ORIGINAL ARTICLE

Role of stress Echo on the Prognosis of Hypertrophic Cardiomyopathy

Rol del eco estrés en el pronóstico de la miocardiopatía hipertrófica

 

AGOSTINA M. FAVA†, JUAN P. OCHOA^MTSAC, ADRIÁN FERNÁNDEZ^MTSAC, FABIÁN SALMO, FABIÁN VAISBUJ, JOSÉ H. CASABÉ^MTSAC , GUILLERMO GANUM^§, HORACIO J. DI NUNZIO^MTSAC, ALEJANDRO QUIROGA, EDUARDO GUEVARA^MTSAC

Hospital Universitario Fundación Favaloro. Echocardiography and Vascular Doppler Laboratory
^MTSAC Full Member of the Argentine Society of Cardiology
^† To apply as Full Member of the Argentine Society of Cardiology
^§ To apply as Adherent Member of the Argentine Society of Cardiology

---

ABSTRACT

Background: Patients with hypertrophic cardiomyopathy (HCM) frequently present with confusing and misleading symptoms. In these instances stress tests may help to stratify the risk of future events.
Objective: The purpose of this study was to assess the prognostic usefulness of the different variables obtained with exercise stress echo (ESE) in patients with HCM.
Methods: A retrospective and observational study was performed in 110 patients evaluated with ESE. Patients were divided into 3 groups according to their left ventricular outflow tract obstruction level (LVOTO): 1) persistent LVOTO (peak instantaneous gradient at rest obtained by continuous Doppler = 30 mmHg), 2) latent LVOTO (gradient = 50 mmHg with exercise); and no LVOTO. Median follow-up was 2.7 years. The primary endpoint was the composite of death, sudden death, sustained ventricular tachycardia or hospitalization for heart failure.
Results: Persistent LVOTO was present in 19.1% of cases, latent LVOTO in 31.8% and no LVOTO in 49.1%. Ventricular function, wall thicknesses and diameters were similar for the three groups. Poor prognostic variables were significantly higher for persistent LVOTO. The latent LVOTO group developed more symptoms, electrocardiographic changes and mitral regurgitation after exercise than the group without LVOTO, although it was not associated with a higher number of events.Variables that were associated with increased rate of events during follow-up were the presence of gradient = 30 mmHg at rest (p=0.07), electrocardiographic changes during the test (p=0.020) and the inverse relationship of METs (p=0.07).
Conclusions: Patients with HCM who achieved a high exercise capacity, expressed as METs = 7, showed excellent mid- to long-term outcomes. LVOTO at rest and electrocardiographic changes during maximal stress exercise were associated with an increased number of events during follow-up.

Key words: Ventricular Outflow Obstruction - Cardiomyopathy, Hypertrophic - Hypertrophy, Left Ventricular - Echocardiography, Stress - Exercise Test - Prognosis

RESUMEN

Introducción: Los pacientes con miocardiopatía hipertrófica (MCH) presentan con frecuencia síntomas confusos y equívocos. En estas instancias, las pruebas de esfuerzo pueden ayudar a la estratificación de riesgo de eventos futuros.
Objetivo: Evaluar el valor pronóstico de las diferentes variables obtenidas mediante el eco estrés con ejercicio (EEE) en pacientes con diagnóstico de MCH.
Material y métodos: Estudio retrospectivo y observacional. Se evaluaron 110 pacientes mediante EEE, los cuales se dividieron según el grado de obstrucción a nivel del tracto de salida del ventrículo izquierdo (OTSVI) en: 1) OTSVI persistente (gradiente máximo instantáneo obtenido en reposo mediante Doppler continuo = 30 mm Hg), 2) OTSVI latente (gradiente = 50 mm Hg ante el ejercicio) y 3) sin OTSVI. La mediana de seguimiento fue de 2,7 años. Se definió punto final primario a la ocurrencia de muerte, muerte súbita, taquicardia ven-tricular sostenida o internación por insuficiencia cardíaca.
Resultados: El 19,1% de los pacientes presentaron OTSVI persistente, el 31,8% OTSVI latente y el 49,1% no presentaban OTSVI. La función ventricular, los espesores parietales y los diámetros fueron similares para los tres grupos. Las variables de mal pronóstico fueron significativamente mayores para la OTSVI persistente. El grupo con OTSVI latente desarrolló más síntomas, alteraciones electrocardiográficas e insuficiencia mitral posejercicio que el grupo sin OTSVI, aunque no se asoció con un número mayor de eventos. Las variables que se asociaron con más eventos en el seguimiento fueron la presencia de gradiente = 30 mm Hg en reposo (p = 0,07), alteraciones electrocardiográficas durante la prueba (p = 0,020) y los MET en su relación inversa (p = 0,07).
Conclusiones: Los pacientes con MCH que alcanzaron una alta capacidad de ejercicio, expresada como MET = 7, presentaron excelentes resultados a mediano-largo plazo. La OTSVI en reposo y los cambios del electrocardiograma durante el esfuerzo máximo se asociaron con más eventos en el seguimiento.

