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Circulation. 2003;108:2342-2348
Published online before print October 27, 2003, doi: 10.1161/01.CIR.0000097110.55312.BF
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(Circulation. 2003;108:2342.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Adverse Prognosis of Patients With Hypertrophic Cardiomyopathy Who Have Epicardial Coronary Artery Disease

Paul Sorajja, MD; Steve R. Ommen, MD; Rick A. Nishimura, MD; Bernard J. Gersh, MB ChB, DPhil; Peter B. Berger, MD; A. Jamil Tajik, MD

From the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minn.

Correspondence to Steve R. Ommen, MD, Mayo Clinic, 200 1st St SW, Rochester, MN 55905. E-mail ommen.steve{at}mayo.edu

Received February 12, 2003; de novo received June 25, 2003; revision received August 12, 2003; accepted August 12, 2003.


*    Abstract
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Background— Adult patients with hypertrophic cardiomyopathy (HCM) may develop concomitant atherosclerotic coronary artery disease (CAD). There is a paucity of data on the clinical outcomes of HCM patients who have CAD.

Methods and Results— We examined the outcome of 433 adult patients with HCM according to the presence and severity of CAD. All patients were aged >=21 years, had a left ventricular ejection fraction of >=50%, and were without a history of prior surgical revascularization (mean age, 63 years; 212 men). Compared with HCM patients with mild-to-moderate or no CAD, those with severe CAD demonstrated markedly reduced survival. Ten-year overall survival was 46.1%, 70.5%, and 77.1% for patients with severe, mild-to-moderate, and no CAD, respectively (unadjusted P=0.0001; adjusted P=0.0006). For the end point of cardiac death, this survival was 62.3%, 81.0%, and 80.9% (unadjusted P=0.009; adjusted P=0.004). For the end point of sudden cardiac death, this survival was 77.4%, 93.2%, and 90.3% (unadjusted P=0.01; adjusted P=0.01). The presence of severe CAD also was highly predictive of these events (risk ratio for respective event: 2.31, 2.15, and 2.77) in multivariate models that additionally identified age, prior stroke, hyperlipidemia, and atrial fibrillation as significant covariates.

Conclusions— Among adult patients with HCM who undergo coronary angiography, those who have concomitant severe CAD are at increased risk of death. This risk far exceeds historical death rates of CAD patients with normal left ventricular function.


Key Words: coronary disease • cardiomyopathy • hypertrophy • prognosis


*    Introduction
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Hypertrophic cardiomyopathy (HCM) is a common cardiac disorder, with a prevalence of 1 in 500 persons in the general population.1 Early studies of HCM emphasized its adverse risk among young patients, but there has been increasing recognition of the morbidity of the disease among afflicted adults. Inherent abnormalities in the myocardial substrate, such as diastolic dysfunction and ischemia, increase the susceptibility of these patients to age-related diseases, such as atrial fibrillation, stroke, and heart failure.2,3

Adult patients with HCM may also develop atherosclerotic coronary artery disease (CAD).4,5 Reports on the prevalence of CAD in HCM have varied, but up to 20% of adult HCM patients have been shown to have coexistent CAD.5–7 There is a paucity of longitudinal data on the clinical significance of patients with both HCM and CAD.8 Myocardial ischemia in the absence of coronary atherosclerosis can occur in HCM patients, but to what extent the additional burden of significant, obstructive CAD adversely impacts the prognosis of HCM patients is unknown. This study, therefore, was undertaken to examine the long-term clinical outcome of HCM patients who have CAD.


*    Methods
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Study Population
Between January 1972 and December 2000, 477 patients with HCM underwent coronary angiography at the Mayo Clinic in Rochester, Minn. To restrict our analysis to only adult patients with HCM, those who were <21 years of age (n=13) were excluded. Other exclusion criteria from this analysis were prior history of CABG (n=9), prior cardiac arrest (n=6), and a left ventricular ejection fraction of <50% (n=16), which left a final study population of 433 patients. The diagnosis of HCM was based on typical clinical, electrocardiographic, and echocardiographic features, with ventricular myocardial hypertrophy occurring in the absence of any other cardiac or systemic disease that could have been responsible for the hypertrophy.9–11 The magnitude of myocardial hypertrophy was assessed with M-mode and 2D transthoracic echocardiography by standard techniques. Clinical data were retrieved through review of medical records, stored echocardiographic video, and cinegraphic or digital videotapes of the coronary angiograms. In all cases, investigators were blinded to patient status during collection of the data. Severe CAD was defined as a single luminal stenosis of >=50% in the left main coronary artery or >=70% in other major epicardial branches or the presence of 2 luminal stenoses >=50%.12–14 This definition was based on the CAD Prognostic Index from the American College of Cardiology/American Heart Association/American College of Physicians-American Society of Internal Medicine stable angina guidelines.13 Mild-to-moderate CAD was defined as luminal stenoses that did not meet criteria for severe CAD. Standard nomenclature was used for the description of CAD.12

