Download Risk Stratification and Outcome of Patients With

Risk Stratification and Outcome of Patients With
Hypertrophic Cardiomyopathy ≥60 Years of Age
Barry J. Maron, MD; Ethan J. Rowin, MD; Susan A. Casey, RN; Tammy S. Haas, RN;
Raymond H.M. Chan, MD; James E. Udelson, MD; Ross F. Garberich, MS; John R. Lesser, MD;
Evan Appelbaum, MD; Warren J. Manning, MD; Martin S. Maron, MD
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Background—Hypertrophic cardiomyopathy (HCM) is prominently associated with risk for sudden death and disease
progression, largely in young patients. Whether patients of more advanced age harbor similar risks is unresolved, often
creating clinical dilemmas, particularly in decisions for primary prevention of sudden death with implantable defibrillators.
Methods and Results—We studied 428 consecutive HCM patients presenting at ≥60 years of age and followed for 5.8±4.8
years; 53% were women. Of the 428 patients, 279 (65%) survived to 73±7 years of age (range, 61–96 years), most (n=245,
88%) with no/mild symptoms, including 135 with ≥1 conventional sudden death risk factors and 50 (37%) with late
gadolinium enhancement. Over follow-up, 149 (35%) died at 80±8 years of age, mostly from non--HCM-related causes
(n=133, 31%), including a substantial proportion from noncardiac disease (n=54). Sixteen patients (3.7%) had HCMrelated mortality events (0.64%/y), including embolic stroke (n=6), progressive heart failure or transplantation (n=3),
postoperative complications (n=2), and arrhythmic sudden death events (n=5, 1.2% [0.20%/y]). All-cause mortality was
increased in HCM patients ≥60 years of age compared with an age-matched US general population, predominantly as a
result of non--HCM-related diseases (P<0.001; standard mortality ratio, 1.5).
Conclusions—HCM patients surviving into the seventh decade of life are at low risk for disease-related morbidity/mortality,
including sudden death, even with conventional risk factors. These data do not support aggressive prophylactic defibrillator
implantation at advanced ages in HCM. Other cardiac or noncardiac comorbidities have a greater impact on survival than
HCM in older patients. (Circulation. 2013;127:585-593.)
Key Words: cardiomyopathy ◼ death, sudden ◼ echocardiography ◼ genetics ◼ heart failure ◼ hypertrophy
◼ magnetic resonance imaging
H
Clinical Perspective on p 593
ypertrophic cardiomyopathy (HCM) is an often
unpredictable genetic heart disease associated with a
well-acknowledged risk for sudden death (SD), as well as the
development of heart failure disability.1–8 Once regarded as a
disease most relevant to the young, HCM has been identified
with increasing frequency in older patients,9 largely as a
result of heightened physician awareness and the availability
of advanced imaging modalities.10,11 However, the natural
history of older HCM patients is incompletely resolved with
respect to risk of adverse events, including heart failure,
stroke, and SD. Although SD risk stratification initiatives
have identified many young HCM patients likely to benefit
from implantable cardioverter-defibrillator (ICD) therapy,12–14
guidelines governing decision making for prophylactic ICDs
remain uncertain for older patients surviving decades with
HCM, often without symptoms.15 The present study describes
the clinical course and risk stratification of a large cohort of
patients with HCM beyond the sixth decade of life.
Methods
Patient Selection
Databases of 2 large HCM centers, the Minneapolis Heart Institute
Foundation and Tufts Medical Center, identified 428 HCM patients
consecutively presenting to these institutions for the first time at ≥60
years of age. Referral to the centers and enrollment in the cohort occurred for the following reasons: to establish or confirm HCM diagnosis (n=78), with or without a family history of the disease, or for
targeted subspecialty evaluation, risk stratification, and management
considerations (n=350).