Palabras clave: Obstrucción del flujo ventricular externo - Miocardiopatía hipertrófica - Hipertrofia ventricular izquierda - Ecocardio-grafía Doppler - Ecocardiografía de estrés - Prueba de esfuerzo - Pronóstico

---

Abbreviations

ABPBE	Abnormal blood pressure behavior during exercise
ECG	Electrocardiogram
EsE	Exercise stress echo
FC	Functional Class
GXT	Graded exercise test
HCM	Hypertrophic cardiomyopathy

 

INTRODUCTION

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease, with a prevalence of approximately 0.2%. (1-3) The range of its natural evolution varies from asymptomatic to stages of progressive and terminal heart failure. (1-4)

Disease progression is partly due to diastolic dysfunction, mitral regurgitation (MR) and left ventricular outflow tract obstruction (LVOTO) at rest, result-ing in decreased functional capacity, progression to heart failure, systolic function impairment and death. (5-6)

Patients with HCM often present confusing and misleading symptoms. In these instances, stress tests may help to stratify risk of future events.

The purpose of this study was to determine the prognostic value of the different variables obtained by exercise stress echo (ESE) in a population of patients diagnosed with HCM in Argentina.

METHODS study Population

The diagnosis of HCM was performed by cardiologists, according to current guidelines, based on clinical and electrocardiographic findings and on echocardiographic or cardiac magnetic resonance demonstration of wall thickness >15 mm in the absence of hypertension or other abnormal load-ing conditions that might produce that degree of hypertrophy in any segment. (1-3)

Among a total of 786 patients diagnosed with HCM who are followed-up at our institution, 191 patients were excluded due to follow-up discontinuation. Patients with left ventricular ejection fraction (LVEF) ≤50%, NYHA functional class (FC) =II, moderate-severe MR, under 16 and over 75 years of age, with motor disorders (due to previous stroke) and patients with known history of concomitant symptomatic coronary disease were also excluded.

This was a retrospective observational study with 128 patients evaluated with ESE. Sixty seven patients had been previously excluded for presenting ESE from other centers with incomplete data. Another 18 patients were additionally excluded for having been previously treated with surgery, alcohol septal ablation, or pacemaker or cardioverter defi-brillator implantation. Thus, 110 patients remained for the analysis who were divided into three groups: a group with persistent LVOTO (peak instantaneous gradient at the left ventricular outflow tract level obtained at rest by continuous Doppler =30 mmHg); a second group with latent LVO-TO (gradient =50 mmHg at the level of the left ventricular outflow tract with exercise); and finally a third group with no obstruction. Clinical, ergometric, and echocardiographic variables between groups were compared. The clinical variables compared were age, gender, family history of heart disease, history of hypertension, syncope, nonsustained ventricular tachycardia on Holter monitoring, atrial fibrillation, pharmacological treatment, beta-blocker treatment, anticoagulation, and pacemaker and cardioverter defibrillator implantation. The echocardiographic variables compared at rest were ejection fraction, interventricular septum and posterior wall thickness, LVOT gradient and left atrial anteroposterior diameter.

Procedure

The echocardiographic studies were performed with a Hewlett Packard Sonos 5500 ultrasound imaging system (HP, Andover, Massachusetts, USA). Images were obtained with patients in left lateral decubitus position. Ventricular and atrial dimensions and the maximum velocity at the level of the left ventricular outflow tract were measured with continuous Doppler (7), at baseline and during the pressure phase of the Valsalva maneuver. The gradients were estimated using the simplified Bernoulli equation. Systolic anterior motion and regional wall motion disorders were assessed.