Follow-Up Evaluation
The Mayo Foundation Institutional Review Board approved this study. Clinical follow-up was conducted through mailed questionnaires and/or telephone contact, with informed consent obtained from the patients. For deceased patients, circumstances of and primary reason for death were sought through procurement of death certificates and, if possible, medical records and autopsy reports, with permission of next of kin. Sudden cardiac death (SCD) was defined as instantaneous and unexpected death with or without documented ventricular fibrillation within 1 hour after a witnessed collapse in patients who previously were in stable clinical condition or nocturnal death with no antecedent history of worsening symptoms. Appropriate discharge of an implanted internal cardioverter-defibrillator (ICD) device for therapy of a lethal arrhythmia (ie, ventricular tachycardia or fibrillation) was considered as SCD for end-point analyses. Death due to congestive heart failure was defined as death occurring in the context of long-standing cardiac decompensation with progression of the disease over the preceding year with the development of pulmonary edema or cardiogenic shock.

Data Analyses
The primary end points of this study were SCD, death due to cardiac causes (including SCD), and all-cause mortality within 10 years of follow-up. Appropriate discharge of an ICD for therapy of a lethal arrhythmia was included in all 3 end points. For each end point, the duration of follow-up was considered to represent the interval from the initial evaluation to time of end point or, among survivors, date of the follow-up evaluation. The end point of cardiac death included the occurrence of cardiac transplantation and death due to stroke.

The Kaplan-Meier method was used to calculate survival with 95% CIs. A log-rank test was used to compare survival curves among different patient groups. Patients were grouped according to the degree of CAD (no CAD, mild-to-moderate CAD, and severe CAD) for survival comparisons. Adjustments for differences in baseline characteristics between these groups were performed with multivariate Cox models. Stepwise techniques were used to identify variables independently associated with the end points in these analyses that were incorporated into the final models. These variables were age, male gender, functional class III or IV symptoms, diabetes mellitus, hypertension, hyperlipidemia, history of smoking, history of myocardial infarction, family history of premature death due to CAD, maximal left ventricular wall thickness, significant left ventricular outflow tract obstruction (ie, resting gradient >=30 mm Hg or provocable gradient >=50 mm Hg), history of unexplained syncope, paroxysmal or chronic atrial fibrillation at presentation, family history of sudden death due to HCM, number of vessels with luminal stenoses >=50% (left main disease=2 vessels), history of cerebral vascular accident or transient ischemic attack, percutaneous (PCI) or surgical coronary revascularization (CABG) after the initial evaluation or during follow-up, treatment with septal myectomy, and medication use (ie, aspirin, ß-antagonist, ACE inhibitor, lipid-lowering agent, or amiodarone). Occurrence of each end point (SCD, any cardiac death, or death of any cause) per 100 person-years of follow-up was calculated with assumption of a normal distribution for the CIs to estimate annual incidence of events. Contingency tables were analyzed for association with a {chi}2 or Fisher exact test (where appropriate). Comparisons of continuous variables were made with the appropriate 2-sample test: a 2-sample t test in cases in which the variable distributions were symmetrical and a Wilcoxon rank sum test otherwise. All mean and median variables are reported with 1 SD. Statistical significance was set a priori at P<0.05.


*    Results
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Baseline Characteristics
CAD was severe in 114 patients (26%) and mild-to-moderate in 116 patients (27%); 203 patients (47%) had normal angiograms (Tables 1 and 2Down). Patients with any CAD were older and more commonly had a history of hypertension, diabetes mellitus, and prior stroke than those with no CAD. Patients with severe CAD had more severe angina (Canadian Cardiovascular Society class III/IV), nonobstructive HCM, lower median maximal left ventricular wall thickness, and more frequent aspirin use than the other 2 groups. There were no differences in patient characteristics between the 3 groups with respect to left ventricular ejection fraction, overall functional class, and other medical history.


