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Idiopathic dilated cardiomyopathy in an Omani population of the Arabian Peninsula: prevalence, clinical profile and natural history
International Journal of Cardiology 75 (2000) 147–158 www.elsevier.com / locate / ijcard
Idiopathic dilated cardiomyopathy in an Omani population of the Arabian Peninsula: prevalence, clinical profile and natural history a, a a b A.K. Agarwal *, P. Venugopalan , A.K. Meharali , D. de Debono a
Department of Cardiology, Sultan Qaboos University, Muscat, Oman b Glenfield General Hospital, Leicester, UK
Received 26 November 1999; received in revised form 2 March 2000; accepted 13 June 2000
Abstract We have analysed prospectively the prevalence and clinical profile of idiopathic dilated cardiomyopathy (IDC) in a circumscribed native population of the Sultanate of Oman over 3 years (1992–1994). Identified patients were followed up for a period ranging from 1 to 8 years (median 4 years) and the variables related to outcome determined. IDC was diagnosed in 97 patients, giving a prevalence of 43.2 / 100,000 population during the study period. 84.5% of patients were aged over 35 years and males outnumbered females (M / F51.4:1). Factors related to poor outcome were an initial left ventricular ejection fraction #30% (P 5 0.01), severe symptoms, i.e. NYHA functional class III or IV at presentation (P 5 0.04), and significant ventricular tachycardia during follow up (P 5 0.02). However, multivariate regression analysis yielded only low LVEF as the predictor of poor outcome (P 5 0.01). When analysed from age of onset of symptoms, survival figures were 94% at 1 year (95% CI 88 to 99%), 76% at 5 years (95% CI 67 to 86%) and 68% at 8 years (95% CI 54 to 82%). Mean survival was 6.5 years (95% CI 6 to 7 years). Patients were still at risk of fatal ventricular arrhythmia even when haemodynamically stable and had left ventricular ejection fraction .30%. 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Idiopathic dilated cardiomyopathy; Epidemiology; Survival; Outcome variables; Middle East
1. Introduction Idiopathic dilated cardiomyopathy (IDC) is a primary cardiac muscle disease of an undefined etiology characterized by global hypokinesia of the ventricle(s) resulting in symptoms of heart failure. Diagnosis relies on exclusion of other causes of heart failure like myocardial ischaemia, hypertension, excessive alcohol consumption, diabetes mellitus and viral myocarditis. Although mortality figures of 57 to 75% in the first 2 years [1–4] had been reported in the 1970s, survivals as high as 90% at 4 years are *Corresponding author. Tel.: 1968-513-355-3404; fax: 1968-513419. E-mail address: [email protected] (A.K. Agarwal).
seen in recent publications [5–7]. To our knowledge, collective data on the prevalence and natural history of the disease from any country in the Middle East (Arabian population) have not been reported before, hence this prospective study of 97 patients with IDC in an Omani population of the Arabian Peninsula.
2. Patients and methods
2.1. Patient population Dhakliya region of the Sultanate of Oman with a local population of 225,000 (males 111,000 and females 113,000) was selected for the study due to its close liaison with and an effective referral system to
0167-5273 / 00 / $ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 00 )00315-6
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tertiary care facilities of Sultan Qaboos University Hospital. The non-Omani expatriate population (24,000) living in this area was excluded from the study. All adults (aged .12 years) from the Dhakliya region with symptoms suggestive of heart disease from 1992 to 1994 (3 years) were evaluated by the local physicians at the regional hospital of Dhakliya region in the city of Nizwa. Those suspected of having IDC were then referred to the Sultan Qaboos University Hospital for further investigation. The patient population of the study comprised a mixture of all diagnosed cases of dilated cardiomyopathy already on hospital records and new cases that presented subsequently during the study period. World Health Organization criteria were used to diagnose IDC [8]. Besides detailed history, physical examination, chest X-ray and electrocardiogram, all patients had echo-Doppler studies to confirm impaired myocardial function (left ventricular ejection fraction of ,50%) and exclude identifiable causes of myocardial dysfunction. Exercise testing and coronary angiography were performed to exclude coronary artery disease. Patients with a history of alcohol intake, hypertension, diabetes mellitus, thyroid disease or other systemic diseases, and acute myocarditis were not included in the study. Recent viral infections were excluded by serological testing, however myocardial biopsy was not part of the study protocol. Variables recorded during follow up included the class of heart failure as per the New York Heart Association (NYHA) functional classification [9], arrhythmia, systemic or pulmonary embolic events and death. Patients were followed up periodically with clinical examinations, and the echocardiogram was repeated once a year or earlier if acute heart failure occurred. All patients underwent 24 h Holter ECG at the time of entry and again during follow up if arrhythmias were suspected. Treatment of heart failure included a combination of diuretics and angiotensin converting enzyme inhibitor (ACEI), and digoxin added later when the symptoms continued to worsen with the maximum tolerated dose of ACEI or when atrial fibrillation developed. Anticoagulation was considered in the presence of atrial fibrillation, thromboembolism or when an intracardiac thrombus was demonstrated on echocardiography. None of the patients received beta-blocker therapy. The follow up was concluded in December
1998 after ascertaining the status of the study patients.
2.2. Statistical methods The data were saved in a file prepared with Statistical Package for Social Sciences for Windows 97 and analysed. The outcome was categorised as alive or dead at the termination of the study. The statistical significance of the differences in the variables was tested using the unpaired t-test in the case of continuous and the Chi square test in the case of discrete variables, accepting P , 0.05 as significant [10]. For the purpose of survival analyses the duration of illness from onset of first symptom of heart failure (dyspnoea) was applied. It was assumed that all patients entered the study at the same point and patients were taken from the analysis as they died or completed the follow up period. Survival curves were constructed by the Kaplan–Meier method and the log rank method was used to compare the survival data of patient subgroups defined with reference to possible risk factors.
3. Results
3.1. Prevalence A total of 111 patients were entered into the study with a provisional diagnosis of heart failure of unidentified cause. Of these 111 patients, 14 (12.7%) were found on investigation to have coronary artery disease, leaving 97 patients suitable for analysis. The prevalence of IDC in the Dhakliya region was thus 43.2 / 100,000 population during the study period.
3.2. Demographic profile ( Table 1) Patients were aged 15–69 years (median age 50 years). We did not find any patient aged above 69 years, although this was not a part of the case definition. The study included 56 males and 41 females (M / F51.4:1). The social makeup of patients recorded nearly all females as being house wives and
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Table 1 Demographic profile of patients with idiopathic dilated cardiomyopathy (n 5 97)
Table 2 Symptoms on presentation in patients with idiopathic dilated cardiomyopathy (n 5 97)
Characteristic
Group
Number (%)
Symptom
Number (%)
Age
15–24 years 25–34 years 35–44 years 45–54 years 55–64 years .65 years Male Female Civil servant Business Farmer Student Housewife Unemployed Single Married Divorced Widow Yes No Yes No
5 10 21 24 26 11 56 41 18 3 1 1 40 34 3 91 1 2 31 66 3 94
Shortness of breath
97 (100)
NYHA class Class I Class II Class III Class IV
8 52 37 0
Sex Occupation
Marital status
Consanguineous parents Affected family member
(5.2) (10.3) (21.6) (24.7) (26.8) (11.4) (57.7) (42.3) (18.5) (3.1) (1.1) (1.1) (41.2) (35) (3.1) (93.8) (1.1) (2.2) (31.9) (68.1) (3.1) (96.9)
34 of 56 males (60%) were interestingly either unemployed or only performed odd jobs, mainly living on social benefits. Some of them were retired and had worked briefly in their younger days in different fields. Seven patients had severe symptoms that necessitated discontinuation of their job. No correlation could be found between IDC and their previous work. Nearly all patients were married. Parental consanguinity, a common occurrence in Arab culture, was apparent, however only three patients could be identified as having another affected member in the family, and none of them had consanguineous parents.
