One of the major challenges in the clinical management of patients with hypertrophic cardiomyopathy (HCM) is the identification and treatment of the small number of individuals prone to serious events and sudden cardiac death (SCD) in particular. Gimeno et al. report on the potential of exercise-induced ventricular arrhythmia as a novel additional marker of SCD risk1.
In a prospective cohort study 1380 HCM patients [mean age 42 years (SD 15); 62% male; mean follow-up 54 (SD 49) month] underwent symptom limited cardiopulmonary exercise testing (CPET), echocardiography and ambulatory Holter monitoring. Main purpose was the determination of the frequency of exercise-induced ventricular arrhythmia and its relation to SCD. Clinical characteristics of patients with and without exercise-induced ventricular arrhythmia were compared, the relation of exercise-induced ventricular arrhythmia and conventional SCD risk factors and the association between exercise-induced ventricular arrhythmia and all-cause mortality were determined.
Exercise-induced ventricular arrhythmia was defined as the presence of three or more consecutive ventricular beats at a rate ≥120/min. Primary endpoints in survival analysis consisted of sudden cardiac death and aborted sudden cardiac death. All cause mortality or orthotopic heart transplantation were coded as secondary end points.
27 of 1380 patients (2.0%) showed ventricular arrhythmia during CPET [mean age 40 (SD 14) years (18-64); 22 (81.5%) male], 24 had asymptomatic non-sustained ventricular tachycardia (NSVT), ventricular fibrillation (VF) occurred in three patients. During follow-up eight (29.6%) patients with exercise-induced NSVT/VF reached primary or secondary end points. Three patients with exercise-induced NSVT and two of the three exercise VF patients died suddenly. The latter died 11 and 150 month after CPET, the third exercise VF patient received an implantable cardioverter-defibrillator (ICD) and had no appropriate shocks after 66 month of follow-up. In the exercise NSVT group one patient developed syncope due to sustained ventricular tachycardia requiring resuscitation, one had an appropriate ICD discharge and one received a cardiac transplant.
In comparison to patients without exercise-induced ventricular arrhythmias, patients with exercise-induced NSVT and VF showed significantly higher maximal left ventricular wall diameters, larger left atria and a higher proportion of individuals with NSVTs during Holter monitoring. Male gender was significantly dominant in the exercise NSVT/VF group (81.5% vs. 61.5%). Combined in one group exercise NSVT/VF patients had a 3.73-fold increased risk of SCD or aborted SCD while exercise-induced NSVT alone was associated with a 2.82-fold increased risk compared to patients without exercise-induced ventricular arrhythmia (p=0.002 and p=0.049, respectively). Five years survival from SCD or aborted SCD in the exercise NSVT/VF and also in the group with exercise NSVT alone was significantly lower than in patients without exercise-induced ventricular arrhythmia (81.6% and 83.3%, respectively, vs. 94.4%; p=0.002 and p=0.049, respectively).
The association of exercise-induced ventricular arrhythmia and the secondary endpoint was weaker with a significant 2.18-fold increase in risk for the combined exercise NSVT/VF group (p=0.03), showing no difference when exercise NSVT was considered alone. Eleven patients with exercise-induced NSVT/VF had 2 or more conventional risk factors for SCD. After adjustment for the number of conventional SCD risk factors exercise-induced NSVT/VF was associated with a 3.03-fold increase in risk of SCD or aborted SCD. In multivariable analysis including conventional SCD risk factors exercise-induced NSVT/VF was an independent predictor of SCD or aborted SCD (p=0.001). Study limitations are loss of follow-up in 110 patients (8.0%), defined as no clinical review ≥ 1.5 years, a selection bias towards less symptomatic patients or subjects at lower risk since 362 patients who did not successfully complete symptom limited CPET or did not fit into the age span of 15-75 years, and lack of information on medication on the date of CPET.
The paper of Gimeno and co-authors stresses 2 major issues of treatment stratification of patients with HCM: risk stratification of sudden cardiac death and the risk of CPET itself.
