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Prognostic Assessment and Risk
Stratification of Hypertrophic Cardiomyopathy

Guillermo Romero Farina MD, PhD;
Jaume Candell Riera MD, PhD

Servicio de Cardiología, Hospital Universitari Vall d´Hebron, Barcelona, Spain

INTRODUCTION
   Hypertrophic cardiomyopathy (HC) is a dominant autosomic disease with a highly heterogeneous expression from the genetic, morphologic and clinical points of view (1). The diagnosis is based on the demonstration of symmetrical or asymmetrical left ventricular hypertrophy in the absence of other cardiac or non cardiac abnormalities that might have caused it (2). However, some patients with normal electrocardiogram and echocardiogram already have genetic or histologic characteristics associated with HC (3). This disease is relatively unusual: it appears approximately once in every persons (4).

   Although more than 130 years have elapsed since its first description in 1869 (5) reports with reference to HC are very numerous. During the last years research has been mostly directed to the last therapeutic strategies (pacemaker, alcohol septal ablation) (6,7) and the two aspects developed in this presentation: the prognostic assessment and the stratification of risk.

PROGNOSTIC ASSESSMENT
   A great number of patients with HC remain asymptomatic until the age of 20 or 30 years. Then, symptoms progressively begin to appear and at the age of 40 - 50 years most patients who survive are symptomatic to a higher or lower degree, starting a progressive deterioration. About 50% of the deaths are sudden (8). Patients who were diagnosed during childhood or adolescence and those with a unfavourable familiar history have an yearly mortality of 5.9% (9). Syncope at the moment of the diagnosis is also associated with a poor prognosis, with an yearly mortality of 2.5% (10). Duration of symptoms before death is usually about 10 years. After the fourth decade, mortality due to heart failure increases, especially when atrial fibrillation develops.

   We studied a population of 119 consecutive adult patients (mean age: 52 years) with HC (11) during a mean follow-up of 10 years, and we have observed an yearly mortality of 0.6%. Forty-nine percent of patients had complications, that were severe in 58%: dyspnea class III or IV, angina class III or IV, myocardial infarction, syncope and death.

   Spirito et al. (12) analyzed the clinic evolution of HC based on 78 studies from 1983 to 1987 with a population of 3.404 patients and found 757 (22%) with dyspnea class III - IV. Also atrial fibrillation increased significantly during the follow-up to a more than 30% in old aged patients. Syncope have been reported in 12% - 78% of the patients but has a low tendency to progress during the evolution of the disease. Less frequent complications include: stroke (2% - 13%), myocardial infarction with normal coronary arteries (2%-11%), complete atrioventricular block (1%) and infective endocarditis (0.8% - 2%).

   Progression and regression of the hypertrophy, changes in the left ventricular outflow gradient, ventricular cavity enlargement and systolic dysfunction have been reported during follow-up of HC. In our series, progression of hypertrophy >5 mmwas observed in 8% of the patients, regression of hypertrophy in 5%, decrease (> 10%) of the systolic shortening in 13%, increase (> 10 mm) of the end-diastolic diameter in 5%, and evolution of the obstructive form in 15%. A significant correlation between severity of the dynamic obstruction and the severity of mitral regurgitation was also observed (11)

   Maron et al. (13) evaluated the progression and magnitude of the hypertrophy in a pediatric population during an mean follow-up of 4 years with two-dimensional echocardiography and found an increase of the extension and magnitude of the hypertrophy in 43% of the cases, but in other series there was no evidence of this progression (14,15). Systolic left ventricular function is normal or upper normal in the majority of patients with HC, but a small proportion of them evolve into a morphological and functional phase similar to dilated cardiomyopathy. In some cases evolution from non obstructive to obstructive form of HC has been described (16).

   HC is the most frequent cause of sudden death in young people and athletes, although a great percentage of symptomatic patients with HC can remain clinically stable through many years. Others can live symptoms free until advanced age. Nowadays it is believed that the disease is more benign than it had been previously thought in studies based on series from hospital populations. The fact that HC is not a common disease and that most publications correspond to patients from reference hospital in a limited number of countries (USA, United Kingdom, Japan, Canada, Germany and Italy) limits the study of the natural history of the disease. These referred populations reported an yearly mortality of 4-6% for children. If these percentages were constant throughout the course of HC it would mean that all patients with HC have died under the age of 45 years. However this does not happen because the yearly mortality of non hospital populations is of 0.5 - 1.5% (17,18). Probably this is the real mortality rate of the HC.

   Not all patients with HC have the same risk of complications or death. For this reason there is a sustained investigation addressed to identify risk factors of complications and death.

STRATIFICATION OF RISK
   In patients with HC different predictive variables of complications and mortality have been described from the analyses of clinical data and parameters derived from the electrocardiogram, Holter, echo-Doppler, exercise testing, perfusion scintigraphy, electrophysiologic study and cardiac catheterization. In table I (A and B) we show the results of the recent reports including a minimal number of 100 patients were followed up for more than 5 years (11,15,17-26).