3.3. Clinical features ( Table 2) Duration of symptoms at entry ranged from 1 month to 7 years [median 1 year, mean (S.D.) 1.3 (1.4) years], with a majority (69 / 97) of 12 months or less. Shortness of breath of varying severity was reported by all (100%) as the presenting complaint, with general fatigability being a common association. Other less frequently reported symptoms were palpi-
Fatigue Paroxysmal nocturnal dyspnoea Palpitations Angina Typical Atypical Syncope Post partum onset
(8.2) (53.6) (38.1) (0)
92 (94.8) 54 (55.7) 28 (28.8) 7 (7.3) 35 (36) 4 (4.1) 4 (4.1)
tation, and syncope. Chest pain when reported (36%) was mostly atypical.
3.4. Investigations ( Table 3) Chest X-ray revealed a cardio-thoracic ratio of .50% in all patients, but only 72 (74%) had congested lung fields at presentation. Cardiac rhythm at entry was sinus in 87 (89.6%) patients, atrial fibrillation in eight and atrial flutter and junctional rhythm in one each. Frontal plane QRS axis was either normal (45.3%) or leftward (49.5%). Major conduction abnormality as assessed by QRS configuration and duration was of left bundle branch block and intraventricular conduction delay type. ECG evidence of left or biventricular hypertrophy was the predominant feature (78.4%) and isolated right ventricular hypertrophy was seen in only one patient. Twenty-four hour Holter ECG recorded both atrial and ventricular arrhythmias. Echo-Doppler studies revealed global hypokinesia of the left ventricle with ejection fractions ,50% in all patients. Severe left ventricular dysfunction (LVEF #30%) was seen in 33 (34%) patients, of whom only 18 had class III or IV symptoms. Mitral regurgitation was present in the majority, but was severe in only 27 (27.8%). About one-half of patients
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Table 3 Chest radiograph, ECG and echocardiographic findings in idiopathic dilated cardiomyopathy (n 5 97)a Finding
Number (%)
Chest radiograph CTR 50–69% CTR .70% Congested lung fields
93 (95.9) 4 (4.1) 72 (74)
ECG Sinus rhythm Atrial fibrillation Atrial flutter Junctional rhythm LAD RAD RBBB LBBB IVCD LVH RVH BVH
87 8 1 1 48 5 1 16 25 67 1 9
24 h Holter ECG Atrial tachycardia
(89.6) (8.2) (1.1) (1.1) (49.5) (5.2) (1.1) (16.5) (25.8) (69.1) (1.1) (9.3)
4 / 97 (4.1)
Ventricular tachycardia #10 beats .10 beats
60 / 97 (61.8) 9 / 97 (9.3)
Torsade de pointes
3 / 97 (3.1)
Echo-Doppler studies EF #30% 30–49%
33 (34) 64 (66)
MR Mild Severe
61 (62.8) 27 (27.8)
TR Mild Severe
38 (39.2) 12 (12.3)
AR mild PR mild Diastolic dysfunction
27 (27.7) 21 (21.6) 39 (40.2)
a CTR, cardio-thoracic ratio; ECG, electrocardiogram; LAD, left axis deviation; RAD, right axis deviation; RBBB, right bundle branch block; LBBB, left bundle branch block; IVCD, intraventricular conduction delay; LVH, left ventricular hypertrophy; RVH, right ventricular hypertrophy; BVH, biventricular hypertrophy; EF, ejection fraction; MR, mitral regurgitation; TR, tricuspid regurgitation; AR, aortic regurgitation; PR, pulmonary regurgitation.
also had tricuspid regurgitation and a few had mild aortic and pulmonary regurgitations.
3.5. Clinical course ( Fig. 1) Two patients died from acute heart failure at
presentation. The remaining 95 patients were followed up for periods ranging from 1 to 8 years (median 4 years) from the onset of symptoms. Of these, 40 (41.2%) remained stable in the same functional class of heart failure throughout the study period. Another 28 (28.8%) experienced acute exacerbation of heart failure requiring at least one hospitalization, but remained stable thereafter. These 68 patients were placed in Group A for analysis. Of the remaining 29 patients, 13 (13.4%) had two or more exacerbations of heart failure and deteriorated in spite of the initial improvement and along with another 14 patients (14.4%) who experienced gradual deterioration requiring hospitalisation and modification in therapy were placed in Group B for analysis. Patients in Group A did not exhibit any deterioration in LVEF or require modification of anti-heart failure medication. Group B patients exhibited deterioration in LVEF by 5–11%. Among the 41 patients with exacerbations of heart failure (28 of Group A and 13 of Group B), the recurrence of symptoms could be attributed to non-compliance to medication in 12, development of new arrhythmias in eight, and no specific factor could be identified in the remaining 21. Other notable events were hemiplegia (thromboembolic) in 2 / 97 (2.1%) patients and pulmonary embolism in four (4.2%). Death occurred in 23 of the 97 (23.7%) patients during the study period, two at initial presentation, seven in Group A and 14 in Group B. Deaths in Group A occurred in patients whose heart failure was well under control and could be attributed to fatal ventricular arrhythmias in five (three of whom were at home), pulmonary embolism in one and disseminated malignancy (non-cardiac) in one. The remaining 14 deaths occurring in Group B were due to resistant heart failure. Additional contributing factors in this group included pulmonary embolism in three and Pseudomonas septicaemia in one.
3.6. Survival ( Fig. 2) The survival rates from the onset of first symptoms were 94% at 1 year (95% CI 88 to 99%), 86% at 3 years (95% CI 79 to 93%), 76% at 5 years (95% CI 67 to 86%), and 68% at 8 years (95% CI 54 to 82%). Mean survival was 6.5 years (95% CI 6 to 7 years). Median survival, i.e. time at which 50% of the patients died, could not be computed as more than
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151
Fig. 1. Clinical course of idiopathic dilated cardiomyopathy over an 8-year period (n 5 97).
50% of patients were alive at the conclusion of the study.
3.7. Analysis of outcome variables Live and dead patients were compared with regard to age, sex, duration and severity of symptoms, LVEF on presentation, and presence of ventricular tachycardia during follow up. NYHA functional class III or IV, low LVEF (#30%) and presence of significant ventricular tachycardia (.10 beats or Torsade de pointes) on 24 h ECG Holter were identified as
significant variables for poor outcome (Table 4). A multivariate regression analysis was performed with the above variables, and low LVEF was the only factor that predicted death (P 5 0.01). Survival curves were plotted for the different values of the LVEF. Patients with LVEF #30% (Fig. 3) had a mean survival of 6 years (95% CI 4.5 to 7.4 years) while for those with LVEF .30% it was 10.8 years (95% CI 9.5 to 11.9 years). The difference was highly significant (P 5 0.01). Similarly, NYHA classes 3 and 4 (Fig. 4) were associated with decreased survival (8.3 vs. 10 years; P 5 0.04).
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Fig. 2. Cumulative survival in idiopathic dilated cardiomyopathy (n 5 97).