Most recent clinical assessment was obtained by hospital visit
or telephone contact up to November 2011. Mean duration of
follow-up was 5.8±4.8 years (range, 3 months to 27 years) from
study entry at the first visit to a participating center to the most
recent contact or death. The diagnosis of HCM was based on the
echocardiographic or cardiovascular magnetic resonance (CMR)
demonstration of a hypertrophied and nondilated left ventricle
(LV; maximum wall thickness ≥15 mm) in the absence of another
Received April 12, 2012; accepted December 17, 2012.
From the Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M., S.A.C., T.S.H., R.F.G., J.R.L.);
Hypertrophic Cardiomyopathy Center, Tufts Medical Center, Boston, MA (E.J.R., J.E.U., M.S.M.); PERFUSE Core Laboratory and Data Coordinating
Center, Harvard Medical School, Boston, MA (R.H.M.C., E.A.); and Department of Medicine, Cardiovascular Division, Beth Israel Deaconess Medical
Center, Harvard Medical School, Boston, MA (W.J.M.).
Guest Editor for this article was Salvador Borges-Neto, MD.
Correspondence to Barry J. Maron, MD, Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, 920 E 28th St, Ste 620,
Minneapolis, MN 55407. E-mail [email protected]
© 2012 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.112.136085
585
586 Circulation February 5, 2013
cardiac or systemic disease capable of producing similar magnitude of hypertrophy.2,11,15
Each patient had ≥1 of the following disease features characteristic
of HCM: (1) LV wall thickness ≥18 mm (n=338); systolic anterior
motion of mitral valve (n=266, including 167 with LV outflow gradients ≥30 mm Hg at rest); family history of HCM (n=116, including
57 with HCM-related SD); late gadolinium enhancement (LGE) by
contrast CMR not confined to a coronary arterial vascular territory
(n=53); surgical septal myectomy/alcohol septal ablation (n=93);
LV apical aneurysm with regional scarring (n=11); and sarcomere
protein mutations (n=21), including myosin binding protein (n=15),
β-myosin heavy chain (n=4), and troponin I (n=2) genes.
Coronary arteriograms or computed tomographic angiography was
performed on the basis of clinical indications in 286 patients (67%).
Atherosclerotic coronary artery disease, defined as ≥50% narrowing
in ≥1 epicardial vessels, was present in 84 patients (29%), including
24% of survivors (47 of 198) and 42% who died (37 of 88; P=0.002).
Echocardiography
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Transthoracic echocardiographic studies were performed with commercially available instruments. Maximum LV wall thickness was the
greatest dimension measured at any site within the LV chamber at end
diastole. Left atrial and LV end-diastolic cavity dimensions were assessed by M-mode echocardiography. Peak instantaneous LV outflow
gradient was estimated with continuous-wave Doppler under basal
conditions.
CMR Studies
CMR studies were performed with a 1.5-T clinical CMR scanner
(Phillips Gyroscan ACS-NT, Best, Netherlands; Sonata or Avanto,
Siemens Medical, Erlangen, Germany) in 145 patients.11 Breath-hold
cine steady-state free-precession sequences were performed in horizontal long-axis, vertical long-axis, and contiguous short-axis slices
with full coverage of LV and slice thicknesses of 10 mm with no gap.
Short-axis cine stack was obtained parallel to atrioventricular
groove, covering the entire LV chamber. LGE images were acquired
10 to 15 minutes after intravenous administration of 0.2 mmol/kg
gadolinium-DTPA (Magnevist, Schering, Berlin, Germany) using
breath-held segmented inversion-recovery sequence acquired in the
same orientations as the cine images. Mean signal intensity of normal
myocardium was calculated, and the threshold exceeding the mean by
≥6 SDs was used to define LGE.
Statistical Analysis
Descriptive Statistics
Data are displayed as mean ± SD for continuous variables and as
proportions for categorical variables. When continuous variables had
skewed distributions, data were transformed with ln (value +1) to
achieve normality. Paired or unpaired Student t tests or 1-way ANOVA
assessed statistical significance for continuous variables, with χ2 tests
used for categorical variables. Values of P<0.05 were considered significant; all are reported as 2 sided. Statistical calculations were performed with Stata 11.2 (Stata Corp, College Station, TX).
