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European Journal of Heart Failure 2003 5(1):55-62; doi:10.1016/S1388-9842(02)00179-4
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© 2002 European Society of Cardiology

Prognostic value of serial cardiac assessment and familial screening in patients with dilated cardiomyopathy

Ekkehard Grüniga,1,*, Andreas Benza,1, Derliz Merelesa, Kristina Unnebrinkb, Helmut Kücherera, Markus Haassa, Wolfgang Küblera and Hugo A. Katusa

a Medizinische Klinik III, University of Heidelberg 69115 Heidelberg, Germany
b Coordination Centre for Clinical Trials, University of Heidelberg 69115 Heidelberg, Germany

* Corresponding author. Department of Cardiology, University of Heidelberg, Bergheimer Str. 58, 69115 Heidelberg, Germany. Tel.: +49-6221-568611; fax: +49-6221-565515 E-mail address: ekkehard_gruenig{at}med.uni-heidelberg.de


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objectives: This prospective study was performed to analyse whether routine clinical follow-up investigations at 12±6 months add to risk stratification and improve survival rates in patients with a first diagnosis of dilated cardiomyopathy (DCM).

Methods: Four hundred and eighty consecutive patients (mean age 53.4±12.3 years, 369 males, mean NYHA class 2.4±0.8) with invasively confirmed DCM were included and followed for 3.9±3.5 years. Patients were requested to adhere to a follow up investigation within 6–18 months either at the referring physicians or at our out patient department. Two hundred and eighty-one of the 480 patients presented for follow up which consisted of a detailed evaluation of symptoms, standardized physical examination, 12-lead-electrocardiogram recording and echocardiography. Seventeen patients were lost for follow up, 182 did not seek specialized medical follow up. Patients outcome was assessed by structured telephone interviews.

Results: Independent predictors of death or transplantation at initial diagnosis were LV–ejection fraction <30% (P=0.0001, risk ratio 2.25), LV–end diastolic pressure ≥15 mmHg (P=0.002, risk ratio 2.0), age ≥54 years, (P=0.04, risk ratio 1.55), and presence of left bundle branch block (P=0.046, risk ratio 1.53). On follow up investigations only deterioration of clinical status by at least one NYHA-class (P=0.001, risk ratio 2.6) and new onset or worsening of mitral regurgitation (P=0.02, risk ratio 1.8), remained independent prognostic factors for cardiac death. Patients who presented for routine follow up revealed significant better 5-year survival rates (n=281, 70%) than those who did not (n=153, 55%, P=0.005).

Conclusions: Routine clinical follow up investigations within 6–18 months after first diagnosis of DCM adds to risk stratification and improves survival rates.

Key Words: Dilated cardiomyopathy • Prognosis • Survival • Familial cardiomyopathy • Genetics • Serial assessment

Received February 11, 2002; Revised June 3, 2002; Accepted July 17, 2002


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Risk prediction in patients with dilated cardiomyopathy (DCM) is crucial for selection of treatment strategies including heart transplantation. From a large variety of clinical investigations a substantial number of clinical, hemodynamic, biochemical and electrocardiographic indices were identified as being independently predictive of cardiac events. However, all these indices share a low positive and negative predictive value in an individual patient, which limits their clinical applicability.

Many symptoms and clinical findings change with progression of DCM. It is tempting therefore to speculate that assessment of disease progression in an individual patient over time may be more suitable for monitoring patient risk than the application of predefined indices that are derived from independent clinical trials. However, only a few investigations evaluated the prognostic value of time dependent changes of clinical findings, in an individual patient. Thus, Stevenson et al. 1995 [1] and Florea et al. 2000 [2] reported on the excellent performance of changes of peak VO2 uptake. However, Gullestad et al. 1998 [3] could not confirm these findings but observed that neither changes in peak VO2, left ventricular dimension, nor left ventricular ejection fraction were predictive of cardiac mortality. Furthermore the quoted investigations were retrospective and not confined to the patients with definitive DCM but included patients with different aetiologies of heart failure.