4. Discussion
4.1. Prevalence Nizwa Central Hospital is the only secondary care regional hospital in the Dhakliya region of Oman and receives patients from the state run primary health centres and other small hospitals in the region, and in addition runs a direct access Outpatient Clinic. The system of free medical services and the good health infrastructure ensures that all patients with heart
failure are referred for evaluation to this hospital. We have in our study followed WHO criteria for diagnosis of IDC [8] and excluded patients with alcoholism, diabetes, hypertension, ischaemic heart disease, thyrotoxicosis and myocarditis [11–13]. Thus we believe that we have included all patients with IDC who had come to medical attention from the Dhakliya region. We have also ensured that patients with other possible causes of dilated cardiomyopathy were excluded. Physicians and general practitioners in Oman have
Table 4 Analysis of variables related to outcome in idiopathic dilated cardiomyopathy (n 5 97)a Outcome variable b
Age (years) Sex Duration of symptoms b (years) LVEF b (%) Severity of symptoms b Significant VT c a
Live
Dead
P Univariate
Multivariate
Mean (S.D.) M/F
48 (13) 44 / 30
46 (12) 12 / 11
0.52 (NS) 0.53 (NS)
0.55 (NS) 0.58 (NS)
Mean (S.D.) Mean (S.D.) A/B Yes / no
1.5 (1.3) 36 (8.6) 50 / 24 6 / 74
1 (1.2) 31 (7.5) 10 / 13 6 / 23
0.20 0.01 0.04 0.02
0.17 0.01 0.14 0.10
(NS) (S) (S) (S)
(NS) (S) (NS) (NS)
M, male; F, female; NS, not significant; S, significant; LVEF, left ventricular ejection fraction; VT, ventricular tachycardia; A, NYHA functional classes I and II; B, NYHA functional classes III and IV. b At entry into study. c During follow up.
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Fig. 3. Comparison of survivals in idiopathic dilated cardiomyopathy with initial left ventricular ejection fraction (LVEF). Log rank 7.22 (P 5 0.01).
Fig. 4. Comparison of survivals in idiopathic dilated cardiomyopathy with initial New York Heart Association (NYHA) functional class. Log rank 3.89 (P 5 0.04).
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observed a higher prevalence of IDC in this country (personal communication) compared to other parts of the world particularly Europe, the UK and the USA and this prompted us to evaluate the problem. Published studies on IDC have reported the extent of the problem both in terms of the incidence, which refers to the new cases per year, and the prevalence, which refers to the total number of cases present at any point in time. Some studies have also used the term yearly prevalence to indicate the total prevalence divided by the duration of study in years. While the incidence from Caucasian populations ranges from 5 to 8 / 100,000 population [14], the prevalence has been placed at 36.5 / 100,000 [15]. Williams and Olsen [14], in their study covering a population of about 913,000 in two distinct areas in the United Kingdom, found a yearly prevalence of 8.3 / 100,000 population, while a Scottish study that covered 5 years placed the figure at 9.9 / 100,000 [16]. These studies are not strictly comparable, however, due to the differences in the study designs (prospective versus retrospective), or in the criteria for patient selection (limited to IDC or including all patients with unexplained heart failure). In a post mortem study of 5252 necropsies over a period of 2 years, Rakar et al. [17] reported an incidence of 4.5 / 100,000 in Italy, but the clinical incidence during the same period was only 2.45 / 100,000, indicating the value of post mortem studies in picking up cases undiagnosed during life. A large case registry based study in China [18] during a 5-year period (1985–89) reported an incidence of 2.6 / 100,000 person years, increasing from 1.7 in 1985 to 3.3 in 1989. A relatively limited comparative report of dilated cardiomyopathy in Dubai (United Arab Emirates) and Moscow showed that the prevalence of IDC and peripartum cardiomyopathy was higher in Dubai [19], however this study did not report the racial origin of their study sample and Dubai is a cosmopolitan state with a large expatriate population. Our prospective study of IDC in a native population in a circumscribed region of the Sultanate of Oman ensured exclusion of patients with other causes of dilated cardiomyopathy and concluded a relatively high prevalence (43.2 / 100,000) of IDC in the study population. Since, in a strict sense, this was not a population-based study, the true prevalence is likely to be even higher. We did not find any evidence of
recent viral infection in the study patients to explain the higher prevalence recorded in this region of Oman, however a past viral infection could not be ruled out.
4.2. Clinical profile Idiopathic dilated cardiomyopathy (IDC) can develop at any age and affects both sexes. In our study population, the maximum number of patients was in the age group 35–64 years and males outnumbered females (M / F51.4:1). Our findings are comparable to those of Coughlin et al., who reported an incidence of 3.5 / 100,000 in males compared to 2.5 in females [20,21]. Pan et al. [18] has also reported a slight male preponderance, 3.0:2.2 / 100,000 population. Heart failure in general was shown to be more common in males than females [22] in a Finnish Study. The recognised 2.5-fold increase in the risk of developing IDC [11,23] in black males compared to white females, which is unexplained by other variables, may provide an explanation for our finding of a high prevalence in the Omani male population due to its East African background. Although 34 (35%) patients in our study were reported unemployed, only seven were sick enough to discontinue their previous jobs, the remaining had taken early retirement on their own choice. None of them were involved in any physically demanding employment. The majority of patients could have continued in their jobs or have worked in alternative less demanding work. This has significant financial and social implications. Dyspnoea on exertion of varying severity, the major presenting symptom, was present in all our patients. Other studies [24,25] have reported 75–85% of patients presenting with this complaint, while Sugrue [26], in a population based study of IDC, found that 90% of patients were in NYHA functional class III or IV. In our study, only 38% patients were in these classes. This is due to the early detection of disease in less severe heart failure. The majority of our patients were in sinus rhythm on presentation, except eight who had established atrial fibrillation. This arrhythmia is reported in ,25% of patients [2,27,28], but we found it to be even lower (8.2%). Chest pain, a less common symptom, was present in 36% of our patients, as has been reported in other
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studies [25–27]. Sometimes when typical this pain can be indistinguishable from ischaemic anginal pain. Chest pain could be secondary to the mechanical effect of an enlarged heart, a reduction in the coronary flow reserve [29,30] or a rise in pulmonary artery pressure. Syncope, an uncommon complaint, is due to transient ventricular arrhythmia.
4.3. Natural history Severe symptoms at the time of presentation were an important factor in the subsequent progression of heart failure. More than half (53.6%) of our patients were in NYHA functional class II at entry into the study. Patients who could be identified in class I maintained a steady haemodynamic state with only 10% progressing into lower functional classes. Similarly, patients who entered with severe heart failure (classes III and IV) deteriorated faster and accounted for most of the deaths from resistant heart failure. Therefore, special emphasis should be given to initiation of aggressive therapy for patients with severe symptoms. Treatment of asymptomatic unexplained cardiomegaly also needs to be reviewed. The substrate of myocardial impairment is laid long before symptoms appear. Research in this field has revealed significantly increased circulating N-terminal atrial natriuretic peptide as a marker of symptomless left ventricular (LV) dysfunction [31]. The benefit of treating such patients has been highlighted in two large studies of ACEI vs. placebo in such patients, showing a significant reduction in mortality in the active treatment group [32–34].
4.4. Arrhythmia on 24 h Holter ECG The occurrence of cardiac arrhythmias, both tachy and brady, in IDC is well established [35–39], but emphasis has been on ventricular arrhythmias due to their role as markers of sudden death. Sustained ventricular tachycardia is the most important of these as it can lead to ventricular fibrillation [40]. Ventricular ectopics and non-sustained ventricular tachycardia, although more common, have not been associated with increased morbidity or mortality. Besides precipitating heart failure, all types of arrhythmias cause further myocardial insult, worsening the functional class of heart failure even after the acute
155
episode is controlled and, in addition, atrial fibrillation leads to a loss of the atrial support. Analysis of VT in our patients revealed that non-sustained VT was more common with an equal distribution of mono and polymorphic patterns (48.7 and 51.3%, respectively). Twelve patients who developed prolonged ventricular tachycardia or Torsade de pointes were in a higher functional class of heart failure (NYHA classes III and IV) and lower ejection fractions. Arrhythmia also occurred in otherwise stable patients in controlled heart failure in Group A. The development of sustained VT or Torsade de pointes was related to a poor outcome (P 5 0.02), however multivariate analysis failed to identify it as an independent factor of significance.