All measurements were performed according to the guide-lines of the American Society of Echocardiography. (8)

Exercise stress echo

The studies were conducted in a treadmill with Bruce proto-cols. During exercise the following variables were assessed: deficient performance of graded exercise test (GXT), sub-maximal GXT, double-product and maximum heart rate achieved, changes in electrocardiogram (ECG) during the test, blood pressure responses, atrial or ventricular arrhythmias, presence of symptoms on exertion and metabolic units estimated in MET. Left ventricular ejection fraction, motility disorders, MR and LVOTO were evaluated immediately after exertion.

Electrocardiographic recordings were taken at each stage of treadmill exercise according to the GXT guidelines of the American Society of Sports Medicine at rest and in the first, third and sixth minute of recovery. Abnormal ECG was considered for ST-segment depression =2 mm in patients with leveled ST at baseline ECG or ST-segment depression =4 mm in patients with baseline ST-segment depression. (9)

Criteria for test interruption were muscular exhaustion, severe arrhythmias, reactive hypertension (systolic pressure =240 mmHg or diastolic pressure =110 mmHg), and hypotension with exercise or limiting symptoms. Abnormal blood pressure behavior during exercise (ABPBE) was defined as blood pressure increase ≤25 mmHg or decrease =10 mmHg during exercise.

Endpoints

The primary endpoint was the presence of death, sudden death, sustained ventricular tachycardia or hospitalization for heart failure during follow-up. Sudden death included resuscitated sudden death and proper discharge of cardio-verter defibrillator in case it was implanted after ESE com-pletion.

statistical analysis

Continuous variables were expressed as median (interquar-tile range) and comparisons between groups were made using the Mann-Whitney test when two groups were compared, and the Kruskall-Wallis test when 3 groups were compared (the post-hoc Conover test was used if the difference was significant). Dichotomous and ordinal variables were expressed as integers (percent of total) and compared with the chi-square test (using the post-hoc z test if the difference between groups was significant) or Fisher's exact test as appropriate. Survival curves (freedom of events) were built with variables showing significant differences on univariate analysis (Kaplan-Maier). The curves were compared using the log-rank test (Mantel-Cox). Data were analyzed using SPSS Statistics version 21 (IBM Corp, Chicago, Illinois) software package.

Ethical considerations

This work was approved by the Bioethics Committee of the Hospital Universitario Fundación Favaloro. Follow-up was conducted by clinical visits, review of medical records or tel-ephone interviews. All patients gave verbal consent to use the data for analytical and anonymous study purposes.

RESULTS

In the total study population, 19.1% of patients pre-sented with persistent LVOTO, 31.8% latent LVOTO and 49.1% no LVOTO. The persistent LVOTO group showed differences with respect to the other two groups in some evaluated clinical variables; they were older, presented with higher percentage of hyperten-sion and received more pharmacological treatment (Table 1). No significant differences were found in other clinical variables between groups. Median baseline gradient was 58 mmHg in patients with persistent LVOTO, 15 mmHg in patients with latent LVOTO and 9 mmHg in those with no LVOTO.

Variables associated with poor prognosis in the stress test were significantly higher for patients with persistent LVOTO. These patients presented with more symptoms (referred to as angina or dyspnea) and ECG changes; they reached lower double-product at maximal exercise and higher incidence of moderate to severe MR at the end of the test with respect to the other two groups (Table 2). Univariate analysis find-ings are shown in Table 3.

The difference found in the MET values achieved is remarkable. Patients with persistent LVOTO reached a median of 7.9 METs, with latent LVOTO 12 METs, and those that did not present obstruction 13 METs (with no difference between the latter two groups in post-hoc analysis).

When patients with latent LVOTO and with no LVOTO were compared, it was seen that patients with latent LVOTO significantly presented with more symptoms, ECG changes, and higher post-exercise MR, although these findings were not associated with greater number of events during the follow-up period.

When freedom of events according to the presence of gradient =30 mmHg at rest was compared with gradient ≤30 mmHg, the curves separated very early, even before 6 months, with the presence of significant gradient at rest associated with worse prognosis, (p=0.07) (Figure 1 A). When the evolution of the three groups of patients according to LVOTO were compared, no

differences were found between the curves of latent LVOTO and no LVOTO (p=0.375). Conversely, there were differences in the freedom of events between the group with persistent LVOTO compared with latent LVOTO (p=0.026) and no LVOTO (p=0.02) groups (Figure 1 B), evidencing early curve separation.