CLINICAL VARIABLES
1. Family history of HC and sudden death. The presence of the familial form of HC and sudden death, mostly in young people, is more frequent in those who have died (25,27).

2. Younger than 14 years old at the moment of the diagnosis. The age at the moment of the diagnosis is a predictive variable of a poor evolution. The survival is lower in those patients in whom diagnosis was made at age younger than 14 years (25).

3. Previous sudden death. The antecedent of resuscitated sudden death is an independent predictive variable of new cardiac events and is a clinical indication for a implantable cardioverter-defibrillator (23,28,29).

4. Severe dyspnea. In many studies dyspnea III - IV at the moment of diagnosis is a predictive variable of a poor prognosis (21).

5. Recurrent syncope. Presyncope and syncope in children and adolescents seem to identify people with a high risk of sudden death. However, in contrast with valvular aortic stenosis, some patients have an antecedent of these episodes for long time before without further recurrences (10).

ELECTROCARDIOGRAPHIC VARIABLES
6. Atrial fibrillation. Maron et al. (21) have pointed out that patients with paroxistic or chronic atrial fibrillation have a higher mortality.

7. Conduction abnormalities. Mc Kenna et al. (10) have described that the presence of left or right bundle branch block, although infrequent, is commonly observed in survivors of sudden death.

HOLTER RECORDING VARIABLES
8. Nonsustained ventricular tachycardia. Many prospective studies have observed that nonsustained ventricular tachycardia is associated to a high risk of sudden cardiac death. However this arrhythmia was also present in 21% of surviving patients. It seems to be a variable of poor prognosis, mainly when it is observed in young symptomatic patients with syncope or reduced left ventricular ejection fraction (30,31).

VARIABLES FROM ELECTROPHYSIOLOGICAL STUDY
9. Sustained ventricular tachycardia. Sustained ventricular tachycardia induced by programmed stimulation in the electrophysiological study is a predictive variable of new cardiac events in patients with previous cardiac arrest, syncope or presyncope (23).

EXERCISE TEST VARIABLES
10. Abnormal response of systolic blood pressure. Patients with an increase lower than 25 mmHg of the systolic arterial pressure during the exercise test have been shown to have a worse outcome (32). However, this response is difficult to interpret in patients treated with betablockers.

MYOCARDIAL SPECT PERFUSION VARIABLES
11. Reversible defects. The presence of reversible defects in the myocardial SPECT perfusion in young patients has been related to a higher incidence of syncope and cardiac arrest (33).

ECHO-DOPPLER VARIABLES
12. Left atrial dilatation. In our series the presence of a left atrial index > 25 mm/m2 and a left atrial diameter > 45 mm were predictive of mortality (14).

13. Left ventricular hypertrophy. According to some authors, sudden death rate increases progressively in direct relation to the maximum left ventricular wall thickness, mostly when thickness is > 20 mm (34). This was also confirmed in our series of adult people for left ventricular wall thickness > 25 mm (11).

14. Left ventricular dilatation. Some studies have pointed out that those patients who develop the ventricular dilatation have a high rate of complications and a lower survival (35).

15. Left ventricular systolic dysfunction. Decrease of the left ventricular systolic shortening below 35% is predictive of heart failure, which is usually associated with the left ventricular dilatation (36).

16. Severity of dynamic gradient. For some authors the left intraventricular gradient > 30 mmHg has an unfavourable prognostic meaning. In our serie a gradient > 50 mmHg was a predictor of higher mortality rate (11).

17. Severity of mitral regurgitation. There is a correlation between the severity of the gradient and mitral regurgitation in patients with HC (11). In our patients the presence of mitral regurgitation and its grade of severity were predictive of mortality in the bivariable analysis. In the multivariable analysis the only predictive independent variable of mortality was the severity of mitral regurgitation (11).

CATHETERIZATION VARIABLES
18. Left ventricular end-diastolic pressure increase.
Koga et al. (24) observed that a left end-diastolic ventricular pressure > 20 mmHg was a finding with poor prognosis in catheterized patients.

GENETIC VARIABLES
19. Detection of mutations. Several genetic mutations has been described in HC. There is a correlation between type of mutation, severity of complications and death. In the future this type of study can be fundamental for the stratification of risk in patients with HC (37-39).

SUMMARY
Prognostic evaluation and stratification of risk in patients with HC is difficult because the high variability of the natural history. Reports analyzing different prognostic variables through different tests are biased by the inclusion criteria, follow-up duration, and complexity of the techniques employed. In those reports that included middle aged patients without symptoms, studied in a primary care, and with < 3 years of follow-up, the prognosis was usually good. By contrast, in young symptomatic patients, studied in hospital centers and with a follow-up > 5 years, the yearly mortality is high. Many variables predicting poor prognosis have been reported during the last years, the majority of them (familial history, antecedent of sudden death, atrial fibrillation, systolic murmur, severe left ventricular hypertrophy, left atrial dilatation, severe mitral regurgitation and severe dynamic obstruction) are easily identifiable with a good clinical assessment (history and clinical examination) of the patient and with the practice of two rutine techniques such as electrocardiogram and the echo-Doppler.

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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
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Dr. Raúl Bretal
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