4.5. Embolic phenomena Systemic and pulmonary embolism is a known complication of IDC. Atrial fibrillation, a commonly associated arrhythmia, is an independent risk factor for embolic events. A dilated poorly contracting ventricle in sinus rhythm itself predisposes to thrombus formation due to low blood flow rates. Two strokes and four pulmonary embolisms that occurred in our series were all in patients with atrial fibrillation even though they had been appropriately anticoagulated, reflecting the compounded thrombotic potential in this condition. In approximately 15% of all ischaemic strokes the source of thromboembolism comes from the heart [2,41] and around 40% of such strokes occur in dilated cardiomyopathy (regardless of the cause). The 15% rate of thromboembolism reported by Bloudheim [42] and a similar rate reported by Gottdiener [43] are also higher. Our finding of less than 6% is more in line with the work of Komajda [25] and Fuster [2]. In view of the risk of thromboembolism, routine anticoagulation has been recommended in IDC [2,3,24]. Such a recommendation appears to be an overkill and a more logistic approach could be a periodic assessment by echocardiography to detect thrombus formation and to anticoagulate those patients who show the presence of thrombi in cardiac chambers or spontaneous echo contrast (SEC) on transoesophageal echocardiography. SEC has been shown to be an independent risk factor for thromboembolism [44]. With an estimated
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5% risk of major bleeding and a 1% risk of death associated with anticoagulant therapy [45,46] it will be appropriate to identify high risk group IDC patients for anticoagulation. The presence of atrial fibrillation would obviously be a strong indication for anticoagulation, which was the case in our six patients with embolic events.
4.6. Survival and death In the 1960s and 1970s, the Mayo clinic reported nearly 75% mortality in 2 years [2] and a 5-year mortality of 57% was assessed by Shirey et al. in 1980 [1], while Koide from Japan claimed an overall survival of 8 years after diagnosis [47]. In more recent data, survival has improved considerably [33,48–52]: Di Lenarda from Italy for the Heart Muscle Study Group reported a 4-year survival of around 90% [7]. This improvement in survival has largely been due to early diagnosis, the introduction of ACEI and beta-blockers in the therapy, and prevention of complications such as embolic events and arrhythmias. In our study of 97 patients, an all-cause mortality of only 24% over a 7-year follow up from entry into the study could be achieved even without using beta-blockers. The maximum number of deaths occurred in the first year of follow up and subsequent deaths were distributed over 1–7 years. Published studies have shown both a progressively increasing mortality with time [7,25,53] as well as a high mortality in the first years followed by a steep descent of the curve [27,54]. The natural history and prognosis are dependent to a great extent on the severity of heart failure at the time of initiating therapy [26]. Deaths from IDC are most commonly due to resistant heart failure. Fourteen out of 23 deaths (61%) in our series occurred in patients who were in severe heart failure and had LVEF #30%. There was a positive correlation between the LVEF at presentation and mortality (P 5 0.01), and this was the only predictive variable identified by multivariate analysis. However, care should be exercised when interpreting this result as the number of deaths in our study was only 23. Five patients who died in Group A reflect the other important factor relevant to death in IDC — malignant ventricular arrhythmias. These patients had a stable haemodynamic state in NYHA II / III and an LV ejection fraction of .30%. It is also relevant to
note that all these five patients were already on amiodarone for documented ventricular tachycardia which had previously worsened their heart failure acutely before they joined Group A. A correlation between ventricular arrhythmia and sudden death in IDC has never been fully established [55–57]. In univariate analysis the development of new sustained VT was associated in our study with poor outcome (P 5 0.02) and in our three patients who died suddenly at home, malignant ventricular arrhythmia was the most likely cause. The role of arrhythmia is also interestingly more relevant in stable patients since none of the deaths in Group B were primarily due to arrhythmia. Therefore, the role of arrhythmia is independent of the severity of myocardial impairment. In our study, the nearly 50% mortality in Group B with resistant heart failure and 10% (7 / 68) in Group A of stable patients strongly favour worsening myocardial function as the most important factor in mortality from IDC.
Acknowledgements We are greatly indebted to and acknowledge the guidance of the late Professor David de Bono during the study.
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[31] Lerman A, Gibbons RJ, Rodeheffer RJ et al. Circulating N-terminal atrial natriuretic peptide as a marker of symptomless left-ventricular dysfunction. Lancet 1993;341:1105–9. [32] Barnett DB. Heart failure — Diagnosis of symptomless left ventricular dysfunction. Lancet 1993;341:1124–5. [33] The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. New Engl J Med 1992;327:685– 91. [34] Pfeffer MA, Braunwald E, Moye LA et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. New Engl J Med 1992;327:669–77. [35] Huang J, Xie CY, Kong XQ et al. Prevalence of arrhythmias in patients with idiopathic dilated cardiomyopathy. Chin Med J (Engl) 1994;107:176–80. [36] Tamburro P, Wilber D. Sudden death in idiopathic dilated cardiomyopathy. Am Heart J 1992;124:1035–45. [37] De Maria R, Gavazzi A, Caroli A, Ometto R, Biagini A, Camerini F. Ventricular arrhythmias in dilated cardiomyopathy as an independent prognostic hallmark. Italian Multicenter Cardiomyopathy Study (SPIC) Group. Am J Cardiol 1992;69:1451–7. [38] Chetty S, Mitha AS. Arrhythmias in idiopathic dilated cardiomyopathy. A preliminary study. S Afr Med J 1990;77:190–3. [39] Yamada T, Fukunami M, Ohmori M et al. New approach to the estimation of the extent of myocardial fibrosis in patients with dilated cardiomyopathy: use of signal averaged electrocardiography. Am Heart J 1993;126(3, Pt 1):626–31. [40] Borggrefe M, Block M, Breithardt G. Identification and management of the high-risk patient with dilated cardiomyopathy. Br Heart J 1994;72(6, Suppl):42–5. [41] Sherman DG, Kyken ML, Fischer M, Harrison MJ, Hart RG. Cerebral embolism. Chest 1986;89(2, Suppl):82–98. [42] Blondheim DS, Jacobs LE, Kotler MN, Costacurta GA, Parry WR. Dilated cardiomyopathy with mitral regurgitation: decreased survival despite a low frequency of left ventricular thrombus. Am Heart J 1991;122(3, Pt 1):763–71. [43] Gottdiener JS, Gay JA, Van Voorhees L, DiBianco R, Fletcher FD. Frequency and embolic potential of left ventricular thrombus in dilated cardiomyopathy: assessment by two-dimensional echocardiography. Am J Cardiol 1983;52:1281–5. [44] Daniel WG, Nellessen U, Schroder E et al. Left atrial spontaneous echo contrast in mitral valve disease: an indicator for an increased thromboembolic risk. J Am Coll Cardiol 1988;11:1204–11. [45] Kessler KM. Predictors of left ventricular thrombus formation: flow, asynergy and morphology. J Am Coll Cardiol 1990;15:361–3. [46] Levine MN, Raskob G, Landefelds S, Kearon C. Hemorrhagic complications of anticoagulation treatment. Chest 1998;114(5, Suppl):513–23. [47] Koide T, Kato A, Takabatake Y et al. Variable prognosis in congestive cardiomyopathy. Role of left ventricular function, alcoholism, and pulmonary thrombosis. Jpn Heart J 1980;21:451–63. [48] Cohn JN, Johnson G, Ziesche S et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. New Engl J Med 1991;325:303–10. [49] The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). New Engl J Med 1987;316:1429–35. [50] The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. New Engl J Med 1991;325:293–302.
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[51] Swedberg K, Hjalmarson A, Waagstein F, Wallentin I. Beneficial effects of long-term beta-blockade in congestive cardiomyopathy. Br Heart J 1980;44:117–33. [52] Anderson JL, Lutz JR, Gilbert EM et al. A randomized trial of low-dose beta-blockade therapy for idiopathic dilated cardiomyopathy. Am J Cardiol 1985;55:471–5. [53] Ikram H, Williamson HG, Won M, Crozier G, Wells EJ. The course of idiopathic dilated cardiomyopathy in New Zealand. Br Heart J 1987;57:521–7. [54] Razzolini R, Boffa GM, Stritoni P et al. Natural history of dilated cardiomyopathy. G Ital Cardiol 1989;19:114–20.
