Cardiomyopathy, Dilated, 1A

Alternative Names

  • CMD1A
  • Cardiomyopathy, Dilated, with Conduction Defect 1
  • CDCD1
  • Cardiomyopathy, Idiopathic Dilated
  • Cardiomyopathy, Familial Idiopathic
  • Cardiomyopathy, Congestive

Associated Genes

F-Box Only Protein 32
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WHO-ICD-10 version:2010

Diseases of the circulatory system

Other forms of heart disease

OMIM Number

115200

Mode of Inheritance

Autosomal dominant

Gene Map Locus

1q22

Description

Dilated cardiomyopathy is a heterogeneous primary cardiac muscle disease characterized by a global hypokinesia of the ventricles, resulting in congestive cardiac failure. The etiology of the condition is unknown in Idiopathic Dilated Cardiomyopathy (IDC). The clinical symptoms of the condition vary widely between patients. Initial symptoms may be non-specific, like generalized fatigue, and loss of appetite and weight. In later stages, symptoms may include shortness of breath, especially with physical activity, nocturnal dyspnea, and edema of legs and ankles. Severe cases may present with syncope, chest pain, thromboembolism, and dysrythmias (notably ventricular and supraventricular tachycardia), which may even result in death.

In the USA, the estimated incidence of children born with dilated cardiomyopathy is 36.5 per 100,000. Reliable data from other countries is not available. Diagnosis relies upon chest radiographs, electrocardiograms, echocardiography, and coronary angiography to exclude ischemic heart disease. Treatment aims at controlling the congestive heart failure. Medications used include angiotensin-converting enzyme (ACE) inhibitors, known to decrease morbidity and mortality in heart failures, beta blockers, anticoagulants to prevent thromboembolism, and diuretics to reduce the peripheral edema. As a last stage treatment, heart transplant is considered. A lifestyle change is necessary to counter this condition. A proper diet, exercise and avoidance of all cardio-toxins are essential for the betterment of the patients.

Almost 25-50% of cases of dilated cardiomyopathy are said to be due to genetic causes. All types of inheritance, including autosomal recessive, dominant, and X-linked modes of transmission have been noticed. CMD1A, however, has been found to be transmitted in an autosomal dominant manner, and is caused due to mutations in the Lamin A/C gene (LMNA), which code for structural protein components of the nuclear lamina. It is not clearly known how these mutations affect the functioning of the heart. However, it is postulated that either disruptions of the inner nuclear membrane may affect heterochromatin scaffolding, resulting in mis-expression of tissue specific genes, or a weakened nuclear lamina may leave certain tissues more prone to damage by force.

Epidemiology in the Arab World

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Subject IDCountrySexFamily HistoryParental ConsanguinityHPO TermsVariantZygosityMode of InheritanceReferenceRemarks
115200.1.01Saudi ArabiaFemaleYesYes Respiratory distress; Easy fatigabilit...NM_058229.4:c.727G>CHomozygousAutosomal, RecessiveAl-Hassnan et al. 2016 Proband
115200.1.02Saudi ArabiaFemaleYesYes AsymptomaticNM_058229.4:c.727G>CHomozygousAutosomal, RecessiveAl-Hassnan et al. 2016 Sister of 115200.1.0...
115200.1.03Saudi ArabiaFemaleYesYes AsymptomaticNM_058229.4:c.727G>CHomozygousAutosomal, RecessiveAl-Hassnan et al. 2016 Sister of 115200.1.0...
115200.1.04Saudi ArabiaMaleYesYes Dyspnea; OrthopneaNM_058229.4:c.727G>CHomozygousAutosomal, RecessiveAl-Hassnan et al. 2016 Brother of 115200.1....

Other Reports

Oman

Agarwal et al. (1996) compared the frequency of HLA antigens between IDC patients and controls. For HLA A, B, C, and DR and DQ typing, sera from 50 patients diagnosed with IDC according to the WHO criteria, and 247 healthy blood, kidney and bone marrow donors were centrifuged and processed by modified two-stage microcytotoxicity technique with ethidium bromide/acridine orange staining. Agrawal et al. (1996) found no statistically significant association between HLA A, B and C as well as DR and DQ antigens with IDC. They concluded that the ethnic/racial origin played a major role in the reported HLA associations with this heterogeneous and multifactorial disease.