The functional capacity achieved during the test was associated with greater freedom of events. Completing at least =7 METs during the test was associated with a better prognosis compared to patients who did not reach this value (Figure 1 C).

Electrocardiographic changes during the test (presence of ST-segment depression) were also associated with higher number of events during follow-up (p=0.020) (Figure 1 D).

Table 1. Baseline population characteristics according to left ventricular outflow tract obstruction

Table 2. Stress-echo variables according to left ventricular outflow tract obstruction

Table 3. Univariate analysis of stress echo variables

DISCUSSION

This study demonstrates the added value of MET as a finding of great importance in assessing the func-tional capacity of these patients, since it unmasks their real risk. Effectively, the limit functional capac-ity expressed in METs was a predictor of events dur-ing follow-up. Patients who made an effort equal to or greater than 7 METs had better outcome despite being minimally symptomatic (NYHA FC I).

In a recently published study (10), it was found that if patients achieved 100% of the predicted METs for age and gender, the event rate was 1%, while those who managed 85% of the expected METs had an event rate of 12% during follow-up.

Another poor prognostic variable is the persistent LVOTO. It was documented that these patients had worse outcome regardless the severity of the obstruc-tion both at rest and with exercise. (11) Exercise intolerance is related with the inability to increase systolic volume due to a decreased contractile reserve when afterload increases in patients with LVOTO. (5, 6, 12,

13). Although patients with latent LVOTO developed more symptoms, ECG changes and post-exercise MR than the group with no obstruction, they did not have more cardiac events during follow-up. Previous studies have neither been able to establish a direct relationship between latent gradient and poor prognosis. (12, 14, 15)

Finally, another defining element was ECG changes. This proves that with greater ST-segment depression on exercise testing patients have worse outcomes. As already described in former publications, myocardial ischemia in HCM is multifactorial (16). The probable mechanisms are related with systolic compression of small intramural vessels, elevated enddiastolic left ventricular pressure, arteriolar density reduction relative to myocardial mass increase with impaired vasodilator capacity, imbalance between oxygen supply and demand due to increased myocardial mass, fibrosis and myocyte disarray. Severe microvascular dysfunction is often present in asymptomatic or mildly symptomatic patients and this might precede clinical deterioration in successive years, being an important prognostic marker.

It is noteworthy that in our study the ABPBE was not associated with higher number of events. Some authors demonstrated that the flat intra-exertion or hypotensive blood pressure response is an independ-ent risk factor for sudden death. (17-18) Although in our study patients with worse outcome (those with persistent LVOTO) presented with higher percent ABPBE, no statistical significance was found for this variable, probably due to the very low number of patients who developed ABPBE and having analyzed less sick patients.

Fig. 1. Primary endpointfree survival curves according to different variables analyzed in exercise stress-echo. a Survival curve comparing patients with left ventricular outfow tract obstruction (LVOTO) >30 mm Hg and <30 mm Hg. B. Comparison between the three groups of patients with persistent LVOTO, latent LVOTO, and with no LVOTO. C. Patients achieving =7 METs and ≤7 METs. d. Presence or absence of change in the ECG during stress.

 

The study could establish the importance of ESE in HCM. It is a complementary safe and useful method for evaluating patients with this heart disease. (18)

limitations

This is a retrospective study with a small sample of patients.

Due to the short follow-up period and the few events recorded, it was not possible to perform a mul-tivariate analysis. Probably in the future, with more follow-up time, more events will be added and the pos-sibility of performing this type of analysis will be considered, thus enriching the work.

Other echocardiographic measurements such as volume assessment of the left atrium, diastolic dysfunction or systolic pressure of the pulmonary artery were not uniformly documented and therefore were not analyzed in this study.

CONCLUSIONS

In our study, patients with asymptomatic or minimally symptomatic HCM, who performed ESE and achieved a high functional capacity, expressed as =7 METs, showed excellent mid-to long-term outcomes. Left ventricular outflow tract obstruction at rest and ECG changes during maximal exercise were associated with higher number of events during follow-up.

Conficts of interest

None declared

(See authors' conflict of interest forms in the web/ Supple-mentary Material).