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Editorial Comment
Prevalence and natural history of dilated cardiomyopathy N.G. Mahon*, S. Hamid, W.J. McKenna Department of Cardiological Sciences, St. George’ s Hospital Medical School, Cranmer Terrace, London 5 W17 0 RE, UK Received 1 December 1999; accepted 13 June 2000
Although, in epidemiological terms, dilated cardiomyopathy (DCM) is a relatively uncommon cause of heart failure, its clinical impact is far greater than its position in the league tables would predict. While onset may be at any age, it typically attacks, without warning, adults in the prime of life, frequently presenting with advanced heart failure and occasionally with a catastrophic event such as stroke or sudden cardiac death. Thus, DCM is generally overrepresented in clinical trials of cardiac failure and accounts for almost 50% of all indications for cardiac transplantation internationally [1]. In this issue of the International Journal of Cardiology Agarwal and colleagues report, in a prospective study, on the prevalence and natural history of DCM in a region of Oman [2]. Patients are well-characterised and follow-up is complete. Two clinical observations from the study by Agarwal et al.
*Corresponding author. Tel.: 144-208-7255-91; fax: 144-208-6820944. E-mail address: [email protected] (N.G. Mahon).
are noteworthy. Firstly and predictably, prognosis was worst in those most severely affected at presentation, and, secondly, overall prognosis was considerably better than that reported in earlier studies of the natural history of the condition. The latter observation, which is true also of other populations, reflects the fact that, while there is as yet no specific treatment for DCM, we now have at our disposal an armamentarium of medications which can improve symptoms, retard disease progression and prevent serious complications. The earlier the diagnosis is made, the greater the impact of such treatments. The clinical challenge, therefore, is to detect DCM in its protracted asymptomatic prodromal phase, and to prevent progression to advanced disease. Hence the importance of recent work exploring familial aspects of DCM. Historically, the importance of familial disease has been under-appreciated because of diagnostic difficulties related to the nonspecific phenotype and the phenomenon of variable and age-related penetrance. However, in the past decade prospective family evaluation studies have
0167-5273 / 00 / $ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 00 )00314-4
Idiopathic dilated cardiomyopathy in an Omani population of the Arabian Peninsula: prevalence, clinical profile and natural history a, a a b A.K. Agarwal *, P. Venugopalan , A.K. Meharali , D. de Debono a
Department of Cardiology, Sultan Qaboos University, Muscat, Oman b Glenfield General Hospital, Leicester, UK
Received 26 November 1999; received in revised form 2 March 2000; accepted 13 June 2000
Abstract We have analysed prospectively the prevalence and clinical profile of idiopathic dilated cardiomyopathy (IDC) in a circumscribed native population of the Sultanate of Oman over 3 years (1992–1994). Identified patients were followed up for a period ranging from 1 to 8 years (median 4 years) and the variables related to outcome determined. IDC was diagnosed in 97 patients, giving a prevalence of 43.2 / 100,000 population during the study period. 84.5% of patients were aged over 35 years and males outnumbered females (M / F51.4:1). Factors related to poor outcome were an initial left ventricular ejection fraction #30% (P 5 0.01), severe symptoms, i.e. NYHA functional class III or IV at presentation (P 5 0.04), and significant ventricular tachycardia during follow up (P 5 0.02). However, multivariate regression analysis yielded only low LVEF as the predictor of poor outcome (P 5 0.01). When analysed from age of onset of symptoms, survival figures were 94% at 1 year (95% CI 88 to 99%), 76% at 5 years (95% CI 67 to 86%) and 68% at 8 years (95% CI 54 to 82%). Mean survival was 6.5 years (95% CI 6 to 7 years). Patients were still at risk of fatal ventricular arrhythmia even when haemodynamically stable and had left ventricular ejection fraction .30%. 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Idiopathic dilated cardiomyopathy; Epidemiology; Survival; Outcome variables; Middle East
1. Introduction Idiopathic dilated cardiomyopathy (IDC) is a primary cardiac muscle disease of an undefined etiology characterized by global hypokinesia of the ventricle(s) resulting in symptoms of heart failure. Diagnosis relies on exclusion of other causes of heart failure like myocardial ischaemia, hypertension, excessive alcohol consumption, diabetes mellitus and viral myocarditis. Although mortality figures of 57 to 75% in the first 2 years [1–4] had been reported in the 1970s, survivals as high as 90% at 4 years are *Corresponding author. Tel.: 1968-513-355-3404; fax: 1968-513419. E-mail address: [email protected] (A.K. Agarwal).
seen in recent publications [5–7]. To our knowledge, collective data on the prevalence and natural history of the disease from any country in the Middle East (Arabian population) have not been reported before, hence this prospective study of 97 patients with IDC in an Omani population of the Arabian Peninsula.
2. Patients and methods
2.1. Patient population Dhakliya region of the Sultanate of Oman with a local population of 225,000 (males 111,000 and females 113,000) was selected for the study due to its close liaison with and an effective referral system to
0167-5273 / 00 / $ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 00 )00315-6
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tertiary care facilities of Sultan Qaboos University Hospital. The non-Omani expatriate population (24,000) living in this area was excluded from the study. All adults (aged .12 years) from the Dhakliya region with symptoms suggestive of heart disease from 1992 to 1994 (3 years) were evaluated by the local physicians at the regional hospital of Dhakliya region in the city of Nizwa. Those suspected of having IDC were then referred to the Sultan Qaboos University Hospital for further investigation. The patient population of the study comprised a mixture of all diagnosed cases of dilated cardiomyopathy already on hospital records and new cases that presented subsequently during the study period. World Health Organization criteria were used to diagnose IDC [8]. Besides detailed history, physical examination, chest X-ray and electrocardiogram, all patients had echo-Doppler studies to confirm impaired myocardial function (left ventricular ejection fraction of ,50%) and exclude identifiable causes of myocardial dysfunction. Exercise testing and coronary angiography were performed to exclude coronary artery disease. Patients with a history of alcohol intake, hypertension, diabetes mellitus, thyroid disease or other systemic diseases, and acute myocarditis were not included in the study. Recent viral infections were excluded by serological testing, however myocardial biopsy was not part of the study protocol. Variables recorded during follow up included the class of heart failure as per the New York Heart Association (NYHA) functional classification [9], arrhythmia, systemic or pulmonary embolic events and death. Patients were followed up periodically with clinical examinations, and the echocardiogram was repeated once a year or earlier if acute heart failure occurred. All patients underwent 24 h Holter ECG at the time of entry and again during follow up if arrhythmias were suspected. Treatment of heart failure included a combination of diuretics and angiotensin converting enzyme inhibitor (ACEI), and digoxin added later when the symptoms continued to worsen with the maximum tolerated dose of ACEI or when atrial fibrillation developed. Anticoagulation was considered in the presence of atrial fibrillation, thromboembolism or when an intracardiac thrombus was demonstrated on echocardiography. None of the patients received beta-blocker therapy. The follow up was concluded in December
1998 after ascertaining the status of the study patients.
2.2. Statistical methods The data were saved in a file prepared with Statistical Package for Social Sciences for Windows 97 and analysed. The outcome was categorised as alive or dead at the termination of the study. The statistical significance of the differences in the variables was tested using the unpaired t-test in the case of continuous and the Chi square test in the case of discrete variables, accepting P , 0.05 as significant [10]. For the purpose of survival analyses the duration of illness from onset of first symptom of heart failure (dyspnoea) was applied. It was assumed that all patients entered the study at the same point and patients were taken from the analysis as they died or completed the follow up period. Survival curves were constructed by the Kaplan–Meier method and the log rank method was used to compare the survival data of patient subgroups defined with reference to possible risk factors.