Survival Analysis
The fraction of HCM patients surviving at each follow-up interval
was estimated by the Kaplan-Meier method. The expected fraction
surviving at each time interval was computed by assigning to each
patient the probability of survival after initial evaluation, appropriate
to age and sex, based on US census data.16 Actual and expected surviving fractions were compared by use of the 1-sample log-rank test,
which provides a standardized mortality ratio and the 95% confidence
interval. Annual mortality rates were calculated for 389 patients with
>1 clinical evaluation; the other 39 patients with short follow-up (<3
months) were excluded from this particular analysis. All computations used the survival package (version 2.36-14) of the R software
systems, version 2.15.1R (Development Core Team 2012).
Results
Demographics
The 428 study patients were 60 to 91 years old at study
entry (mean, 70±7 years); 225 patients (53%) were women
(­Figure 1). Age at HCM diagnosis was 65±10 years. At the
most recent evaluation (or death), patients were 61 to 96 years
old (mean, 75±8 years) as follows: 60 to 69 years, n=127; 70
to 79 years, n=172; 80 to 89 years, n=104; and ≥90 years,
n=25. A total of 116 patients (27%) had a known family history of HCM.
Initial echocardiographic study showed maximum LV wall
thickness (usually ventricular septum) of 15 to 33 mm (mean,
20±4 mm); 248 patients (58%) showed ≥20 mm, including 12 with ≥30 mm. Eighty of 89 patients (90%) with LV
Figure 1. Clinical outcome in 428 hypertrophic cardiomyopathy (HCM) patients ≥60
years of age at study entry. AF indicates
atrial fibrillation; CAD, coronary artery disease; CV, cardiovascular; ICD, implantable
cardioverter-defibrillator; OHCA, out-ofhospital cardiac arrest; SD, sudden death;
VT/VF, ventricular tachycardia/ventricular
fibrillation. *Of these 16 patients, atherosclerotic obstructive CAD was excluded in
15 by computed tomography or coronary
angiography (n=10) or by the absence of
angina or acute coronary events, traditional
cardiovascular risk factors, and Q waves
on ECG (n=5). One patient died after septal
myectomy and coronary artery bypass surgery. †Operations to relieve left ventricular
outflow obstruction (146- and 150-mm Hg
gradients at rest) with septal myectomy
includes 1 patient with associated CAD
and bypass surgery. ‡Transplantation for
drug-refractory end-stage heart failure with
systolic dysfunction.
Maron et al Sudden Death Risk in Elderly HCM Patients 587
70
1.0
65%
HCM vs. U.S.; p<0.001
50
0.8
40
30
20
0.24%/y
0.12%/y
0.20%/y
1.4%
0.7%
1.2%
NonNon-HCM Embolic
Cardiac
Cardiac
Stroke
Death
Death
Heart
Failure*
13%
10
0
Survivors
12%
SD †
Proportion of Patients Survivin
ng
% of HCM Cohort
60
0.6
0.4
0.2
HCM Survival (95% CI)
U.S. Expected Survival
HCM Deaths/Events
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Figure 2. Clinical outcome of hypertrophic cardiomyopathy
(HCM) patients first evaluated at ≥60 years of age. SD indicates
sudden death. Graph excludes 2 HCM-related operative deaths
and 27 others resulting from indeterminate causes. *Includes 1
surviving patient with heart transplantation. †Includes 3 surviving
patients with aborted ventricular tachycardia/ventricular fibrillation. ‡Associated atrial fibrillation in 5 of 6 patients.