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  		TABLE 1. Baseline Patient Characteristics


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  		TABLE 2. Coronary Angiography Data for the Study Population (n=433)

Indications for coronary angiography in the study population were symptom evaluation in 322 patients, preoperative evaluation before septal myectomy in 85, new or recent (within 6 months) myocardial infarction in 10, ventricular tachycardia in 9, abnormal nuclear perfusion study in 1, positive exercise ECG in 1, new-onset atrial fibrillation in 1, and abnormal ECG in 1. Three patients had angiography performed in conjunction with a left ventricular outflow tract gradient assessment. Therapy immediately after angiography consisted of surgical septal myectomy in 72 patients, CABG in 13, CABG in conjunction with surgical septal myectomy in 13, PCI in 8, and percutaneous septal myocardial ablation without revascularization in 6.

Follow-Up Data
Clinical follow-up was achieved in 432 (99.8%) of 433 patients (median, 5.9 years; range, 1 month to 25.3 years). There were 100 deaths in the study population (Table 3). Three patients had appropriate discharge of an ICD. Patients with HCM who had severe CAD demonstrated reduced survival for each study end point compared with patients without severe CAD (Figures 1 and 2 Down). Ten-year overall survival was 46.1% (95% CI, 34.2% to 58.1%) for patients with severe CAD, 70.5% (59.9% to 81.0%) for patients with mild-to-moderate CAD, and 77.1% (69.4% to 84.7%) for HCM patients with no CAD (P=0.0001, log rank). For the end point of freedom from cardiac death, this survival was 62.3% (50.1% to 74.4%), 81.1% (71.5% to 90.6%), and 80.9% (73.8% to 88.1%) for the same respective patient groups (P=0.009). For the end point of SCD, this survival was 77.4% (65.9% to 89.0%), 93.2% (85.7% to 100.7%), and 90.3% (84.9% to 95.6%) for the respective patient groups (P=0.01). Survival free of SCD for all patients without severe CAD (n=319) was 91.2% (86.8% to 95.6%; P=0.009 versus patients with severe CAD; Figure 3).


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  		TABLE 3. Causes of Death According to Presence or Absence of CAD



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  		Figure 1. Overall survival for study population according to presence of CAD. Solid line, patients with severe CAD; long-dashed line, patients with mild-to-moderate CAD; short-dashed line, patients with no CAD.



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  		Figure 2. Survival free of any cardiac death (Top) and sudden cardiac death (Bottom). Solid line, patients with severe CAD; dashed line, patients with mild-to-moderate CAD; dotted line, patients with no CAD.



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  		Figure 3. Comparison of survival free of sudden cardiac death among patients with severe CAD (n=114) and patients without severe CAD (n=319). Solid line, patients with severe CAD; dashed line, patients without severe CAD.

The incidences of death per 100 person-years were 6.59 (95% CI 4.64 to 9.54), 3.41 (2.05 to 5.48), and 2.69 (1.76 to 4.09) for patients with severe, mild-to-moderate, and no CAD, respectively (P=0.0002; Figure 4). The incidences of cardiac death per 100 person-years of follow-up were 4.34 (2.76 to 6.74), 1.99 (0.95 to 3.57), and 2.18 (1.34 to 3.45) for the same respective patient subgroups (P=0.01). For the end point of SCD, these incidences were 2.10 (1.00 to 3.76), 1.85 (8.44 to 3.37), and 0.25 (-0.03 to 0.68) for the same respective patient subgroups (P=0.02). For all patients without severe CAD (n=319), the incidence of SCD per 100 person-years was 0.85 (0.44 to 1.49; P=0.01 versus severe CAD).



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  		Figure 4. Comparison of incidence of events among patients severe CAD (black bar) to patients with mild-to-moderate CAD (dark gray bar) and patients with no CAD (light gray bar). Vertical lines represent 95% CIs. Adjusted covariates are listed in Table 4.