3. Results
3.1. Prevalence A total of 111 patients were entered into the study with a provisional diagnosis of heart failure of unidentified cause. Of these 111 patients, 14 (12.7%) were found on investigation to have coronary artery disease, leaving 97 patients suitable for analysis. The prevalence of IDC in the Dhakliya region was thus 43.2 / 100,000 population during the study period.
3.2. Demographic profile ( Table 1) Patients were aged 15–69 years (median age 50 years). We did not find any patient aged above 69 years, although this was not a part of the case definition. The study included 56 males and 41 females (M / F51.4:1). The social makeup of patients recorded nearly all females as being house wives and
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149
Table 1 Demographic profile of patients with idiopathic dilated cardiomyopathy (n 5 97)
Table 2 Symptoms on presentation in patients with idiopathic dilated cardiomyopathy (n 5 97)
Characteristic
Group
Number (%)
Symptom
Number (%)
Age
15–24 years 25–34 years 35–44 years 45–54 years 55–64 years .65 years Male Female Civil servant Business Farmer Student Housewife Unemployed Single Married Divorced Widow Yes No Yes No
5 10 21 24 26 11 56 41 18 3 1 1 40 34 3 91 1 2 31 66 3 94
Shortness of breath
97 (100)
NYHA class Class I Class II Class III Class IV
8 52 37 0
Sex Occupation
Marital status
Consanguineous parents Affected family member
(5.2) (10.3) (21.6) (24.7) (26.8) (11.4) (57.7) (42.3) (18.5) (3.1) (1.1) (1.1) (41.2) (35) (3.1) (93.8) (1.1) (2.2) (31.9) (68.1) (3.1) (96.9)
34 of 56 males (60%) were interestingly either unemployed or only performed odd jobs, mainly living on social benefits. Some of them were retired and had worked briefly in their younger days in different fields. Seven patients had severe symptoms that necessitated discontinuation of their job. No correlation could be found between IDC and their previous work. Nearly all patients were married. Parental consanguinity, a common occurrence in Arab culture, was apparent, however only three patients could be identified as having another affected member in the family, and none of them had consanguineous parents.
3.3. Clinical features ( Table 2) Duration of symptoms at entry ranged from 1 month to 7 years [median 1 year, mean (S.D.) 1.3 (1.4) years], with a majority (69 / 97) of 12 months or less. Shortness of breath of varying severity was reported by all (100%) as the presenting complaint, with general fatigability being a common association. Other less frequently reported symptoms were palpi-
Fatigue Paroxysmal nocturnal dyspnoea Palpitations Angina Typical Atypical Syncope Post partum onset
(8.2) (53.6) (38.1) (0)
92 (94.8) 54 (55.7) 28 (28.8) 7 (7.3) 35 (36) 4 (4.1) 4 (4.1)
tation, and syncope. Chest pain when reported (36%) was mostly atypical.
3.4. Investigations ( Table 3) Chest X-ray revealed a cardio-thoracic ratio of .50% in all patients, but only 72 (74%) had congested lung fields at presentation. Cardiac rhythm at entry was sinus in 87 (89.6%) patients, atrial fibrillation in eight and atrial flutter and junctional rhythm in one each. Frontal plane QRS axis was either normal (45.3%) or leftward (49.5%). Major conduction abnormality as assessed by QRS configuration and duration was of left bundle branch block and intraventricular conduction delay type. ECG evidence of left or biventricular hypertrophy was the predominant feature (78.4%) and isolated right ventricular hypertrophy was seen in only one patient. Twenty-four hour Holter ECG recorded both atrial and ventricular arrhythmias. Echo-Doppler studies revealed global hypokinesia of the left ventricle with ejection fractions ,50% in all patients. Severe left ventricular dysfunction (LVEF #30%) was seen in 33 (34%) patients, of whom only 18 had class III or IV symptoms. Mitral regurgitation was present in the majority, but was severe in only 27 (27.8%). About one-half of patients
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Table 3 Chest radiograph, ECG and echocardiographic findings in idiopathic dilated cardiomyopathy (n 5 97)a Finding
Number (%)
Chest radiograph CTR 50–69% CTR .70% Congested lung fields
93 (95.9) 4 (4.1) 72 (74)
ECG Sinus rhythm Atrial fibrillation Atrial flutter Junctional rhythm LAD RAD RBBB LBBB IVCD LVH RVH BVH
87 8 1 1 48 5 1 16 25 67 1 9
24 h Holter ECG Atrial tachycardia
(89.6) (8.2) (1.1) (1.1) (49.5) (5.2) (1.1) (16.5) (25.8) (69.1) (1.1) (9.3)
4 / 97 (4.1)
Ventricular tachycardia #10 beats .10 beats
60 / 97 (61.8) 9 / 97 (9.3)
Torsade de pointes
3 / 97 (3.1)
Echo-Doppler studies EF #30% 30–49%
33 (34) 64 (66)
MR Mild Severe
61 (62.8) 27 (27.8)
TR Mild Severe
38 (39.2) 12 (12.3)
AR mild PR mild Diastolic dysfunction
27 (27.7) 21 (21.6) 39 (40.2)
a CTR, cardio-thoracic ratio; ECG, electrocardiogram; LAD, left axis deviation; RAD, right axis deviation; RBBB, right bundle branch block; LBBB, left bundle branch block; IVCD, intraventricular conduction delay; LVH, left ventricular hypertrophy; RVH, right ventricular hypertrophy; BVH, biventricular hypertrophy; EF, ejection fraction; MR, mitral regurgitation; TR, tricuspid regurgitation; AR, aortic regurgitation; PR, pulmonary regurgitation.
also had tricuspid regurgitation and a few had mild aortic and pulmonary regurgitations.
3.5. Clinical course ( Fig. 1) Two patients died from acute heart failure at
presentation. The remaining 95 patients were followed up for periods ranging from 1 to 8 years (median 4 years) from the onset of symptoms. Of these, 40 (41.2%) remained stable in the same functional class of heart failure throughout the study period. Another 28 (28.8%) experienced acute exacerbation of heart failure requiring at least one hospitalization, but remained stable thereafter. These 68 patients were placed in Group A for analysis. Of the remaining 29 patients, 13 (13.4%) had two or more exacerbations of heart failure and deteriorated in spite of the initial improvement and along with another 14 patients (14.4%) who experienced gradual deterioration requiring hospitalisation and modification in therapy were placed in Group B for analysis. Patients in Group A did not exhibit any deterioration in LVEF or require modification of anti-heart failure medication. Group B patients exhibited deterioration in LVEF by 5–11%. Among the 41 patients with exacerbations of heart failure (28 of Group A and 13 of Group B), the recurrence of symptoms could be attributed to non-compliance to medication in 12, development of new arrhythmias in eight, and no specific factor could be identified in the remaining 21. Other notable events were hemiplegia (thromboembolic) in 2 / 97 (2.1%) patients and pulmonary embolism in four (4.2%). Death occurred in 23 of the 97 (23.7%) patients during the study period, two at initial presentation, seven in Group A and 14 in Group B. Deaths in Group A occurred in patients whose heart failure was well under control and could be attributed to fatal ventricular arrhythmias in five (three of whom were at home), pulmonary embolism in one and disseminated malignancy (non-cardiac) in one. The remaining 14 deaths occurring in Group B were due to resistant heart failure. Additional contributing factors in this group included pulmonary embolism in three and Pseudomonas septicaemia in one.
3.6. Survival ( Fig. 2) The survival rates from the onset of first symptoms were 94% at 1 year (95% CI 88 to 99%), 86% at 3 years (95% CI 79 to 93%), 76% at 5 years (95% CI 67 to 86%), and 68% at 8 years (95% CI 54 to 82%). Mean survival was 6.5 years (95% CI 6 to 7 years). Median survival, i.e. time at which 50% of the patients died, could not be computed as more than
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151
Fig. 1. Clinical course of idiopathic dilated cardiomyopathy over an 8-year period (n 5 97).
