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Nonobstructive Hypertrophic Cardiomyopathy
EDITORIAL March 2016 Volume 91 Number 3
Nonobstructive Hypertrophic Cardiomyopathy: Overlooked But Not Forgotten
H
ypertrophic cardiomyopathy (HCM) is recognized as a relatively common genetic heart disease with diverse clinical expression, including dynamic left ventricular outflow tract obstruction.1 Notable in this regard is that subaortic gradients can be present under resting (basal) conditions or can be induced with a variety of provocations, historically including Valsalva maneuver, amyl nitrite inhalation, isoproterenol infusion, and, most importantly, physiologic exercise.2 Rest and/or provokable gradients are (1) usually due to systolic anterior motion of the mitral valve with septal contact, (2) present in 70% of patients with HCM, and (3) often responsible for the exercise-limiting symptom of exertional dyspnea.2 Notably, heart failure due to outflow obstruction in HCM is reversible by surgical septal myectomy (or selectively with alcohol septal ablation), and the most extensive myectomy experience resides at Mayo Clinic in Rochester, Minnesota.3,4 Management considerations for patients with obstructive HCM have been a highly visible and sometimes contentious issue.5-9 In contrast, information on the clinical course and treatment specifically for patients without the capacity to generate left ventricular outflow gradient under resting or provokable conditions has been much less prominent in the vast literature on this disease. Indeed, despite the considerable number of patients with nonobstructive HCM (NO-HCM) (approximately one-third of all those with this disease), in the more than 50-year HCM experience, only 1 paper can be found in PubMed that specifically focuses on NO-HCM; it was published 25 years ago and reported only 25 patients.10
In this issue of Mayo Clinic Proceedings, Hebl et al,11 from the clinician-investigator group of the HCM center at Mayo Clinic, which has contributed so much to HCM knowledge, extended our understanding further by performing a focused outcome analysis in a large group of 706 patients considered to have NO-HCM. The criterion for inclusion was the absence of an outflow gradient both at rest and with a variety of physiologic and nonphysiologic maneuvers and drugs. Using a strategy based on all-cause total mortality (rather than preferred HCMrelated mortality), the authors demonstrated that survival with NO-HCM did not differ from that expected in the general population matched for age and sex. This low frequency of adverse HCM events is consistent with the low mortality rates recently reported in large HCM populations when using contemporary management options, including implantable defibrillators, surgical myectomy, and heart transplant.8,9 An important implication of these Mayo Clinic data in NO-HCM is that such patients should be afforded a measure of reassurance regarding their disease. Specifically, patients with NO-HCM (and other types of HCM) should no longer be regarded as uniformly conveying an unrelenting and grim outcome without effective treatment options.8,9 These data also underscore the importance of using stress echocardiography to segregate patients into hemodynamic subgroups that define their natural history and management options.2 On the other hand, NO-HCM cannot necessarily be regarded as benign because it is well established that patients with NO-HCM can experience adverse disease complications
Mayo Clin Proc. n March 2016;91(3):277-278 n http://dx.doi.org/10.1016/j.mayocp.2016.01.004 www.mayoclinicproceedings.org n ª 2016 Mayo Foundation for Medical Education and Research
See also page 279
277
MAYO CLINIC PROCEEDINGS
(eg, as occasional candidates for transplant with severe drug-refractory end-stage heart failure, sudden death, or as patients with embolic stroke associated with paroxysmal atrial fibrillation).1,8,9,12-14 Finally, Hebl et al11 have once again reported a lack of correlation between genotype (ie, individual pathogenic sarcomere mutations) and survival with HCM, substantiating the wellrecognized principle that genetic testing does not have a role in predicting future clinical course or outcome in this disease. This interpretation is consistent with other data previously reported from this same institution.15 In conclusion, although the Mayo Clinic series published here in the Proceedings contributes importantly to our understanding of patients with NO-HCM and the overall clinical spectrum of this disease, inevitably further clinical studies are necessary to fully understand the clinical implications of this complex group of patients. Barry J. Maron, MD Hypertrophic Cardiomyopathy Center Minneapolis Heart Institute Foundation Minneapolis, MN
Martin S. Maron, MD Hypertrophic Cardiomyopathy Center Division of Cardiology Tufts Medical Center Boston, MA
Correspondence: Address to Barry J. Maron, MD, Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, 920 E 28th St, Suite 620, Minneapolis, MN 55407 ([email protected]).
REFERENCES 1. Maron BJ, Ommen SR, Semsarian C, Spirito P, Olivotto I, Maron MS. Hypertrophic cardiomyopathy: present and future, with translation into contemporary cardiovascular medicine. J Am Coll Cardiol. 2014;64(1):83-99.