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  		TABLE 4. Multivariate Cox Proportional Hazards Models for the End Points of Overall Death, Cardiac Death, and SCD

Among HCM patients with severe CAD who were treated initially with PCI or CABG (n=32), there were 11 deaths (34%), including 7 cardiac deaths (4 SCD). None of these deaths occurred within 30 days of the procedure. Among patients with severe CAD who did not undergo revascularization (n=81), there were 33 deaths (41%), including 22 cardiac deaths (10 sudden). Patients who had initially undergone PCI or CABG more frequently had severe or class III/IV angina ({chi}2=8.6; P=0.003), severe dyspnea ({chi}2=3.7; P=0.06), history of tobacco use ({chi}2=3.6; P=0.06), hyperlipidemia ({chi}2=4.8; P=0.02), and severe CAD that involved either the left main coronary artery or 3 vessels ({chi}2=6.1; P=0.01) at the time of diagnosis than those who had not. Patients with severe CAD who had not undergone revascularization initially did not demonstrate a greater risk of events either before or after adjustment for age, male gender, and the significant baseline differences. The unadjusted risk ratios for no revascularization (versus revascularization) were 0.92 (95% CI 0.44 to 1.85), 1.00 (0.42 to 2.39), and 0.79 (0.24 to 2.59) for overall death, cardiac death, and SCD, respectively. The age- and gender-adjusted risk ratios for these end points were 0.64 (0.33 to 1.21), 1.32 (0.33 to 1.5), and 0.48 (0.16 to 1.41; all P=NS).

The relation between severity of CAD and survival remained when patients were classified according to distance of their residence from the institution in an attempt to address referral bias. Among patients whose residence was within 50 miles of the institution (n=43), 10-year overall survival for those with severe, mild-to-moderate, and no CAD was 47.3% (20.5% to 74.1%), 77.9% (50.2% to 100.0%), and 81.8% (59.0% to 100.0%), respectively. Among patients whose residence was 50 miles or beyond (n=390), 10-year overall survival for those with severe, mild-to-moderate, and no CAD was 48.4% (35.3% to 65.1%), 67.4% (55.4% to 79.3.0%), and 77.7% (69.4% to 86.1%).

Multivariate Analyses
The presence of severe CAD was predictive of overall mortality and other study end points in multivariate analyses that adjusted for age, male gender, and covariates with statistical association (Table 4). The additional significant covariates for the study end points were a history of chronic atrial fibrillation, prior stroke, and hyperlipidemia. Figure 4 illustrates the predictive power of severe CAD for overall mortality and other study end points before and after multivariate adjustment.


*    Discussion
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There has been increasing recognition of the inherent susceptibility of adult HCM patients to age-related disorders. The impact of CAD on the prognosis of patients with HCM is unknown, because although there have been a number of reports citing the coexistence of CAD in HCM patients,4–6,15–17 there have been only a few small studies of their long-term outcome.8 Moreover, patients with cardiomyopathy have been excluded from virtually all clinical investigations of coronary atherosclerosis.18

The present investigation revealed an adverse prognosis for HCM patients undergoing routine coronary angiography who were found to have severe CAD. Compared with HCM patients without severe CAD, those with severe CAD had a significantly greater risk of death that was evident despite a normal left ventricular ejection fraction and predominantly single-vessel disease and after adjustments for other covariates with statistical association. With the exception of several CAD risk factors (ie, age, hypertension, diabetes mellitus, and prior stroke), the severity of angina, and the presence of left ventricular outflow tract obstruction, there were no baseline differences between the patients with and without severe CAD. The greater risk of death among the HCM patients who had severe CAD was driven by an increase in both SCD and overall mortality, the annual rates for which were 2.1% and 6.6%, respectively. These incidences exceed the rates of both unselected HCM populations (<1% mortality per year) and adult patients examined at tertiary referral centers (2% to 3% per year).19–21 Studies of general populations of CAD patients suggest that patients with annual mortality rates of >3.0% constitute a high-risk population.13 In the present investigation, the incidence of death among HCM patients with CAD far exceeded such rates. The incidence of death among HCM patients with CAD in the present study also far exceeded the historical death rates of CAD patients with normal left ventricular function, which suggests that the observations in the present study probably were not due to CAD alone.22