wall thickness of 15 to 17 mm showed ≥1 other clinical features characteristic of HCM: family history of HCM (n=21,
including 12 with HCM-related SD); LV outflow gradient ≥30
mm Hg at rest, or systolic anterior motion of mitral valve without obstruction (n=43); LGE by contrast CMR ≥2% of the LV
mass (n=9); prior surgical septal myectomy (n=9) or alcohol
ablation (n=4); LV apical aneurysm (n=4); and sarcomere protein mutations (n=4). The other 9 patients had atrial fibrillation, a particularly common consequence of HCM.2
Mortality Rates
Of 428 patients in the overall cohort, 279 (65%) had survived
over the follow-up period to 73±7 years of age (61–96 years);
149 (35%) had died at a mean of 80±8 years of age (61–96
years; Figures 1 and 2). Survival at 5 and 10 years (accounting
for all-cause mortality) was 77% (95% confidence interval,
73–82) and 54% (95% confidence interval, 48–62),
respectively. Compared with the expected mortality in the US
general population, HCM patients ≥60 years of age showed a
reduced life expectancy resulting predominantly from non-HCM-related comorbidities (P<0.001; Figure 3). The standard
mortality ratio for HCM was 1.5 (95% confidence interval,
1.3--1.8; P<0.001). Univariate predictors of HCM-related
mortality were: 1) symptoms at study entry (88% in New York
Heart Association (NYHA) classes II and III versus 51% of
survivors in class I; P=0.02) and 2) left atrial size (47±8 versus
43±7 mm in survivors; P=0.02).
Non--HCM-Related Mortality
Of 428 patients, 133 died of non-HCM causes, including 54
who died of noncardiac causes, most commonly cancer (n=28;
(Figure 1 and Table 1). In 52 patients, a variety of non-HCM
cardiovascular causes, including operative complications,
were judged to be primarily responsible for death (Table 1).
Of these, 14 had ≥1-vessel obstructive CAD, experiencing
acute myocardial infarction (1 patient with myocardial rupture; n=7) or therapeutic intervention, for example, coronary
0.0
0
3
6
9
12
15
51
127
29
137
Years from First Evaluation
# at risk: 428
# died: 0
243
51
154
81
89
107
Figure 3. Kaplan-Meier survival curves describing total mortality
(death resulting from any cause, including hypertrophic cardiomyopathy [HCM]), at ≥60 years of age among 428 HCM patients,
compared with that expected in the US general population after
adjustment for age and sex. Dotted lines represent 95% confidence intervals for survival probability.
artery bypass surgery or percutaneous transluminal angioplasty/stent (n=8).
In the remaining 27 elderly patients, most well beyond normal life expectancy, the precise cause of death (at 82±9 years
of age) could not be ascertained with certainty (including 9
patients who died in nursing home environments at 90±6.6
Table 1. Non–Hypertrophic Cardiomyopathy–Related Causes
of Death
Non-Cardiac (n=54)
Cancer
Multiorgan
Non-HCM Cardiovascular (n= 52)
28
4
Multiorgan, including
pulmonary or cardiac (CAD;
valvular) comorbidities
32
14
Gastrointestinal bleeding
4
CAD: heart failure/SD*
Obstructive pulmonary disease
3
Operative complications
Hemorrhagic stroke
3
Brain/abdominal aneurysm
3
Pneumonia/sepsis
3
Blunt trauma/drowning
2
Hepatitis
2
Bowel obstruction
1
Dementia
1
6†
CAD indicates coronary artery disease; HCM, hypertrophic cardiomyopathy;
and SD, sudden death.
*Includes myocardial infarction (n=7), coronary artery bypass surgery (n=3),
percutaneous transluminal coronary angioplasty/stent (n=3), and CAD without
prior intervention or event (n=1).
†Operation-related complications during mitral valve surgery (at 68 and 79
years of age), coronary artery bypass (at 79 years of age), or hip replacement (at
80 years of age), or hemorrhage (n=2; at 73 and 75 years of age).