278
Mayo Clin Proc.
n
2. Maron MS, Olivotto I, Zenovich AG, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006;114(21): 2232-2239. 3. Dearani JA. Septal myectomy remains the gold standard. Eur Heart J. 2012;33(16):1999-2000. 4. Schaff HV, Dearani JA, Ommen SR, Sorajja P, Nishimura RA. Expanding the indications for septal myectomy in patients with hypertrophic cardiomyopathy: results of operation in patients with latent obstruction. J Thorac Cardiovasc Surg. 2012; 143(2):303-309. 5. Maron MS, Olivotto I, Betocchi S, et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med. 2003;348(4): 295-303. 6. Ommen SR, Maron BJ, Olivotto I, et al. Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005; 46(3):470-476. 7. Maron BJ, Dearani JA, Ommen SR, et al. Low operative mortality achieved with surgical septal myectomy: role of dedicated hypertrophic cardiomyopathy centers in the management of dynamic subaortic obstruction. J Am Coll Cardiol. 2015;66(11): 1307-1308. 8. Maron BJ, Rowin EJ, Casey SA, Maron MS. How hypertrophic cardiomyopathy became a contemporary treatable genetic disease with low mortality: shaped by 50 years of clinical research and practice. JAMA-Cardiol In press. 9. Maron BJ, Rowin EJ, Casey SA, et al. Hypertrophic cardiomyopathy in adulthood associated with low cardiovascular mortality with contemporary management strategies. J Am Coll Cardiol. 2015;65(18):1915-1928. 10. Aron LA, Hertzeanu HL, Fisman EZ, Nosrati IS, Kellermann JJ. Prognosis of nonobstructive hypertrophic cardiomyopathy. Am J Cardiol. 1991;67(2):215-217. 11. Hebl VB, Miranda WR, Ong KC, et al. The natural history of nonobstructive hypertrophic cardiomyopathy. Mayo Clin Proc. 2016;91(3):279-287. 12. Siontis KC, Geske JB, Ong K, Nishimura RA, Ommen SR, Gersh BJ. Atrial fibrillation in hypertrophic cardiomyopathy: prevalence, clinical correlations, and mortality in a large high-risk population. J Am Heart Assoc. 2014;3(3): e001002. 13. Pasqualucci D, Fornaro A, Casetlli G, et al. Clinical spectrum, therapeutic options, and outcome of advanced heart failure in hypertrophic cardiomyopathy. Circ Heart Fail. 2015;8(6): 1014-1021. 14. Harris KM, Spirito P, Maron MS, et al. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation. 2006; 114(3):216-225. 15. Van Driest SL, Maron BJ, Ackerman MJ. From malignant mutations to malignant domains: the continuing search for prognostic significance in the mutant genes causing hypertrophic cardiomyopathy. Heart. 2004;90(1):7-8.
March 2016;91(3):277-278
n
http://dx.doi.org/10.1016/j.mayocp.2016.01.004 www.mayoclinicproceedings.org
Nonobstructive Hypertrophic Cardiomyopathy: Overlooked But Not Forgotten
H
ypertrophic cardiomyopathy (HCM) is recognized as a relatively common genetic heart disease with diverse clinical expression, including dynamic left ventricular outflow tract obstruction.1 Notable in this regard is that subaortic gradients can be present under resting (basal) conditions or can be induced with a variety of provocations, historically including Valsalva maneuver, amyl nitrite inhalation, isoproterenol infusion, and, most importantly, physiologic exercise.2 Rest and/or provokable gradients are (1) usually due to systolic anterior motion of the mitral valve with septal contact, (2) present in 70% of patients with HCM, and (3) often responsible for the exercise-limiting symptom of exertional dyspnea.2 Notably, heart failure due to outflow obstruction in HCM is reversible by surgical septal myectomy (or selectively with alcohol septal ablation), and the most extensive myectomy experience resides at Mayo Clinic in Rochester, Minnesota.3,4 Management considerations for patients with obstructive HCM have been a highly visible and sometimes contentious issue.5-9 In contrast, information on the clinical course and treatment specifically for patients without the capacity to generate left ventricular outflow gradient under resting or provokable conditions has been much less prominent in the vast literature on this disease. Indeed, despite the considerable number of patients with nonobstructive HCM (NO-HCM) (approximately one-third of all those with this disease), in the more than 50-year HCM experience, only 1 paper can be found in PubMed that specifically focuses on NO-HCM; it was published 25 years ago and reported only 25 patients.10
In this issue of Mayo Clinic Proceedings, Hebl et al,11 from the clinician-investigator group of the HCM center at Mayo Clinic, which has contributed so much to HCM knowledge, extended our understanding further by performing a focused outcome analysis in a large group of 706 patients considered to have NO-HCM. The criterion for inclusion was the absence of an outflow gradient both at rest and with a variety of physiologic and nonphysiologic maneuvers and drugs. Using a strategy based on all-cause total mortality (rather than preferred HCMrelated mortality), the authors demonstrated that survival with NO-HCM did not differ from that expected in the general population matched for age and sex. This low frequency of adverse HCM events is consistent with the low mortality rates recently reported in large HCM populations when using