patients with signs of overt heart failure at the time of first evaluation. We analyzed the data of 747 patients with DCM enlisted in the Heart Muscle Disease Registry of Trieste from 1978 to 2007. We divided our population into four groups; group 1 comprised 118 asymptomatic [New York Heart Association (NYHA) I] patients without a history of congestive symptoms (16%), group 2 comprised 102 asymptomatic (NYHA I) patients (14%) with a positive anamnesis for heart failure stabilized in medical therapy, group 3 comprised 327 patients (44%) with signs of mild heart failure (NYHA II) and group 4 comprised 200 patients (26%) in NYHA III-IV. During the follow-up of 112+/-63 months, 46 (21%) of 220 asymptomatic patients with DCM died or underwent heart transplantation. By Cox proportional model, left ventricular ejection fraction of 30% or less was a unique independent predictor either for death/heart transplantation (hazard ratio 3.15, 95% confidence interval 1.5-6.7, P=0.003) or for sudden death/major ventricular arrhythmias (hazard ratio 3.9, 95% confidence interval 1.7-9.3, P=0.002). Patients from group 1 had a trend for a better outcome with respect to those from group 2 (P=0.06). In comparison with the asymptomatic patients, those with signs of overt heart failure at baseline had a worse prognosis. The proportion of asymptomatic patients with DCM at the moment of first evaluation at our center is significant (30%). Among them, those without a previous history of heart failure had a less advanced disease and a trend for a better long-term outcome on optimal medical treatment. Therefore, early diagnosis may offer better long-term quality of life and even better survival. Further studies on larger populations are indicated.

Dilated cardiomyopathy in childhood: prognostic features and outcome

The natural history of dilated cardiomyopathy in children is difficult to predict due to the heterogeneous character of the disease. The outcome in infants and children is highly variable from complete recovery to death.In this study, 40 children diagnosed with dilated cardiomyopathy between 1995 and 2004 in our paediatric cardiology unit were reviewed with respect to clinical course and outcome, retrospectively. The medical history of these patients with dilated cardiomyopathy was reviewed to determine age, gender, family history, preceding viral illness, duration of symptoms before the diagnosis, symptoms and signs at presentation, treatment and outcome. The diagnosis was made on the basis of cardiomegaly and evidence of poor left ventricular function by echocardiography.Median age at diagnosis was 14 months, ranging from 2 months to 8 years. At presentation, 28 patients (70%) were under and twelve (30%) were above the age of two years.Twenty-eight (70%) patients had signs of congestive heart failure. Mean duration of follow-up was 40 ± 24 months (ranging from 6 months to 9 years), 21 patients (52.5%) recovered, 17 patients (42.5%) had residual disease and two (5%) died. The cause of death in both patients was progressive cardiac failure. Sixteen of 28 patients (57%) who were below the age of two years and five of 12 patients (42%) who were above the age of two years at presentation recovered.The rate of recovery was significantly different between the two age groups (p < 0.05). Seventeen of 21 (81%) patients with a history of recent viral illness at presentation recovered. The mean duration of the disease among those who recovered was 11 ± 8.3 months. Five of 19 (26%) patients without recent viral illness recovered.The mean duration of the disease in this group was 22 ± 12 months.There was a significant difference between the two groups with respect to recovery and recovery time (p < 0.05). During the first 6 months after diagnosis, there was a significant difference between the patients who recovered and the patients who had residual disease with respect to improvement in the left ventricular FS (22 ± 3.5%, 15.2 ± 2.8%, respectively) (p < 0.05).In conclusion, in this study, the rate of recovery and survival is higher than in previous studies. A good outcome is related to age at presentation (≤ two years old), a history of viral disease within three months of presentation and improvement in ventricular function during the first 6 months after diagnosis. Intractable heart failure has an adverse effect on the outcome.