Four years later, Agarwal et al. (2000) conducted a prospective study over three years to determine the prevalence and natural history of idiopathic dilated cardiomyopathy in the Omani population of the Dhakliya region. Out of 111 patients in this population diagnosed with heart failure, 97 (M/F = 1.4:1, and 84.5% were above 35 years) were found suitable for the study, as they were labeled as having IDC after interviewing, examination, and investigations (chest X-ray, ECG, echo-doppler studies, exercise testing, 24-h Holter ECG, coronary angiography, and viral serology). They were followed up for a period of one to eight years with periodical clinical examination and yearly echocardiogram. They were put on appropriate anti-failure, anti-arrhythmic and anticoagulant drugs, when necessary. The prevalence of IDC in the Dhakliya region was found to be 43.2/100,000 population during the study period. Only three patients (with non consanguineous parents) had a positive family history of the disease. All patients had shortness of breath as the presenting symptom, with fatigue as a common association, while 36% reported atypical chest pain. Palpitation and syncope were the less frequently reported symptoms. At presentation, all patients had a cardio-thoracic ratio of >50%, but only 74% had congested lung fields. Moreover, 89.6% were in sinus rythum, while the rest had atrial fibrillation (eight patients), atrial flutter (one patient) and junctional rythum (one patient). The major conduction abnormality was of intraventricular conduction delay (25.8%) and left bundle branch block (16.5%), and in 78.4%, left or biventricular hypertrophy was evident on ECG. Echo-doppler studies revealed global hypokinesia of the left ventricle with ejection fractions <50% in all patients, with 34% having severe left ventricular dysfunction (ejection fraction <30%). In the majority, mitral regurgitation was present (severe in 27.8% of the patients), and half the patients had tricuspid regurgitation. During the study period, the patients were divided into two groups, group A were those who remained stable during the study period (41.2%) or had one exacerbation of heart failure (28.8%), and group B in whom the LVEF dropped by 5%-11%, or those who had two or more exacerbations of heart failure (13.4%) or their condition continued to deteriorate requiring modification of their medications (14.4%). No specific cause for the exacerbations of heart failure in both groups was found in 21 patients, while it was due to noncompliance in 12 and new arrhythmias in eight patients. About 24% of the patients died during the study period, two died at presentation from acute heart failure, seven in group A (five had arrhythmia, pulmonary embolism in one, and non-cardiac malignancy in one) and 14 in group B (resistant heart failure in 10, pulmonary embolism in three, and septicemia in one). The survival rates from the onset of symptoms were found to be 94% at one year (95% CI 88% to 99%), 86 % at three years (95% CI 79 to 93%), 76% at five years (95% CI 67% to 86%), and 68% at eight years (95% CI 54% to 82%), and 6.5 years (95% CI 6 to 7 years) was the mean survival. When outcome variables were analyzed, NYHA functional class 3 or 4 at presentation, initial low LVEF (<30%), and significant ventricular tachycardia on 24h ECG Holter were the significant variables for poor outcome, and when multivariate regression analysis was done, low LVEF was found to be the factor that predicted death, with the mean survival for those with LVEF <30% being six years and 10.8 years for those with LVEF >30%. Agrawal et al. (2005) concluded that the role of arrhythmia was independent of the severity of myocardial impairment, deterioration of which was the most important factor in mortality.

Venugopalan et al. (2001) conducted a prospective study to determine the frequency of familial dilated cardiomyopathy (FDC) in the population. They examined and investigated (chest X-ray, ECG and echo-Doppler studies, and those above 30 years were investigated for coronary artery disease by exercise testing and coronary angiogram) all patients who were diagnosed with IDC according to WHO criteria during a three year period between 1992 and 1994, with emphasis on their family history. All their living first degree relatives (parents, siblings and children) were interviewed, examined and investigated with ECG and echo-Doppler study, and data regarding the dead ones was acquired by asking their live relatives, and from death certificates, if available. All the subjects included in the study group did not have history of alcohol intake, and were investigated for metabolic causes of cardiomyopathy. During the study period, 108 patients were diagnosed with IDC, of whom 30% had consanguineous parents and a total of 890 first degree relatives were identified, but only 770 (87%) were screened, as out of the remaining 120, 102 were asymptomatic and leading a healthy life and 18 had died from non cardiac causes. Out of the 108 patients, only seven (65%) had an affected relative (one of the seven had two affected relatives), so the familial group with FDC (affected relatives and the index patients) was 15 in total (only one was asymptomatic), in which an underlying metabolic cause of cardiomyopathy was excluded and the sporadic group constituted of the 101 patients with no family history. By comparing the age, sex, parental consanguinity, New York Association (NYA) functional class, initial left ventricular ejection fraction and outcome between the familial and the sporadic group, only the age and consanguinity were statistically different between the groups, as those with FDC presented at a younger age with median of eight years reflecting the severity of the familial disease than the sporadic group (median of 44 years), and consanguinity was present among those with FDC. There was no significant difference in the outcome (alive or dead) between the two groups who also had no difference in the ratio of males to females affected, NYA functional class, and the left ventricular ejection fraction. Venugopalan et al. (2001) attributed the low proportion of FDC (6.5%) in high prevalence of consanguinity to possible geographical variation. As a sequel to this study, Agarwal et al. (2005) followed-up on these patients for 10-years and reported on their survival rates. Two patients died at the start of the study and the rest were followed up for one to ten years. During the study period, including the above two, 28 (26.8%) patients died. Group B had 19 deaths due to resistant heart failure, with pulmonary embolism and septicemia as contributing factors in three and one, respectively, while group A had seven deaths (five were due to ventricular arrhythmias, pulmonary embolism in one and disseminated non cardiac malignancy in another). According to multivariate regression analysis, LVEF less than 30% and severe mitral regurgitation were predictors of poor outcome. The calculated survival rates were found to be 94% at one year, 86% at three years, 76% at five years, 68% at eight years, and 64% at ten years. Mean survival was found to 6.3 years for those with LVEF less than 30% , and 12.5 years for those with LVEF more than 30%. Predictors of short survival were the presence of severe mitral regurgitation (4.7 versus 13.6 years) and NYHA class III or IV (8.8 versus 12 years) at presentation.