contemporary management options, including implantable defibrillators, surgical myectomy, and heart transplant.8,9 An important implication of these Mayo Clinic data in NO-HCM is that such patients should be afforded a measure of reassurance regarding their disease. Specifically, patients with NO-HCM (and other types of HCM) should no longer be regarded as uniformly conveying an unrelenting and grim outcome without effective treatment options.8,9 These data also underscore the importance of using stress echocardiography to segregate patients into hemodynamic subgroups that define their natural history and management options.2 On the other hand, NO-HCM cannot necessarily be regarded as benign because it is well established that patients with NO-HCM can experience adverse disease complications
Mayo Clin Proc. n March 2016;91(3):277-278 n http://dx.doi.org/10.1016/j.mayocp.2016.01.004 www.mayoclinicproceedings.org n ª 2016 Mayo Foundation for Medical Education and Research
See also page 279
277
MAYO CLINIC PROCEEDINGS
(eg, as occasional candidates for transplant with severe drug-refractory end-stage heart failure, sudden death, or as patients with embolic stroke associated with paroxysmal atrial fibrillation).1,8,9,12-14 Finally, Hebl et al11 have once again reported a lack of correlation between genotype (ie, individual pathogenic sarcomere mutations) and survival with HCM, substantiating the wellrecognized principle that genetic testing does not have a role in predicting future clinical course or outcome in this disease. This interpretation is consistent with other data previously reported from this same institution.15 In conclusion, although the Mayo Clinic series published here in the Proceedings contributes importantly to our understanding of patients with NO-HCM and the overall clinical spectrum of this disease, inevitably further clinical studies are necessary to fully understand the clinical implications of this complex group of patients. Barry J. Maron, MD Hypertrophic Cardiomyopathy Center Minneapolis Heart Institute Foundation Minneapolis, MN
Martin S. Maron, MD Hypertrophic Cardiomyopathy Center Division of Cardiology Tufts Medical Center Boston, MA
Correspondence: Address to Barry J. Maron, MD, Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, 920 E 28th St, Suite 620, Minneapolis, MN 55407 ([email protected]).
REFERENCES 1. Maron BJ, Ommen SR, Semsarian C, Spirito P, Olivotto I, Maron MS. Hypertrophic cardiomyopathy: present and future, with translation into contemporary cardiovascular medicine. J Am Coll Cardiol. 2014;64(1):83-99.
278
Mayo Clin Proc.
n
2. Maron MS, Olivotto I, Zenovich AG, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006;114(21): 2232-2239. 3. Dearani JA. Septal myectomy remains the gold standard. Eur Heart J. 2012;33(16):1999-2000. 4. Schaff HV, Dearani JA, Ommen SR, Sorajja P, Nishimura RA. Expanding the indications for septal myectomy in patients with hypertrophic cardiomyopathy: results of operation in patients with latent obstruction. J Thorac Cardiovasc Surg. 2012; 143(2):303-309. 5. Maron MS, Olivotto I, Betocchi S, et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med. 2003;348(4): 295-303. 6. Ommen SR, Maron BJ, Olivotto I, et al. Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005; 46(3):470-476. 7. Maron BJ, Dearani JA, Ommen SR, et al. Low operative mortality achieved with surgical septal myectomy: role of dedicated hypertrophic cardiomyopathy centers in the management of dynamic subaortic obstruction. J Am Coll Cardiol. 2015;66(11): 1307-1308. 8. Maron BJ, Rowin EJ, Casey SA, Maron MS. How hypertrophic cardiomyopathy became a contemporary treatable genetic disease with low mortality: shaped by 50 years of clinical research and practice. JAMA-Cardiol In press. 9. Maron BJ, Rowin EJ, Casey SA, et al. Hypertrophic cardiomyopathy in adulthood associated with low cardiovascular mortality with contemporary management strategies. J Am Coll Cardiol. 2015;65(18):1915-1928. 10. Aron LA, Hertzeanu HL, Fisman EZ, Nosrati IS, Kellermann JJ. Prognosis of nonobstructive hypertrophic cardiomyopathy. Am J Cardiol. 1991;67(2):215-217. 11. Hebl VB, Miranda WR, Ong KC, et al. The natural history of nonobstructive hypertrophic cardiomyopathy. Mayo Clin Proc. 2016;91(3):279-287. 12. Siontis KC, Geske JB, Ong K, Nishimura RA, Ommen SR, Gersh BJ. Atrial fibrillation in hypertrophic cardiomyopathy: prevalence, clinical correlations, and mortality in a large high-risk population. J Am Heart Assoc. 2014;3(3): e001002. 13. Pasqualucci D, Fornaro A, Casetlli G, et al. Clinical spectrum, therapeutic options, and outcome of advanced heart failure in hypertrophic cardiomyopathy. Circ Heart Fail. 2015;8(6): 1014-1021. 14. Harris KM, Spirito P, Maron MS, et al. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation. 2006; 114(3):216-225. 15. Van Driest SL, Maron BJ, Ackerman MJ. From malignant mutations to malignant domains: the continuing search for prognostic significance in the mutant genes causing hypertrophic cardiomyopathy. Heart. 2004;90(1):7-8.
March 2016;91(3):277-278
n
http://dx.doi.org/10.1016/j.mayocp.2016.01.004 www.mayoclinicproceedings.org