588 Circulation February 5, 2013
Table 2. Patients With Hypertrophic Cardiomyopathy--Related Deaths/Events
Age at Initial
Evaluation, y
Sex
NYHA
Age at
Death, y
Initial
Last
LVOTG (Rest),
mm Hg
LV Thickness,
mm
Risk Factors
LGE,
%
LA,
mm
EF,
%
Event/Outcome
Sudden death/events
1
60
F
61
1
1
0
20
Syncope, NSVT
14.1
27
55
Alive: ATP for VT
2
61
M
61
3
1
70*
20
NSVT
N/A
46
70
Alive: ICD shock for VT†
3
64
M
69
3
N/A
70*
21
0
N/A
41
70
SD 4 mo after myectomy‡
4
66
F
69
3
1
80*
21
0
N/A
37
65
SD 1 y after myectomy‡
5
72
M
77
1
1
0
22
Syncope
0
62
60
Alive/out of hospital VF; TH
Heart failure and other death/events
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6
60
M
62
3
1
0
22
Syncope
N/A
56
32
Alive: heart transplantation (end stage)
7
64
F
67
2
4
100§
20
NSVT
N/A
47
55
Died: progressive HF
8
65
M
67
2
2
0
22
0
0
49
60
Died: embolic stroke (AF)
9
66
F
66
3
3
146
26
0
N/A
48
wnl
Died: postoperative HCM (SM; MVR)
10
67
F
71
3
3
150
20
0
N/A
41
60
Died: postoperative HCM (SM; CABG)
11
68
F
70
3
3
40
20
Syncope; NSVT
N/A
48
70
Died: progressive HF
12
71
F
72
2
2
35
25
Family history of
SD; syncope
N/A
52
80
Died: embolic stroke (AF)
13
77
F
80
2
3
36
20
Syncope
N/A
50
70
Died: embolic stroke (AF)
14
78
F
79
2
2
0
28
0
N/A
50
25
Died: embolic stroke (AF);end-stage
15
82
F
84
2
2
54
15
0
N/A
47
65
Died: embolic stroke
16
86
F
86
2
2
0
28
0
N/A
48
60
Died: embolic stroke (AF)
AF indicates atrial fibrillation; ATP, antitachycardia pacing; CABG, coronary artery bypass grafting; EF, ejection fraction; HF, heart failure; ICD, implantable cardioverterdefibrillator; LA, left atrium; LGE, late gadolinium enhancement; LV, left ventricle; LVOTG, left ventricular outflow tract gradient; MVR, mitral valve replacement; N/A,
not available; NSVT, nonsustained ventricular tachycardia on 24-hour ambulatory (Holter) ECG; NYHA, New York Heart Association; SD, sudden death; SM, surgical
myectomy; TH, therapeutic hypothermia; VF, ventricular fibrillation; VT, ventricular tachycardia; and wnl, within normal limits.
*LV outflow gradient before myectomy.
†Occurred 1 month before myectomy.
‡Patient without conventional SD risk markers; postmyectomy outflow gradient was zero.
§Patient elected treatment with dual-chamber pacing, which was ineffective.
years of age and up to 96 years of age), although the available
information was most consistent with multiorgan involvement
and was insufficient to incriminate HCM as the cause of (or a
significant contributor to) demise.
(n=65), including 41 for whom this was the only marker, and
nonsustained ventricular tachycardia (n=59; Table 3). Of 5
patients with SD events, 2 had 1 risk factor and 1 had 2 markers (Tables 2 and 3).
HCM-Related Mortality/Adverse Events
Mortality events attributable to HCM occurred in 16
patients (3.7%; 0.64%/y) at 72±8 years of age: embolic stroke
(n=6; atrial fibrillation in 5 patients, with 2 patients on warfarin), progressive heart failure (n=2), heart transplantation for
end-stage disease17 (n=1); postoperative complications (n=2),
and arrhythmic SD events (n=5; Figures 1–3 and Table 2).
The 5 SD events (1.2%; 0.20%/y) included 3 survivors:
2 with appropriate primary prevention ICD therapy for ventricular tachycardia/ventricular fibrillation at 60 and 61 years
of age, and 1 with aborted out-of-hospital cardiac arrest with
therapeutic hypothermia at 72 years of age. Coronary artery
disease was excluded in each of these 5 patients.