Therefore, we prospectively tested the hypothesis that routine clinical follow-up investigations of DCM patients within 6–18 months following the first diagnosis may translate into a reduced cardiac event rate and improved survival.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Index patients
The study group consisted of 480 consecutive patients with DCM confirmed by left heart catheterization and coronary angiography investigated at the Department of Cardiology of the University of Heidelberg. DCM was diagnosed according to the criteria of World Health Organisation [4,5], when angiographic left ventricular ejection fraction was <50% in the absence of significant coronary artery stenosis and no further evidence for specific heart muscle diseases. In 85 of the 480 index patients DCM diagnosis was already suspected 1–25 months before diagnosis was confirmed by heart catheterization. Since these patients were already treated appropriately, they were not included for calculation of Kaplan–Meier survival curves. All statistical analyses were calculated with and without inclusion of the data of this patients subgroup. The ethics committee on human research of the University of Heidelberg approved the study protocol and all participants gave their written informed consent after thorough explanation of the purpose of this study and study protocol.

2.2. Baseline data
At entry into study all patients were hospitalised for at least 3 days to confirm the diagnosis and to initiate medical therapy. During this hospital stay a detailed medical and family history was obtained followed by thorough physical examination, a 12-lead-electrocardiogram (ECG) recording, chest X-ray, echocardiographic studies, left heart catheterization with coronary angiography and clinical chemistry testing. A 24-h-Holter-ECG was performed when the patients complained of symptoms of arrhythmias. The time interval to follow-up examination was related to the date of left heart catheterization.

2.3. Segregation analysis
A detailed family history was obtained in 445 of the 480 index patients allowing the construction of pedigrees. To proof or exclude presence of familial DCM all first- and second-degree family members were examined as reported previously [6].

2.4. Medical history
Functional status of the patients was determined according to the classification of the New York Heart Association [7].

2.5. ECG-recording
A 12-lead-ECG was recorded in all patients and analyzed by two cardiologists (E.G. and A.B.).

ECG-stress test was performed as a symptom-limited test on bicycle ergometer in upright position with increasing work loads of 25 W every second minute.

Echocardiography used standard equipment (Toshiba SSH 160A, Aloka SSD 870, 2200 3.5 MHz transducers). Left and right ventricular dimensions, left atrial diameter and interventricular septal thickness were measured from parasternal long and short axis views in M-mode technique. Fractional shortening of the left ventricular myocardium was calculated using standard methods. Valvular regurgitation or stenosis was assessed using color and continuous wave Doppler echocardiography. Mitral regurgitation was graded according to CW- and color Doppler indices [8]. The echocardiograms were re-analyzed off-line by experienced experts in cardiac ultrasound (D.M. and H.K.) in a blinded fashion.

Left heart catheterization and coronary angiography were performed using the transfemoral approach. Left ventricular ejection fraction was measured by the area length method in the 30° right anterior oblique projection.

2.6. Medication
At study entry patients were treated or had already received the following treatment: angiotensin converting enzyme (ACE) inhibitors (n=361, 75%), diuretics (n=367, 77%), digitalis (n=259, 54%), calcium channel blocker (n=148, 31%), acetylsalicyle acid (n=63, 13%), and beta-blockers (n=32, 8%), phenprocumarine (n=257, 54%), antiarrhythmic therapy (n=116, 24%).

2.7. Follow-up visit
All index patients were requested to return for follow-up within 6–18 months after left heart catheterization. This follow up assessment consisted of a detailed medical history, physical examination, 12-lead-ECG recording and echocardiography. ECG-stress test and 24-h-Holter-ECG were performed, if the patients had evidence of arrhythmias. When patients preferred to see their personal physician or physician of their local hospital for control examination we asked the attending physicians for transfer of medical records and discharge summaries.

2.8. Study groups
The patients were allocated to three groups according to the adherence and medical center of follow up. Patients who underwent heart transplantation or had died within 6 months following initial diagnosis were excluded (n=29) as were those who were lost to follow up (n=17). Group A: patients who came for follow up to the outpatient Department of the University of Heidelberg; group B: patients who visited their local physicians; group C: patients who did not present for specialized medical follow up. The patients who referred for follow up visits later than 18 months after heart catheterization were also assigned to group C.

2.9. Interview at end of study
At the end of the study the patients were interviewed by telephone using a half-structured questionnaire. Questionnaires were mailed to 7 patients who had no telephone and asked for detailed response. Surrogate interviews by close family members and/or treating physicians were obtained for those cases that were deceased, unable to participate or had returned incomplete questionnaires. To minimise potential problems related to interviewer bias and to improve the validity and reliability of the obtained information all patients were contacted at least two times by two examiners (A.B. and E.G.). The patients were asked for their actual symptoms to allow NYHA-classification, for any cardiac events that might have occurred, the date and location of their first ambulatory follow up and their current medications. Family histories and pedigrees were completed according to this information. When the index patient was deceased, date of death was recorded and their relatives and/or treating physicians were asked for the cause and circumstances of death. Sudden death was defined as unexpected death within 1 h of the onset of new symptoms or during sleep [9].