Repression of alpha myosin heavy chain gene expression and promoter activity by the b-agonist isoproterenol – role for Ca2+/calmodulin protein kinase and ERK1/2 pathway

Dilated cardiomyopathy (DCM) from either primary or secondary causes is a major cause of chronic heart failure, and is a result of a prolonged condition of compensatory cardiac hypertrophy. The DCM phenotype consists of two pathophysiological components, contractile dysfunction and pathological hypertrophy/remodeling. b-adrenergic activation plays an important role in the natural history of DCM and its activation during periods of decreased myocardial performance or increased hemodynamic load results in increases in heart rate and contractility, effectively improving cardiac output. Heart failure is also characterized by changes in the expression levels of many of the components of the contractile apparatus. Of the changes that are observed in failing hearts, increases in b-MyHC, skeletal a-actin, and ANF, with coordinate decreases in a-MyHC and SRCA2a, are perhaps the most well-known and are generally referred to as fetal gene induction. We have recently shown that patients that respond to b1or b1, b2, a1adrenergic receptor blockade, also have a partial reversal of the fetal gene program with up-regulation of a-MyHC and Serca2A and down-regulation of b-MyHC and ANP. We have also shown that the transcription factor YY1 is upregulated in Human Heart Failure and represses the activity of the aMyHC promoter. In the work presented here, we show that stimulation of b-ARs with isoproterenol does cause a “fetal” response in the relative activities of the human cardiac MyHC promoter that includes the repression of the human a-MyHC promoter with simultaneous activation of the ANF promoter. Furthermore, we show that this “fetal” response of the MyHC promoters to isoproterenol treatment is specifically mediated by the b1-AR, 154

Natural history of dilated cardiomyopathy due to lamin A/C gene mutations

ObjectivesWe examined the prevalence, genotype-phenotype correlation, and natural history of lamin A/C gene (LMNA) mutations in subjects with dilated cardiomyopathy (DCM). BackgroundMutations in LMNAhave been found in patients with DCM with familial conduction defects and muscular dystrophy, but the clinical spectrum, prognosis, and clinical relevance of laminopathiesin DCM are unknown. MethodsA cohort of 49 nuclear families, 40 with familial DCM and 9 with sporadic DCM (269 subjects, 105 affected), was screened for mutations in LMNAusing denaturing high-performance liquid chromatography and sequence analysis. Bivariate analysis of clinical predictors of LMNAmutation carrier status and Kaplan-Meier survival analysis were performed. ResultsMutations in LMNAwere detected in four families (8%), three with familial (R89L, 959delT, R377H) and one with sporadic DCM (S573L). There was significant phenotypic variability, but the presence of skeletal muscle involvement (p < 0.001), supraventricular arrhythmia (p = 0.003), conduction defects (p = 0.01), and “mildly” DCM (p = 0.006) were predictors of LMNAmutations. The LMNAmutation carriers had a significantly poorer cumulative survival compared with non-carrier DCM patients: event-free survival at the age of 45 years was 31% versus 75% in non-carriers. ConclusionsMutations in LMNAcause a severe and progressive DCM in a relevant proportion of patients. Mutation screening should be considered in patients with DCM, in particular when clinical predictors of LMNAmutation are present, regardless of family history.

Evidence for autosomal recessive inheritance of infantile dilated cardiomyopathy: studies from the Eastern Province of Saudi Arabia.

Familial dilated cardiomyopathy is being increasingly recognized, but affected individuals <10 y are rarely identified. We describe the natural history of dilated cardiomyopathy and evaluate the mode of inheritance among infants of Arab descent from the Eastern Province of Saudi Arabia. We evaluated 55 consecutive cases of dilated cardiomyopathy in patients <10 y of age seen during a 5-y interval. Echocardiography was the primary diagnostic modality. The 55 cases represented 20% of the offspring of 41 families of Arab descent. In 19 families (46%), parents were first cousins; there was no obvious consanguinity in 22 families (54%). Age at presentation was <30 mo (95%) (range, 1 to 100 mo); males (38%) and females (62%) were affected. Patients died (25 patients, 46%), improved (15 patients, 27%), or recovered (15 patients, 27%). The left ventricular shortening fraction at diagnosis ranged from 5 to 28% and did not differ in those who died, improved, or recovered. Complex segregation analysis of the family data using the mixed model of inheritance showed that a model of recessive inheritance best fits the data. Recessively inherited dilated cardiomyopathy has been infrequently reported, perhaps because it may be difficult to recognize in other patient groups in which consanguineous marriage is uncommon and the number of children per family is small. In the setting of consanguineous marriage, homozygosity mapping should lead to identification of the gene(s) causing dilated cardiomyopathy in the families we studied.