50% of patients were alive at the conclusion of the study.
3.7. Analysis of outcome variables Live and dead patients were compared with regard to age, sex, duration and severity of symptoms, LVEF on presentation, and presence of ventricular tachycardia during follow up. NYHA functional class III or IV, low LVEF (#30%) and presence of significant ventricular tachycardia (.10 beats or Torsade de pointes) on 24 h ECG Holter were identified as
significant variables for poor outcome (Table 4). A multivariate regression analysis was performed with the above variables, and low LVEF was the only factor that predicted death (P 5 0.01). Survival curves were plotted for the different values of the LVEF. Patients with LVEF #30% (Fig. 3) had a mean survival of 6 years (95% CI 4.5 to 7.4 years) while for those with LVEF .30% it was 10.8 years (95% CI 9.5 to 11.9 years). The difference was highly significant (P 5 0.01). Similarly, NYHA classes 3 and 4 (Fig. 4) were associated with decreased survival (8.3 vs. 10 years; P 5 0.04).
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152
Fig. 2. Cumulative survival in idiopathic dilated cardiomyopathy (n 5 97).
4. Discussion
4.1. Prevalence Nizwa Central Hospital is the only secondary care regional hospital in the Dhakliya region of Oman and receives patients from the state run primary health centres and other small hospitals in the region, and in addition runs a direct access Outpatient Clinic. The system of free medical services and the good health infrastructure ensures that all patients with heart
failure are referred for evaluation to this hospital. We have in our study followed WHO criteria for diagnosis of IDC [8] and excluded patients with alcoholism, diabetes, hypertension, ischaemic heart disease, thyrotoxicosis and myocarditis [11–13]. Thus we believe that we have included all patients with IDC who had come to medical attention from the Dhakliya region. We have also ensured that patients with other possible causes of dilated cardiomyopathy were excluded. Physicians and general practitioners in Oman have
Table 4 Analysis of variables related to outcome in idiopathic dilated cardiomyopathy (n 5 97)a Outcome variable b
Age (years) Sex Duration of symptoms b (years) LVEF b (%) Severity of symptoms b Significant VT c a
Live
Dead
P Univariate
Multivariate
Mean (S.D.) M/F
48 (13) 44 / 30
46 (12) 12 / 11
0.52 (NS) 0.53 (NS)
0.55 (NS) 0.58 (NS)
Mean (S.D.) Mean (S.D.) A/B Yes / no
1.5 (1.3) 36 (8.6) 50 / 24 6 / 74
1 (1.2) 31 (7.5) 10 / 13 6 / 23
0.20 0.01 0.04 0.02
0.17 0.01 0.14 0.10
(NS) (S) (S) (S)
(NS) (S) (NS) (NS)
M, male; F, female; NS, not significant; S, significant; LVEF, left ventricular ejection fraction; VT, ventricular tachycardia; A, NYHA functional classes I and II; B, NYHA functional classes III and IV. b At entry into study. c During follow up.
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Fig. 3. Comparison of survivals in idiopathic dilated cardiomyopathy with initial left ventricular ejection fraction (LVEF). Log rank 7.22 (P 5 0.01).
Fig. 4. Comparison of survivals in idiopathic dilated cardiomyopathy with initial New York Heart Association (NYHA) functional class. Log rank 3.89 (P 5 0.04).
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observed a higher prevalence of IDC in this country (personal communication) compared to other parts of the world particularly Europe, the UK and the USA and this prompted us to evaluate the problem. Published studies on IDC have reported the extent of the problem both in terms of the incidence, which refers to the new cases per year, and the prevalence, which refers to the total number of cases present at any point in time. Some studies have also used the term yearly prevalence to indicate the total prevalence divided by the duration of study in years. While the incidence from Caucasian populations ranges from 5 to 8 / 100,000 population [14], the prevalence has been placed at 36.5 / 100,000 [15]. Williams and Olsen [14], in their study covering a population of about 913,000 in two distinct areas in the United Kingdom, found a yearly prevalence of 8.3 / 100,000 population, while a Scottish study that covered 5 years placed the figure at 9.9 / 100,000 [16]. These studies are not strictly comparable, however, due to the differences in the study designs (prospective versus retrospective), or in the criteria for patient selection (limited to IDC or including all patients with unexplained heart failure). In a post mortem study of 5252 necropsies over a period of 2 years, Rakar et al. [17] reported an incidence of 4.5 / 100,000 in Italy, but the clinical incidence during the same period was only 2.45 / 100,000, indicating the value of post mortem studies in picking up cases undiagnosed during life. A large case registry based study in China [18] during a 5-year period (1985–89) reported an incidence of 2.6 / 100,000 person years, increasing from 1.7 in 1985 to 3.3 in 1989. A relatively limited comparative report of dilated cardiomyopathy in Dubai (United Arab Emirates) and Moscow showed that the prevalence of IDC and peripartum cardiomyopathy was higher in Dubai [19], however this study did not report the racial origin of their study sample and Dubai is a cosmopolitan state with a large expatriate population. Our prospective study of IDC in a native population in a circumscribed region of the Sultanate of Oman ensured exclusion of patients with other causes of dilated cardiomyopathy and concluded a relatively high prevalence (43.2 / 100,000) of IDC in the study population. Since, in a strict sense, this was not a population-based study, the true prevalence is likely to be even higher. We did not find any evidence of
recent viral infection in the study patients to explain the higher prevalence recorded in this region of Oman, however a past viral infection could not be ruled out.
4.2. Clinical profile Idiopathic dilated cardiomyopathy (IDC) can develop at any age and affects both sexes. In our study population, the maximum number of patients was in the age group 35–64 years and males outnumbered females (M / F51.4:1). Our findings are comparable to those of Coughlin et al., who reported an incidence of 3.5 / 100,000 in males compared to 2.5 in females [20,21]. Pan et al. [18] has also reported a slight male preponderance, 3.0:2.2 / 100,000 population. Heart failure in general was shown to be more common in males than females [22] in a Finnish Study. The recognised 2.5-fold increase in the risk of developing IDC [11,23] in black males compared to white females, which is unexplained by other variables, may provide an explanation for our finding of a high prevalence in the Omani male population due to its East African background. Although 34 (35%) patients in our study were reported unemployed, only seven were sick enough to discontinue their previous jobs, the remaining had taken early retirement on their own choice. None of them were involved in any physically demanding employment. The majority of patients could have continued in their jobs or have worked in alternative less demanding work. This has significant financial and social implications. Dyspnoea on exertion of varying severity, the major presenting symptom, was present in all our patients. Other studies [24,25] have reported 75–85% of patients presenting with this complaint, while Sugrue [26], in a population based study of IDC, found that 90% of patients were in NYHA functional class III or IV. In our study, only 38% patients were in these classes. This is due to the early detection of disease in less severe heart failure. The majority of our patients were in sinus rhythm on presentation, except eight who had established atrial fibrillation. This arrhythmia is reported in ,25% of patients [2,27,28], but we found it to be even lower (8.2%). Chest pain, a less common symptom, was present in 36% of our patients, as has been reported in other
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studies [25–27]. Sometimes when typical this pain can be indistinguishable from ischaemic anginal pain. Chest pain could be secondary to the mechanical effect of an enlarged heart, a reduction in the coronary flow reserve [29,30] or a rise in pulmonary artery pressure. Syncope, an uncommon complaint, is due to transient ventricular arrhythmia.