2.10. Statistical methods
For analysis of survival, patients with cardiac death or transplantation were counted as endpoints, survivors and patients who died from non-cardiac reasons were regarded as censored. The univariate analyses were performed using Logrank-Tests for comparing Kaplan–Meier survival curves, [10] multivariate analysis was performed using Cox proportional hazards model [11]. In the figures and tables the data are expressed as mean values±S.D. P-values <0.05 were considered as statistically significant.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Prognostic variables derived from re-evaluation
At the end of the study 463 of 480 index patients or their relatives were reached by telephone and interviews were completed (Fig. 1). Seventeen patients were lost to follow-up. Analysis of prognostic variables and all other follow-up results were similar for the entire study cohort (n=463) and for the 395 patients who were firstly classified as DCM patients at our centre. Of the 463 patients 281 followed our invitation for re-evaluation at a mean of 10.6±4.0 months after initial diagnosis: 191 patients were seen in our outpatient department (group A), 90 at the referring hospitals or by their general practitioners (group B). One hundred and eighty-two patients did not follow our recommendation for ambulatory re-evaluation within 18 months after initial diagnosis. Sixteen patients because they had died and 13 because they had received heart transplantation within 6 months after initial diagnosis. Thus, a total of 153 patients were not supervised by an experienced physician (group C, Fig. 1).


Figure 1
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  		Fig. 1 Study design and patients allocation. Four hundred and eighty index patients with invasively diagnosed DCM were prospectively included. All patients were requested for re-evaluation 6–18 months following initial diagnosis, 17 were lost to follow-up. At study termination 463 patients or their relatives were interviewed by telephone. One hundred and forty had died, 323 survived (274 on medication, 46 with heart transplantation, 3 with cardiomyoplasty). Patients of group A were re-evaluated in the University hospital of Heidelberg, those of group B were seen in the referring hospital or by general practitioners and patients of group C did not seek any medical supervision.

 
During a mean follow-up period of 3.9±3.5 years (0–7 years) 140 of 463 patients (30.2%) died, 56 (12.1%) patients had received heart transplantation and 5 patients underwent cardiomyoplasty. The causes of death are shown in Fig. 2. Baseline parameters predictive of survival in univariate analysis (Logrank test) were dyspnea, NYHA class III or IV (P<0.0001), LV–end diastolic diameter >=65 mm (P<0.0001), LV–EF <30% (P<0.0001) elevated LV–end diastolic pressure >=15 mmHg (P<0.0002), left atrial dimension >45 mm (P<0.0001); elevated mean pulmonary artery pressure >=40 mmHg (P<0.002), cardiac index <2.0 l/min m2 (P<0.0002), ventricular arrhythmias LOWN IVb in 24-h-Holter-ECG (P<0.0006), left bundle branch block (P<0.0002), cardio thoracic ratio >=0.6 in chest X-ray (P<0.0001), maximal functional capacity on supine bicycle ergometer <100 W (P<0.0001), survived sudden cardiac death (P<0.004) and age >=54 years (P<0.002). Presence of second or third degree AV-block, atrial fibrillation, positive family history, gender, alcohol consumption <80 g/day and ECG-changes such as ST-T-depression did not reach statistical significance. Independent predictors of patients outcome at baseline are listed in Table 1 (multivariate analysis according to Cox proportional hazards model). There were no significant differences in initial medical treatment between survivors and non-survivors or transplanted patients.


Figure 2
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  		Fig. 2 Causes of death of 140 deceased patients with DCM. Most patients (46.4%) died of progressive pump failure, 20.7% of sudden cardiac death, 8.6% had a non-cardiac death, 7.9% died due to heart failure after transplantation or cardiomyoplasty and in 16.4% cardiac death was unclassified.

 


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  		Table 1 Variables on time in point of recruitment that independently predict outcome

 
At re-evaluation 60 of the 191 patients of group A had improved by one (n=45), two (n=12), or three (n=3) functional classes, 81 patients remained unchanged. The functional class deteriorated by one (n=47) or two classes (n=3), respectively. The deterioration by at least one NYHA class (P=0.0001, risk ratio 2.6) and new onset (n=16) or worsening (n=22) mitral regurgitation (P=0.02, risk ratio 1.8) were identified as additional independent prognostic factors (Table 2). The remaining variables assessed at re-evaluation were not predictive of patient outcome.