Dilated cardiomyopathy in children: determinants of outcome.

To determine the outcome of dilated cardiomyopathy presenting in childhood and the features that might be useful for prognostic stratification. Supraregional paediatric cardiology unit. Retrospective analysis. The natural history of dilated cardiomyopathy in children is not well characterised. Previous studies have shown a variable relation between age at presentation and outcome, and sudden death has been infrequent. Retrospective study of 63 consecutive patients with idiopathic dilated cardiomyopathy presenting between 1979 and 1992. Survival curves were constructed by the Kaplan-Meier method. Age at diagnosis ranged from 1 day to 15 years (median 12 months) and follow up ranged from 1 day to 13 years (median 19 months). Actuarial survival from presentation was 79% at one year (95% confidence interval (95% CI) 66%-88%) and 61% (44%-74%) at five years. Univariate analysis showed that mural thrombus, left ventricular end diastolic pressure > 20 mm Hg, and age at presentation > 2 years were predictors of adverse outcome, but on multivariate analysis only age at presentation was significant. Left ventricular echocardiographic indices either did not improve or deteriorated in 36 children (17 of whom died, four suddenly, and three were transplanted), partially improved in 16 (three of whom died, all suddenly), and returned to normal in 11 (all of whom have survived). Older age at presentation and lack of improvement in systolic function are associated with an adverse outcome, and early transplantation should be considered in these patients. There is a persistent risk of late sudden death in those children in whom echocardiographic dimensions remain abnormal.

Diagnosis and outcome of dilated cardiomyopathy in the fetus

SummaryTo identify the echocardiographic features and natural history of dilated cardiomyopathy in fetal life, we reviewed records of all fetal echocardiograms over the 10 year period 1980–1989 to identify cases of dilated cardiomyopathy without left ventricular outflow obstruction and conducted a retrospective review of the fetal echocardiograms and clinical course of those fetuses with dilated cardiomyopathy. In addition, all fetal losses, perinatal deaths and live-born infants presenting with dilated cardiomyopathy in the first seven days of life were identified from the British Columbia Pediatric Cardiovascular Pathology Registry and from inpatient records. The pathological findings and outcome for this group were also reviewed. Marked left ventricular dilatation and dysfunction without left ventricular outflow obstruction was diagnosed in five of 1,158 fetuses undergoing feta lechocardiography. These five fetuses were correctly distinguished from two others with critical aortic stenosis and severe left ventricular dysfunction. Two of the five fetuses had additional right ventricular dysfunction and dilatation and developed hydrops, while the remaining three with isolated severe left ventricular dysfunction did not and showed normal somatic growth. All fetuses were live-born with spontaneous labour occurring in four of five cases at a mean gestational age of 36.5 weeks. Four of the five infants died, with three deaths occurring in the first week of life. During the same 10 year period, two of 2450 autopsied stillbirths (both hydropic) were diagnosed with dilated cardiomyopathy. An additional 15 neonates (including the five identified by fetal echocardiography) were diagnosed in the first week of life with dilated cardiomyopathy, congenital myocarditis or endocardial fibroelastosis. Four were hydropic (all with associated right ventricular dysfunction). Only three of the 15 survive. Fetal echocardiography can accurately distinguish dilated cardiomyopathy from left ventricular outflow obstruction. In the absence of right-sided disease or premature closure of the oval fossa, severe left ventricular dysfunction is well tolerated in utero. The prognosis for fetal dilated cardiomyopathy is very poor.