4.3. Natural history Severe symptoms at the time of presentation were an important factor in the subsequent progression of heart failure. More than half (53.6%) of our patients were in NYHA functional class II at entry into the study. Patients who could be identified in class I maintained a steady haemodynamic state with only 10% progressing into lower functional classes. Similarly, patients who entered with severe heart failure (classes III and IV) deteriorated faster and accounted for most of the deaths from resistant heart failure. Therefore, special emphasis should be given to initiation of aggressive therapy for patients with severe symptoms. Treatment of asymptomatic unexplained cardiomegaly also needs to be reviewed. The substrate of myocardial impairment is laid long before symptoms appear. Research in this field has revealed significantly increased circulating N-terminal atrial natriuretic peptide as a marker of symptomless left ventricular (LV) dysfunction [31]. The benefit of treating such patients has been highlighted in two large studies of ACEI vs. placebo in such patients, showing a significant reduction in mortality in the active treatment group [32–34].
4.4. Arrhythmia on 24 h Holter ECG The occurrence of cardiac arrhythmias, both tachy and brady, in IDC is well established [35–39], but emphasis has been on ventricular arrhythmias due to their role as markers of sudden death. Sustained ventricular tachycardia is the most important of these as it can lead to ventricular fibrillation [40]. Ventricular ectopics and non-sustained ventricular tachycardia, although more common, have not been associated with increased morbidity or mortality. Besides precipitating heart failure, all types of arrhythmias cause further myocardial insult, worsening the functional class of heart failure even after the acute
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episode is controlled and, in addition, atrial fibrillation leads to a loss of the atrial support. Analysis of VT in our patients revealed that non-sustained VT was more common with an equal distribution of mono and polymorphic patterns (48.7 and 51.3%, respectively). Twelve patients who developed prolonged ventricular tachycardia or Torsade de pointes were in a higher functional class of heart failure (NYHA classes III and IV) and lower ejection fractions. Arrhythmia also occurred in otherwise stable patients in controlled heart failure in Group A. The development of sustained VT or Torsade de pointes was related to a poor outcome (P 5 0.02), however multivariate analysis failed to identify it as an independent factor of significance.
4.5. Embolic phenomena Systemic and pulmonary embolism is a known complication of IDC. Atrial fibrillation, a commonly associated arrhythmia, is an independent risk factor for embolic events. A dilated poorly contracting ventricle in sinus rhythm itself predisposes to thrombus formation due to low blood flow rates. Two strokes and four pulmonary embolisms that occurred in our series were all in patients with atrial fibrillation even though they had been appropriately anticoagulated, reflecting the compounded thrombotic potential in this condition. In approximately 15% of all ischaemic strokes the source of thromboembolism comes from the heart [2,41] and around 40% of such strokes occur in dilated cardiomyopathy (regardless of the cause). The 15% rate of thromboembolism reported by Bloudheim [42] and a similar rate reported by Gottdiener [43] are also higher. Our finding of less than 6% is more in line with the work of Komajda [25] and Fuster [2]. In view of the risk of thromboembolism, routine anticoagulation has been recommended in IDC [2,3,24]. Such a recommendation appears to be an overkill and a more logistic approach could be a periodic assessment by echocardiography to detect thrombus formation and to anticoagulate those patients who show the presence of thrombi in cardiac chambers or spontaneous echo contrast (SEC) on transoesophageal echocardiography. SEC has been shown to be an independent risk factor for thromboembolism [44]. With an estimated
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5% risk of major bleeding and a 1% risk of death associated with anticoagulant therapy [45,46] it will be appropriate to identify high risk group IDC patients for anticoagulation. The presence of atrial fibrillation would obviously be a strong indication for anticoagulation, which was the case in our six patients with embolic events.
4.6. Survival and death In the 1960s and 1970s, the Mayo clinic reported nearly 75% mortality in 2 years [2] and a 5-year mortality of 57% was assessed by Shirey et al. in 1980 [1], while Koide from Japan claimed an overall survival of 8 years after diagnosis [47]. In more recent data, survival has improved considerably [33,48–52]: Di Lenarda from Italy for the Heart Muscle Study Group reported a 4-year survival of around 90% [7]. This improvement in survival has largely been due to early diagnosis, the introduction of ACEI and beta-blockers in the therapy, and prevention of complications such as embolic events and arrhythmias. In our study of 97 patients, an all-cause mortality of only 24% over a 7-year follow up from entry into the study could be achieved even without using beta-blockers. The maximum number of deaths occurred in the first year of follow up and subsequent deaths were distributed over 1–7 years. Published studies have shown both a progressively increasing mortality with time [7,25,53] as well as a high mortality in the first years followed by a steep descent of the curve [27,54]. The natural history and prognosis are dependent to a great extent on the severity of heart failure at the time of initiating therapy [26]. Deaths from IDC are most commonly due to resistant heart failure. Fourteen out of 23 deaths (61%) in our series occurred in patients who were in severe heart failure and had LVEF #30%. There was a positive correlation between the LVEF at presentation and mortality (P 5 0.01), and this was the only predictive variable identified by multivariate analysis. However, care should be exercised when interpreting this result as the number of deaths in our study was only 23. Five patients who died in Group A reflect the other important factor relevant to death in IDC — malignant ventricular arrhythmias. These patients had a stable haemodynamic state in NYHA II / III and an LV ejection fraction of .30%. It is also relevant to
note that all these five patients were already on amiodarone for documented ventricular tachycardia which had previously worsened their heart failure acutely before they joined Group A. A correlation between ventricular arrhythmia and sudden death in IDC has never been fully established [55–57]. In univariate analysis the development of new sustained VT was associated in our study with poor outcome (P 5 0.02) and in our three patients who died suddenly at home, malignant ventricular arrhythmia was the most likely cause. The role of arrhythmia is also interestingly more relevant in stable patients since none of the deaths in Group B were primarily due to arrhythmia. Therefore, the role of arrhythmia is independent of the severity of myocardial impairment. In our study, the nearly 50% mortality in Group B with resistant heart failure and 10% (7 / 68) in Group A of stable patients strongly favour worsening myocardial function as the most important factor in mortality from IDC.
Acknowledgements We are greatly indebted to and acknowledge the guidance of the late Professor David de Bono during the study.
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Editorial Comment
Prevalence and natural history of dilated cardiomyopathy N.G. Mahon*, S. Hamid, W.J. McKenna Department of Cardiological Sciences, St. George’ s Hospital Medical School, Cranmer Terrace, London 5 W17 0 RE, UK Received 1 December 1999; accepted 13 June 2000
Although, in epidemiological terms, dilated cardiomyopathy (DCM) is a relatively uncommon cause of heart failure, its clinical impact is far greater than its position in the league tables would predict. While onset may be at any age, it typically attacks, without warning, adults in the prime of life, frequently presenting with advanced heart failure and occasionally with a catastrophic event such as stroke or sudden cardiac death. Thus, DCM is generally overrepresented in clinical trials of cardiac failure and accounts for almost 50% of all indications for cardiac transplantation internationally [1]. In this issue of the International Journal of Cardiology Agarwal and colleagues report, in a prospective study, on the prevalence and natural history of DCM in a region of Oman [2]. Patients are well-characterised and follow-up is complete. Two clinical observations from the study by Agarwal et al.
*Corresponding author. Tel.: 144-208-7255-91; fax: 144-208-6820944. E-mail address: [email protected] (N.G. Mahon).
are noteworthy. Firstly and predictably, prognosis was worst in those most severely affected at presentation, and, secondly, overall prognosis was considerably better than that reported in earlier studies of the natural history of the condition. The latter observation, which is true also of other populations, reflects the fact that, while there is as yet no specific treatment for DCM, we now have at our disposal an armamentarium of medications which can improve symptoms, retard disease progression and prevent serious complications. The earlier the diagnosis is made, the greater the impact of such treatments. The clinical challenge, therefore, is to detect DCM in its protracted asymptomatic prodromal phase, and to prevent progression to advanced disease. Hence the importance of recent work exploring familial aspects of DCM. Historically, the importance of familial disease has been under-appreciated because of diagnostic difficulties related to the nonspecific phenotype and the phenomenon of variable and age-related penetrance. However, in the past decade prospective family evaluation studies have
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