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  		Table 2 Variables at re-examination that were independently predictive of outcome

 
3.2. Survival rates depending on adherence to ambulatory follow up
The 5-year survival rates of the 281 patients who followed the recommendation for ambulatory follow up (group A and B, 70%) were significantly better than that of patients who did not (group C, 55%, P<0.005, Fig. 3) although patients characteristics were not different on their initial visit (Table 3). This benefit in survival was also seen when all patients who had died (n=27) or had undergone heart transplantation (n=14) within 18 months after diagnosis were excluded from analysis. Patients who preferred their ambulatory visits at their referring hospitals or physicians (group B) were less symptomatic and had better LV function than patients of group A and C (Table 3).


Figure 3
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  		Fig. 3 Cumulative cardiac mortality of group A (n=191), B (n=90) and C (n=153). The re-evaluated patients (group A and B) had significant better survival rates than the not re-evaluated group C (P=0.005). The mean survival rate of all index patients is symbolized by a bold line.

 


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  		Table 3 Clinical characteristics at recruitment

 
Whereas at initial assessment medication did not differ between the groups, significantly more patients of group A (91%) took ACE-inhibitors at last follow-up than did patients of group B (82%) and C (85%, P<0.006). The proportion of patients who underwent heart transplantation during follow-up was significantly higher in group A (20%) than in group B (3%, P<0.002) or C (8%, P<0.001).

3.3. Outcome of patients with familial DCM
Familial DCM was confirmed in 39 of the 395 index patients (9.9%). In 91 further index patients (23%) pedigree analysis revealed the evidence of familial aggregation of DCM, while in 265 patients DCM occurred as sporadic disease. Five year survival rate of the 39 patients with confirmed familial disease was 45% as compared to 58% in the 265 patients with sporadic DCM (P<0.02, Fig. 4). Survival rates in index patients with suspected familial disease (n=91) by pedigree analysis was not different from sporadic cases.


Figure 4
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  		Fig. 4 Overall survival rates of patients with familial and sporadic DCM. Median follow up was 58.2 months.

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This study investigated the impact of clinical re-examination on outcome of patients with invasively proven DCM. To our knowledge, this study is the first to demonstrate that clinical re-evaluation within 6–18 months after diagnosis improves risk stratification and survival in patients with DCM. Patients adhering to the recommended re-examination were more often treated by state of the art therapy such as ACE-inhibitors and were more often treated by heart transplantation. This prospective study also indicates that patients with proven familial aggregation of DCM have a worse prognosis than patients with sporadic disease.

4.1. Clinical re-evaluation adds to risk stratification
There are only few studies reported investigating the impact of routine clinical follow up examinations on outcome of patients with DCM [1–3,12]. Therefore, practice guidelines on follow up examinations are lacking in patients with DCM and specific variables that need to be taken into account for risk assessment are only poorly defined [13]. In the present prospective study on a large and well defined patient cohort it is shown for the first time that new onset or worsening of mitral regurgitation and worsening of functional NYHA-class were independently predictive in patients followed by routine re-examination at 6–18 months following first diagnosis of DCM. New or worsening mitral regurgitation was not a surrogate of progressive left ventricular dysfunction but was independently predictive of patients outcome. Thus, assessment of mitral regurgitation was superior to other indices of left ventricular dysfunction such as LV–ejection fraction, LV–enddiastolic pressure, LV–enddiastolic dimension. The better predictive performance of degree of mitral regurgitation may also result from more precise assessment of mitral regurgitation as compared to LV diameters or function. In support of our data enlargement of the left atrium and presence of mitral regurgitation on initial diagnosis was also described by Modena et al. [12] and Blondheim et al. [14] as being indicative of patients outcome.

The most predictive indicator of patients outcome, which could be derived from our routine re-examination, was deterioration of functional status by at least one NYHA class. Measurement of peak oxygen uptake by cardiopulmonary exercise testing [15] or the 6 min walking test [16] were only analyzed in a minor fraction of the study group, since at the time this study was initiated the predictive power of these indices was not yet well established.

The prognostic variables that were identified at recruitment of the patients are those also reported by others before [17]. However, our data base on a large patient cohort with well defined disease status which was followed over a extended time period with minimal loss to follow up indicates clearly that assessment of NYHA class and mitral regurgitation is paramount for proper risk stratification of patients with DCM.