Contemporary risk stratification strategy in patients with HCM is based on 5 major risk factors - prior cardiac arrest, unexplained syncope, family history of premature sudden cardiac death, maximal left ventricular wall thickness ≥30 mm, abnormal blood pressure response to exercise, non-sustained ventricular tachycardia during 48 hours ambulatory Holter-ECG). Furthermore, other parameters are discussed to be of clinical importance like for example left ventricular outflow tract obstruction, extensive late gadolinium enhancement on MRI, intense physical exertion, exercise induced ischemia, and atrial fibrillation. While presence of two or more major risk factors is unquestionably followed by prevention of SCD by an implantable cardioverter-defibrillator, difficulties emerge in patients with only one conventional major risk factor that make up approximately 25% of HCM patients and who may still be at high risk for SCD 2.
Due to the fact that ICD implantation has a major impact on lifelong morbidity and quality of life especially in young patients improvement in risk stratification is necessary. Gimeno et al. describe a significantly increased SCD risk in patients with exercise-induced ventricular arrhythmia. Furthermore exercise-induced ventricular arrhythmia predicts SCD or aborted SCD risk independently from conventional major risk factors in a multivariable analysis. Thus, exercise-induced ventricular arrhythmia appears to be a promising novel indicator of SCD risk, which especially could be taken into account in patients with only one conventional major risk factor. In several studies left ventricular outflow tract obstruction (LVOTO) was shown to be associated with increased SCD risk with varying relation of severity of LVOTO and risk. The actual study also confirms the association for resting LVOTO > 90 mmHg as a strong independent predictor of SCD.
Beyond the utility as a clinical parameter in addition to the nowadays used 5 clinical risk factors appearance of exercise-induced ventricular arrhythmia could also serve as part of a future risk stratification model, which combines structural and functional parameters emphazising on the interaction of the parameters. The fact that severe left ventricular hypertrophy in this study was not associated with SCD, in contrast to previous reports, underlines the need for a more elaborated approach functionally describing the pathophysiological substrate of HCM and thereby hopefully better predicting SCD risk. In this context further functional parameters easily assessed by CPET could be parameters of ventilatory efficiency or the ST segment hump sign (STHS).
Ventilatory efficiency in HCM determined by peak VE/VCO2 has been shown to reflect elevated intracardiac pressures at rest 3. Elevated intracardiac pressures might increase arrhythmic potential by promoting myocardial ischemia.
The prognostic value VE/VCO2 relationship - preferably expressed as a slope - in HCM is promising and has to be elucidated in future studies. In a small study including 81 HCM patients undergoing exhaustive CPET STHS was a strong independent predictor of SCD or aborted SCD 4.
Besides the impact on risk stratification the study implies the issue of safety of CPET in patients with HCM. According to international guidelines exercise testing in patients with HCM is still relatively contraindicated. Thus, many physicians are reluctant to perform CPET accepting loss of information concerning risk stratification, degree of exercise limitation, evaluation of therapeutic efficiency or differential diagnosis. Few studies on the issue of CPET safety in HCM with small patient numbers each have been reported to date. Drinko et al. analyzed 263 HCM patients who underwent symptom-limited treadmill CPET with ongoing medication. They found no death, no syncope, one patient requiring cardioversion due to sustained ventricular tachycardia and 23% minor events, consisting of angina pectoris (11.7%), NSVT (4.2%), new non-sustained supraventricular tachycardia (3.0%) and pre-syncope (12.9%) 5. In our population of 396 HCM patients who underwent exhaustive incremental bicycle CPET under continued medication we reported no death, no syncope or sustained hemodynamically relevant tachycardias 6. Gimeno reports on the biggest HCM population so far that underwent CPET. No death and no sustained ventricular tachycardia occurred during the test procedure. Three patients with VF during CPET survived at least 11 month after the procedure.
Summarizing, CPET in patients with HCM may improve management of the disease with respect to risk as well as treatment stratification and appears to be safe. But, considering the low risk of VF calculated with 0.2% in the present study it is prudent to be prepared – as in every exercise testing situation.
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