Late Gadolinium Enhancement
Contrast-enhanced CMR was analyzed in 145 patients
71±6 years old. LGE was present in 53 patients (37%).
Among the 135 survivors, LGE occupied 5.2±6.3% of the LV
mass (range, 0.2%–29.0%) and was marked (≥10%; range,
10.5%–29%) in 9 patients (7%; Table 3). LGE extent did not
differ with respect to most recent NYHA class: 6.2±7.4%,
5.8±5.9%, and 2.9±2.7% for classes I, II, and III, respectively
(P=0.7; Figure 4).
SD Risk Markers
Conventional Risk Factors
Among the 279 survivors, 135 (48%) had ≥1 major clinical
marker conventionally used to stratify SD risk in HCM pati
ents;1,2,7,14,18 144 patients (52%) had no risk marker (Table 3).
The most common risk factors were unexplained syncope
Heart Failure
At the most recent evaluation, most patients (245, 88%) were
either asymptomatic (168; class I) or mildly symptomatic
(77; class II). Initial and recent NYHA class for the study
group did not differ significantly (P=0.18; Figure 5). Of 64
patients who improved during follow-up by ≥1 NYHA class,
this change was judged to be attributable primarily to relief of
LV outflow obstruction by surgical myectomy (n=37); alcohol
septal ablation (n=8); mitral valve replacement (n=2); pharmacological treatment (β-blockers, verapamil, disopyramide;
≥1
211
135
8
3
Patients,
n
428
279
16#
5
2
6
96
149
1
1
2
33
49
2
110
57
39
1
0
13
6
0
0
1
4
65
Syncope
Family History
of HCM SD
>3
20*
90
59
3
2
12
6
0
0
1
1
15
ABPR
NSVT
LV Thickness
≥30 mm
Patients With Individual Risk Factor, n
2(40)
9(56)
108(39)
165(39)
LVOTG ≥30 mm Hg
(Rest), n (%)
53/145(37)
50/135‖ (37)
1/3(33)
1/2(50)
190(44)
107(38)
11(69)
3(60)
21‡
17
0
0
72†
53§
3
7
LGE, n (%)
AF,
n (%)
Alcohol
Ablation, n
1/2
1/3
9/135(7)
11/145(8)
LGE ≥10%,
n (%)
14
14
5.2±6.3
5.7±6.6
LGE, %
ABPR indicates abnormal blood pressure response (to exercise); AF, atrial fibrillation; LGE, late gadolinium enhancement; LV, left ventricular; LVOTG, left ventricular outflow tract gradient; NSVT, nonsustained ventricular
tachycardia (on 24-hour ambulatory [Holter] ECG; ≥3 beats at >120 bpm); and SD, sudden death.
*Of 87 patients studied with exercise (stress) echocardiography.
†Includes 13 patients with surgical myectomy performed before the first visit to the participating institution at ≥60 years of age.
‡Includes 2 patients with (failed) alcohol septal ablation performed before the first visit to the participating institution at ≥60 years of age who later underwent surgical myectomy.
§Includes 3 patients with myectomy performed before the first visit to the participating institution at ≥60 years of age.
‖Includes 1 patient with cardiovascular magnetic resonance after alcohol septal ablation (LGE=5.2%).
¶Includes 4 nonfatal events: 3 patients with life-threatening events aborted by an implantable cardioverter-defibrillator (ICD) or external defibrillation for out-of-hospital cardiac arrest and 1 other patient with heart transplantation
for refractory failure.
#Of these 16 patients, obstructive atherosclerotic coronary artery disease was excluded in 15 by either selective coronary or computed tomography angiography (n=10) or absence of angina, acute coronary events, traditional
cardiovascular risk factors, and Q-waves on ECG (n=5). The remaining patient died after septal myectomy and coronary artery bypass surgery.