The Frequency of Familial Dilated Cardiomyopathy in a Series of Patients with Idiopathic Dilated Cardiomyopathy

Dilated cardiomyopathy is characterized by an increase in ventricular size and impairment of ventricular function. Most cases are believed to be sporadic, and familial dilated cardiomyopathy is usually considered to be a rare and distinct disorder. We studied the proportion of cases of idiopathic dilated cardiomyopathy that were familial in a large sequential series of patients whose first-degree relatives were investigated regardless of whether these relatives had cardiac symptoms. We studied relatives of 59 index patients with idiopathic dilated cardiomyopathy of obtaining a family history and performing a physical examination, electrocardiography, and two-dimensional, M-mode, and Doppler echocardiography. A total of 315 relatives were examined. Eighteen relatives from 12 families were shown to have dilated cardiomyopathy. Thus, 12 of the 59 index patients (20.3 percent) had familial disease. There was no difference in age, sex, severity of disease, exposure to selected environmental factors, or electrocardiographic or echocardiographic features between the index patients with familial disease and those with nonfamilial disease. A noteworthy finding was that 22 of 240 healthy relatives (9.2 percent) with normal ejection fractions had increased left ventricular diameters during systole or diastole (or both), as compared with 2 of 112 healthy control subjects (1.8 percent) who were studied separately. Dilated cardiomyopathy was found to be familial in at least one in five of the patients in this study, a considerably higher percentage than in previous reports. This finding has important implications for family screening and provides direction for further investigation into the causes and natural history of dilated cardiomyopathy.

The Natural History of Dilated Cardiomyopathy — A Community Study

The incidence, clinical features and natural history of dilated cardiomyopathy within a clearly defined population of Scotland was studied retrospectively. From 1982 to 1986, 57 cases were recorded in a population of 145,00, representing an annual incidence of 7.9 per 100,000 per year. This incidence rate is higher than that reported from other centres, and the overall survival rates were poorer.

Clinical aspects and haemodynamics in the follow-up of dilated cardiomyopathy and myocarditis

Many studies on the natural history of dilated cardiomyopathy show high probability of death or of cardiac transplantation in a large percentage of patients. These studies have several methodological limitations. Our prospective study, carried out from 1971, and which evaluated 120 patients, showed improved survival in more recent years. Survival 3 years after diagnosis changed from 30% (1971-6/1981) to 88.4% (7/1986-1/1989). Thirty patients were investigated by haemodynamic exercise test to assess their haemodynamic behaviour during exercise, to evaluate the effects of pharmacological treatment and to define parameters of prognostic value. Different haemodynamic behaviours were observed. Haemodynamic investigation during exercise is useful to assess the effect of treatment and may have prognostic value. Myocarditis presents a spectrum of clinical symptoms and echocardiographic abnormalities. In patients with congestive heart failure left ventricular dysfunction is common. Patients with atrioventricular block or chest pain usually have good left ventricular function. During follow-up, improvement is possible but persistent left ventricular dysfunction is associated with a high mortality rate. When left ventricular function is good at presentation and does not deteriorate during follow-up the prognosis is good.

Natural history of dilated cardiomyopathy in children

To assess the natural history and potential risk factors in childhood dilated cardlomyopathy, we investigated 25 patients (ages 9.6 ± 4.4 years) who presented after they were 2 years old. All patients had symptoms of congestive heart failure and reduced contractility with a dilated left ventricle at presentation. Two factors at presentation were significantly different between patients who died less than 1 year after the presentation ( n = 14) and those who survived for more than 1 year ( n = 9); cardiothoracic ratio (65.1% ± 6.8% vs 57.1% ± 6.1%, p < 0.01) and left ventricular ejection fraction (31.3% ± 7.0% vs 40.0% ± 6.2%, p < 0.05). Irrespective of intensive medical therapy, dilated cardiomyopathy in children had a poor prognosis; the actuarial survival rate was 41% at 1 year and 20% at 3 years. Other forms of therapy should be considered in the early stages of dilated cardiomyopathy in this high-risk group.