REFERENCES

1. Maron BJ, McKenna WJ, Danielson GK, Kappenbergr LJ, Kuhn HJ, Seidman CE, et al. ACC/ESC clinical expert consensus document on hypertrophic cardiomyopathy: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guide-lines (Committee to Develop an Expert Consensus Document on Hy-pertrophic Cardiomyopathy). Eur Heart J 2003;24:1965-91. http:// doi.org/d37zf5

2. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, et al. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Associ-ation Task Force on Practice Guidelines. Circulation 2011;124:2761-96. http://doi.org/d88rsk

3. Elliott PM, Anastasakis A, Borger M, Borggrefe M, Cecchi F, Char-ron P, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European So-ciety of Cardiology. Eur Heart J 2014;35:2733-79. http://doi.org/4xx

4. Fernández A, Vigliano C, Casabé JH, Diez M, Favaloro L, Guevara E, et al. Favaloro Foundation. Comparison of prevalence, clinical course, and pathological findings of left ventricular systolic impair-ment versus normal systolic function in patients with hypertro-phic cardiomyopathy. Am J Cardiol 2011;108:548-55. http://doi.org/ dr92qn

5. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, et al. Effect of left ventricular outflow tract obstruction on clinical out-come in hypertrophic cardiomyopathy. N Engl J Med 2003;348:295-303. http://doi.org/bkdpcv

6. Autore C, Bernabò P, Barillà CS, Bruzzi P, Spirito P. The prognostic importance of left ventricular outflow obstruction in hypertrophic cardiomyopathy varies in relation to the severity of symptoms. J Am Coll Cardiol 2005;45:1076-80. http://doi.org/c3zfgm

7.  Panza JA, Petrone RK, Fanapazir L, Maron BJ. Utility of con-tinuous wave Doppler echocardiography in the noninvasive assess-ment of left ventricular outflow tract pressure gradient in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1992;19:91-9. http://doi.org/bmvn6q

8. Lang RM, Badano L P, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;233-71. http://doi. org/63m

9. Thompson PD, Arena R, Riebe D, Pescatello LS; American College of Sports Medicine. ACSM's new preparticipation health screening recommendations from ACSM's guidelines for exercise testing and prescription, ninth edition. Curr Sports Med Rep 2013;12:215-7. http://doi.org/63n

10. Desai MD, Bhonsale A, Patel P, Naji P, Smedira N, Thamilarasan M, et al. Exercise echocardiography in asymptomatic HCM: exercise capacity, and not LV outflow tract gradient predicts long-term out-comes. JACC Cardiovasc Imaging 2014;7:26-36. http://doi.org/63p

11. Olivotto I, Maron BJ, Montereggi A, Mazzuoli F, Dolara A, Cec-chi F. Prognostic value of systemic blood pressure response during exercise in a community based patient population with hypertrophic cardiomyopathy. J Am Coll Cardiol 1999;33:2044-51. http://doi.org/ bk2szv

12. Peteiro J, Bouzas-Mosquera A, Fernández X, Monserrat L, Pazos P, Estevez-Loureiro R, et al. Prognostic value of exercise echocardiography in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr 2012;25:182-9. http://doi.org/fkbc5n

13. de la Morena G, Caro C, Saura D, Marín F, Gimeno JR, González J y cols. EcoDoppler de ejercicio en pacientes con miocardiopatía hipertrófica. Factores determinantes de la limitación funcional. Rev Esp Cardiol 2013;66:98-103. http://doi.org/f2jvbx

14.  Le V V, Pérez M, Wheeler M, Myers J, Schnittger I, Ashley E. Mechanisms of exercise intolerance in patients with hypertrophic cardiomyopathy. Am Heart J 2009;158:27-34. http://doi.org/dm8726

15. Elliot P, Poloniecki J, Dickie S, Sharma S, Monserrat L, Varnava A, et al. Sudden death in hypertrophic cardiomyopathy: Identification of high risk patients. J Am Coll Cardiol 2000;36:2212-8. http:// doi.org/drg4qm

16. Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici PG. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. N Engl J Med 2003;349:1027-35. http://doi.org/ crcmzg

17. Autore C, Bernabò P, Barillà CS, Bruzzi P, Spirito P. The prognostic importance of left ventricular outflow obstruction in hypertrophic cardiomyopathy varies in relation to the severity of symptoms. J Am Coll Cardiol 2005;45:1076-80. http://doi.org/c3zfgm

18. Drinko JK, Nash PJ, Lever HM, Asher CR. Safety of stress test-ing in patients with hypertrophic cardiomyopathy. Am J Cardiol 2004;93:1443-4. http://doi.org/b859zw