**Includes 3 patients with ICD-aborted SD events or defibrillation for cardiac arrest.
HCM SD/events**
All HCM deaths/events¶
Survivors
All patients
Patient Subset
Risk Factors, n
Myectomy,
n
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Table 3. Markers of Increased Sudden Death Risk in Hypertrophic Cardiomyopathy Patients ≥60 Years of Age
Maron et al Sudden Death Risk in Elderly HCM Patients 589
A
B
**
*
RV
RV
RV
LV
LV
C
*
D
LV
RA
LV
LA
Figure 4. Cine and contrast-enhanced cardiovascular magnetic resonance images in hypertrophic cardiomyopathy (HCM)
patients ≥60 years of age. A, Left ventricular (LV) short-axis
slice from a 66-year-old woman with massive LV hypertrophy
involving the anterior septum (36 mm; asterisks) extending into
the anterolateral wall. B, Contrast-enhanced LV short-axis slice
from a 73-year-old woman with a localized area of transmural
late gadolinium enhancement (LGE) in the basal anterior septum
(arrows). C, Four-chamber slice from a 67-year-old woman with
hypertrophy confined to the LV apex (asterisks). D, Four-chamber slice from a 71-year-old-woman with transmural LGE of septum (small arrows) and posterobasal free wall (large arrows). LA
indicates left atrium; RA, right atrium; and RV, right ventricle.
n=14); percutaneous transluminal coronary angioplasty for
obstructive CAD (n=1); and radiofrequency ablation for atrial
fibrillation (n=2).
Thirty-four patients were in NYHA classes III and IV at
the last evaluation, primarily because of atrial fibrillation
(n=12), obstructive pulmonary disease (n=4), CAD complications (n=2), or noncardiopulmonary disease (n=1). In 15
other patients, severe symptoms persisted despite myectomy
or alcohol ablation or because those interventions were withheld as a result of patient preference.
LV Outflow Obstruction
LV outflow obstruction at rest (gradient, 30–180 mm Hg;
average, 73±31 mm Hg)5 was present at study entry in 165
patients (39%). Sixteen of these patients had outflow gradients (assessed by echocardiography) of 75±41 mm Hg, 5.6±1
years earlier at 63±6 years of age, compared with a gradient of
70±32 mm Hg on study entry at 69±6 years of age (P=0.65).
Age at HCM Diagnosis
To ascertain whether age at diagnosis was relevant to disease
presentation or outcome, patients identified with HCM at <60
and ≥60 years of age were compared (Table 4). Earlier diagnosis at <60 years of age was associated with slightly greater
LV wall thickness and end-diastolic dimension, but more
frequent atrial fibrillation and male predominance (Table 4).
590 Circulation February 5, 2013
Most Recent
Evaluation
Initial
Evaluation
NYHA
FC-1
NYHA
FC-2
142*
69
123
41
168
77
Table 4. Relation of Age at Diagnosis to Clinical Features and
Outcome in Hypertrophic Cardiomyopathy
Parameter
Age <60 y
Age ≥60 y
at Diagnosis at Diagnosis P Value
Patients, n (%)
112 (26)
316 (74)
Male, n (%)
66 (59)
137 (43)
Age diagnosis, y
52±7.7
69±6.8
0.005
LVOT gradient ≥30 mm Hg at rest, n (%)
47 (42)
118 (37)
0.39
Left atrium, mm
45±8.4
43±8.3
0.02
LVED, mm
44±6.8
42±7.1
0.01
Maximum LV thickness, mm
21+3.6
20±3.6
0.01
Atrial fibrillation, n (%)
64 (57)
126 (40)
0.002
1
46 (41)
140 (44)
0.20
2
30 (27)
101 (32)
3/4
36 (32)
75 (24)
1
59 (53)
148 (47)
2
36 (32)
95 (30)
3/4
17 (15)
73 (23)
NYHA, initial evaluation, n (%)
NYHA
FC-3/4
68
24
34
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NYHA, last evaluation, n (%)
Figure 5. Changes in symptom level (New York Heart Association functional class [NYHA FC]) from initial to most recent evaluation in 279 surviving patients. *Includes 1 patient with surgical
myectomy 1 year before the first evaluation. †Includes 2 patients
with alcohol ablation and 2 patients with myectomy performed
before the first evaluation.