4.2. Routine clinical re-examination may improve survival in DCM-patients
Repeated assessment of functional capacity is recommended for the management of patients with heart failure particularly when timing and selection for heart transplantation is to be defined [13,15]. However, the significance of routine follow up of DCM patients by different health care providers is undetermined. In our study 281 patients that adhered to the recommended re-examinations (group A+B patients) did significantly better than the patients not re-evaluated (group C). This difference was found although the groups were equally treated at the time of initial diagnosis if at all a bias may exist that would act contrary to these results. Eventually a bias may exist that the patients adhering to the proposed re-examination protocol may actually be those that were more symptomatic during follow up.

In the telephone interview at study end some of the patients who did not come for re-evaluation within 18 months after diagnosis gave unchanged or even better feeling as reason. However, the reasons for their absence were not analyzed systematically.

Interestingly patients during continuous medical supervision (group A and B) were more frequently taking ACE inhibitors than did patients of group C (91 vs. 85%, P=0.006). These finding suggest that the better survival of group A patients may be due to improved risk assessment and more appropriate medical therapy. Furthermore, the rate of heart transplantation was significantly higher in the re-evaluated patients (group A and B) as compared to group C (20 vs. 8%, P=0.001). Patients re-evaluated at University hospital (group A) did have better survival although these patients at initial assessment did not differ from group C patients in their prognostic variables.

4.3. Prognosis of patients with familial DCM
Although familial DCM occurs in 20–35% of all DCM cases [18,6] little is known on the history of these patients on the current medical therapy. Csanády et al. [19] stated that familial DCM has a worse prognosis than sporadic cases. In contrast to our study Csanády et al. used coronary angiography to exclude presence of significant coronary artery disease in only 101 of the 240 index patients [19]. Lower 1- and 5-year survival rates have also been reported in Japanese families with DCM when NYHA class III and IV patients were analyzed [20].

In our study the 5-year survival rate of 39 index patients with confirmed familial DCM was significantly lower than survival in the 326 patients with sporadic disease (45 vs. 58%, P<0.02). This finding highlights the importance of early detection of familial cases by family studies. The higher cardiac event rate of familial DCM may result from an earlier onset of DCM and a more rapidly progressive course particularly in juvenile patients. In fact this DCM phenotype is one of the five that were identified as distinctive phenotypic variance of familial DCM before [6]. However, identification of the distinct phenotypes and genotype in each patient may lead to more differentiated prognostic informations. The family history alone did not reveal prognostic information in our study.

4.4. Study limitations
Whereas the prognostic factors derived from cardiac re-evaluation in patients with DCM were studied prospectively in a well defined study population, the analysis of the benefit of routine re-examination had to be performed retrospectively. It was deemed unethical to randomise the index patients to a group that would not be allowed for re-examination. Therefore, our study may suffer from selection bias that drives the sicker patients to visit their physicians.

Treatment was not uniform throughout the group of patients studied and only 8% of patients received modern regime of β-blocking agents. When the study was initiated β-blockade was not yet part of routine clinical management. However, there were no significant differences in initial medical treatment between survivors and non-survivors or transplanted patients. Non-therapeutic influences on survival such as social class differences and ill health preventing attendance at follow up were not analyzed.

As 24-h-Holter-ECG were only performed in patients with symptoms suggestive of an arrhythmia (n=302, 65% of all patients), the prognostic implication of this parameter is limited in our study.

4.5. Clinical implications
Routine re-examination within 6–18 months after initial diagnosis of DCM is strongly recommended even in asymptomatic patients due to its impact on risk stratification and survival. Whereas worsening of functional status and new onset or deterioration of mitral regurgitation are independent prognostic variables at routine re-examination, changes in left ventricular dimensions and ejection fraction, results of 24-h-Holter-monitoring, and ECG-changes are not. Patients with familial disease should be identified early by thorough history taking and pedigree analysis in all DCM-patients since familial DCM carries a worse prognosis than sporadic disease.


   Acknowledgements
 
The authors are grateful to the many community physicians who contributed to this study. We thank Dr Per Barlinn, Dr Frank Brenn and Dr Tanja Koebel for their help in collecting medical records and obtaining pedigrees in numerous patients. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 320).


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
1 These authors contributed equally to this work. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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  16. Zugck C., Krueger C., Durr S., et al. Is the 6-minute walk test a reliable substitute for peak oxygen uptake in patients with dilated cardiomyopathy? Eur Heart J (2000) 21:540–549.[Abstract/Free Full Text]
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