Myocardial ischemia in the absence of coronary atherosclerosis is a well-recognized phenomenon in patients with HCM. Approximately 25% of HCM patients have evidence of ischemia during regular daily activity.23 The presence of ischemia has been associated with a worse prognosis in HCM.24–26 Several studies have cited a higher incidence of structural abnormalities (greater maximal wall thickness and left ventricular or atrial enlargement) and a propensity for developing cardiac symptoms and adverse conduction system disease among HCM patients with objective evidence of ischemia.25,26 Putative mechanisms of ischemia are complex and include distortion of the arteriolar architecture, intramural small-vessel disease, a high prevalence of myocardial bridging, impairment of endothelium-dependent vasodilation, and an imbalance of myocardial oxygen supply and demand due to the hypertrophied myocardium and ventricular loading conditions.27–35 Both reduced lumen size of the intramyocardial small arteries and decreased arteriolar density have been observed in HCM patients.27,29 There also is evidence that coronary blood flow is maximal or near maximal in most HCM patients (ie, impaired coronary reserve).29,31–33,36–38 Thus, there are multiple etiologic factors that may contribute to myocardial ischemia in patients with HCM. Concomitant atherosclerotic disease and its associated morbidities (eg, hyperlipidemia and hypertension) could exacerbate the structural abnormalities and the inherent endothelial dysfunction in HCM. The data herein suggest that the additional presence of epicardial coronary disease does have a marked detrimental impact on prognosis, likely via an interaction with the pathophysiological abnormalities of HCM as opposed to the independent effects of coronary atherosclerosis.

Not infrequently, adult patients with HCM are reassured of having a benign prognosis by virtue of having survived to an older age.39 However, the present study and several others have demonstrated that this generalization is not accurate, and the presence of concomitant severe CAD defines a high-risk population.2,3,40 CAD is not uncommon in this population, as nearly one-fourth of the patients in the present study population were found to have severe CAD during angiography.

There is a subset of patients with HCM who are at an increased risk for SCD. In the younger population, risk factors for SCD include a family history of SCD due to HCM, massive hypertrophy, unexplained syncope, hypotensive response to exercise, and nonsustained ventricular tachycardia.39 The role of genetic mutations could not be addressed in the present study. In the older population, the results of the present study indicate that the presence of concomitant severe CAD may be an additional risk factor for overall mortality, including SCD. Optimal treatment of these patients with combined disease remains to be determined. There was no apparent survival benefit for revascularization (PCI or CABG) versus those who were treated medically in the present study. However, these 2 groups of patients differed in their baseline clinical characteristics, and definite conclusions about the effect of revascularization could not be made. Preventive strategies aimed at reducing the risk of developing concomitant atherosclerotic disease should be considered in these patients.

Study Limitations
This study was a retrospective analysis with known inherent biases. Because a number of these patients were evaluated at the Mayo Clinic before the recognition of certain risk factors for SCD, the ability to interpret the results of this study in the context of other risk factors is limited. The retrospective nature of this study also did not allow us to quantify the degree of coexisting small-vessel abnormalities, such as coronary vasodilator reserve. Certainly, microvascular derangements could exacerbate the effects of epicardial CAD, and this potential explanation deserves further investigation. Functional assessment of the overall ischemic burden, which carries prognostic information even in the absence of CAD in patients with HCM, also was not available.23–25 Reliance on angiographic visual assessment for severity of CAD is a study limitation, but these data are of clinical relevance for those patients with HCM who are found to have CAD during routine coronary angiography. Although retrospective classification of causes of death can be difficult, determination of alive or deceased status was obtained with certainty in 99.8% of patients. The majority of patients in the present study were referred from other institutions for their medical care, which reflects the referral nature of the practice at the Mayo Clinic. Although this observation could limit the ability to extrapolate the results of this study to other HCM populations, similar results were observed irrespective of whether the patient was from the local patient population or referred from elsewhere. Nonetheless, referral bias exists because each patient underwent coronary angiography. Thus, the study results are applicable to such HCM patients.


*    Conclusions
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The finding of severe epicardial CAD in patients with HCM is associated with a reduced overall survival, reduced survival free of cardiac death, and reduced survival free of SCD compared with patients with no CAD or mild-to-moderate CAD. This finding can thus be used as an additional prognostic factor in the evaluation of patients with HCM. Because epicardial coronary disease is one of several etiologic mechanisms that contribute to myocardial ischemia in patients with HCM, additional prospective studies are required to examine the effect of the total ischemic burden on survival in these patients.


*    Acknowledgments
 
Acknowledgments

A Scholarly Clinician Award from the Mayo Foundation supported this study. We also acknowledge the statistical support received from the Center for Patient-Oriented Research at Mayo Clinic in Rochester, Minn.


*    References
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