Jaiyesmi and Kasem (2009) studied 32 patients (17 males and 15 females; median age-7 months) seen with pediatric dilated cardiomyopathy during an 8-year period (1999-2007). About 50% of these patients had the idiopathic form of the disease. The condition was severe in most of the patients, with about 80% of them presenting with cardiac failure. Although aggressive anti-failure treatment was carried out, only 33% of patients showed recovery, with 25% still requiring continuous treatment. Over 40% of the patients with the idiopathic form died.

Qatar

El-Menyar et al. (2006) analyzed data pertaining to all patients less than 50-years of age, who were hospitalized between 1996 and 2003 with cardiomyopathy in Qatar. Of the total of 132 such patients, 42 were Qataris. On the basis on their echocardiographic measurements, 30 of these Qatari patients (71.4%) were diagnosed with dilated cardiomyopathy (DCM). DCM was found to be the most common cardiomyopathy in this group, and its prevalence was calculated at 17.5 affected individuals per 100,000 of the population (male: female ratio-2:1). About 48.6% of children (between 1 and 15-years) with cardiomyopathy were found to have DCM. Four patients with DCM, all within the 16-35-years age group, died. Rare associations of DCM were noted with diseases such as Antiphospholipid Syndrome, Familial Conus Dystrophy, Hb H Disease, and scleroderma in one patient each, with thalassemia in two patients, and with thyroid disorders in three patients. In year 2006, El-Menyar and Gendi reported a patient with congestive heart failure and noncompaction cardiomyopathy (NCCM). The patient was a 17-year old female who presented with progressive shortness of breath of a few days' duration. She was found to be mildly dyspnic, with a pulse of 90 beats/min, blood pressure of 110/60 mm Hg, raised jugular venous pressure (JVP), and lower limb edema. She was also found to have a grade 2/4 systolic murmur in the lower sternal edge, which increased with inspiration, and a ¼ short systolic murmur outside the apex. X-ray chest revealed cardiomegaly and congested lungs, whereas a persistent atrial standstill was found on ECF, and was confirmed by the absence of A wave in JPG and P wave in ECG, and the detection of only E wave by Doppler imaging. The patient was started on antifailure treatment, to which she showed a good response. Examination after 1-year revealed persistence of the atrial standstill. One of the patients' brothers died suddenly at the age of 26-years for unexplained reasons, raising the possibility of a familial arrhythmogenic disorder. Two of her sisters and another brother were not reported to have any problems.

Saudi Arabia

Al-Hassnan et al. (2016) reported a 26-year-old woman with dilated cardiomyopathy (DCM).  She first presented with a history of shortness of breath and easy fatigability. An examination found cardiomegaly, pulmonary edema and sinus tachycardia with bifascicular block.  She had a dilated left ventricle with severe global hypokinesia and poor left ventricular systolic function.  The patient’s parents were first cousins.  Subsequent echocardiograms of her parents and siblings revealed three affected siblings with DCM: 2 asymptomatic sisters (ages 22 and 20) and a 14-year-old brother suffering from dyspnea and orthopnea.  The patients did not have skeletal muscle weakness or abnormal levels of creatine kinase.  The index patient suffered decompensated heart failure and successfully underwent a heart transplant.  Genetic analysis uncovered a homozygous mutation p.Gly243Arg in the FBXO32 gene that was shared by all affected siblings.  The parents were found to be heterozygous for the mutation. A biopsy of the proband’s left ventricular myocardial tissue also showed hypertrophied myocytes, bizarrely shaped hyperchromatic nuclei and reduced expression of FBXO32 protein compared to healthy control tissues.  The study stressed the importance of screening first degree relatives in cases of DCM owing to the variability in presentation of symptoms.

United Arab Emirates

Faez et al. (1992) conducted a comparative study on hypertrophic cardiomyopathy (HC) and dilated cardiomyopathy (DC) in 108 patients living in Dubai and Moscow (Russia). Out of 49 citizens of Dubai 17 had HC, 32 DC. While HC in Dubai tends to run a silent latent course, involving mainly basal septum and right ventricle, DC in Dubai produces weaker cardiac insufficiency and arrhythmia. Incidence of idiopathic and periportal DC also proved higher in Dubai.

Hamdan et al. 2015 reported that out of 1950 pregnant women undergoing fetal echocardiography, 152 fetuses were diagnosed with congenital heart disease. 139 of these were of Arab ethnic background and 60-70% of the Arabs were of Emirati origin. Parental consanguinity was noted in 69% of the Arab cases (96/139). Findings in the cohort included left heart obstruction (n=30), conotruncal malformations (n=26), septal defects (n=22), cardiomyopathy (n=19), right heart obstruction (n=8), arrhythmia (n=8), heterodoxy syndromes (n=3), cardiac tumors (n=3) and anomalous venous connection (n=1).  

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