Dilated Cardiomyopathy

Dilated Cardiomyopathy

Reproducibility of Radionuclide Left Ventricular Ejection Fraction in Patients Awaiting Cardiac Transplantatio

Radionuclide-derived left ventricular ejection fraction (LVEF) is used to assess LV systolic function, to follow trends in the natural history of dilated cardiomyopathy, and to prioritize patients waiting for cardiac transplantation. Reproducibility of LVEF at extremely low levels has not, however, been reported. To assess the reproducibility of radionuclide LVEF at levels below 0.30 EF U, 17 highly symptomatic patients (NYHA Class III/IV) with dilated cardiomyopathy were studied on two occasions, 72 hours apart. Sequential scans were analyzed by two independent observers. Mean LVEF was 0.18 +/- 0.06 U (scan 1) and 0.17 +/- 0.06 U (scan 2). Interoperator reproducibility (SD) was 0.03 U (R = 0.76), interscan reproducibility (SD) was 0.03 U (R = 0.62), and overall reproducibility (SD) was 0.04 U (R = 0.50). The interobserver variation of 0.03 (actually 0.027) was just over one half that seen in normal volunteers (variation 0.05, n = 29) studied previously in this department. A change of greater than or equal to 0.08 U (2SD) in either direction is highly likely to represent a real change in LV function in those with LVEF less than or equal to 0.30 units, compared with the change of at least 0.10 units required in those with normal LV function. Lower interobserver and interscan reproducibility should be taken into account when interpreting sequential scans in patients with severe LV dysfunction.

Prevalence of overt dilated cardiomyopathy in two regions of England.

The prevalence of dilated cardiomyopathy was assessed in two regions in England from 420 replies to 771 questionnaires sent to general practitioners. Overall point prevalence was 8.317 per 100 000 population in areas covering a total sample of 913 836 inhabitants. There was a statistically significant regional variation between East Anglia (Norfolk, Suffolk, and Cambridgeshire) and Essex, Hertfordshire, and Bedfordshire. Though the natural history of dilated cardiomyopathy remains to be defined, this study has provided an assessment of point prevalence of overt cases of this condition.

Dilated cardiomyopathy: functional status, hemodynamics, arrhythmias, and prognosis.

The natural history of dilated cardiomyopathy is variable, and the prognosis difficult to predict. Several clinical and hemodynamic parameters have been proposed as prognostic indicators. Reports on the relationship between ventricular arrhythmias, degree of hemodynamic impairment, and sudden death are controversial. To define accurately the prognosis in dilated cardiomyopathy, 55 patients with this clinical syndrome underwent clinical evaluation, radionuclide ventriculography, echocardiography, 12-lead electrocardiography, and 24 hr ambulatory monitoring, and the data thus obtained were evaluated based on predictive value. Over a follow-up period of 14.1 +/- 7.9 months, 11 patients (20%) died, all suddenly. Univariate analysis revealed that patients with more severe functional impairment (P = 0.0449), lower cardiac index (P = 0.0226), lower ejection fraction (P = 0.0426), and higher pulmonary artery wedge pressure (P = 0.0314) had greater mortality risk. Age, duration of symptoms, 12-lead electrocardiographic abnormalities, and atrial arrhythmias were not predictive of higher mortality. The number of PVCs per hr, the occurrence of couplets, the degree of PVCs prematurity, and the presence, frequency, rate, and duration of ventricular tachycardia did not have prognostic significance. A stepwise discriminant analysis identified functional class, cardiac index, and presence or absence of multiform PVCs as the group of variables that together could more accurately predict outcome in our dilated cardiomyopathy patients. Using a formula derived from the results of this analysis, the outcomes of 36 of 49 patients (74%) was correctly predicted, with a specificity of 100% and a sensitivity of 70%.