Age at diagnosis did not affect HCM-related mortality or
NYHA class.
Associated Systemic Hypertension
Fifty-six patients (13%) had associated hypertension based on
blood pressure ≥140/90 mm Hg recorded on the first visit, a
history of hypertension for >3 years, or a history of antihypertensive drug administration (including at initial visit). HCM
patients with and without hypertension did not differ with
respect to demographic and clinical variables; hypertension
did not enhance mortality risk (Table 5).
Discussion
Sudden unexpected death is a well-recognized and devastating
consequence of HCM.1–4,12,15 Risk stratification markers have
demonstrated strong predictive power in identifying many
susceptible children, adolescents, and adults who have benefited from the introduction of prophylactic ICD therapy to
this disease.1,12–14 However, HCM patients of more advanced
age beyond midlife are recognized with increasing frequency
because of the heightened index of suspicion for this disease
and the increasing penetration of high-resolution diagnostic
imaging such as CMR11 and cardiac computed tomographic
angiography.10 The influx of older HCM patients often recognized for the first time, and frequently with conventional SD
risk factors,1 has created unique clinical decision-making and
management uncertainties, particularly with respect to recommendations for primary prevention ICDs.12 To confront these
difficult clinical scenarios, we assembled the present large
HCM cohort of advanced age and assessed them with respect
to demographics, clinical and imaging profiles, risk stratification models, and natural history.
The present data in >400 patients, selected by virtue of
achieving age ≥60 years at the first visit to the participating
0.21
Mortality, n (%)
HCM-related
6/31 (19)
10/118 (8)
Non-HCM
25/31 (81)
108/118 (92)
0.08
HCM indicates hypertrophic cardiomyopathy; LV, left ventricular; LVED, left
ventricular end-diastolic dimension; LVOT, left ventricular outflow tract; and
NYHA, New York Heart Association functional class.
institutions, provide novel insights into the natural history of
HCM. For example, the common perception among patients
that the course of HCM is one of unwavering progression
throughout a lifetime is not supported by our data. Indeed,
although this cohort cannot take into consideration higher-risk
patients who may have died earlier in life, it nevertheless supports the principle that achieving older age in a genetic disease
such as HCM may itself convey relative protection from ongoing SD risk and afford more favorable prognosis—that is, for
many patients, their underlying HCM (present for >6 decades)
has largely declared its natural history. This principle is underscored by the relatively low HCM-related SD event rate of
0.20%/y (in the absence of CAD). Three of these 5 patients
with SD events survived ventricular tachycardia/ventricular
fibrillation by virtue of prophylactically implanted ICDs or
external defibrillation that appropriately terminated ventricular tachyarrhythmias (for a true HCM SD mortality rate of
only 0.08%/y).12,13,15 In contrast, the most common cause of
HCM-related death was embolic stroke associated with atrial
fibrillation, underscoring the importance of considering anticoagulation therapy early in such HCM patients.
In a subgroup of 27 patients (6% of the overall cohort), it
was not possible to reliably ascertain the true contribution
(if any) of HCM to demise from the available evidence. Of
note, however, these patients were of particularly advanced
age (mean, 82±9 years), including 9 who died while under
nursing home care and surveillance at 90 years of age on average (and well past estimated life expectancy). Furthermore,
the available evidence was most consistent with multiorgan
Maron et al Sudden Death Risk in Elderly HCM Patients 591
Table 5. Comparison of Clinical and Demographic Features in Hypertrophic Cardiomyopathy Patients
With and Without Systemic Hypertension
Hypertension-Negative
Hypertension-Positive
372 (87)
56 (13)
Age at HCM diagnosis, y
64±10 (15–91)
66±8 (49–84)
0.15
Age at first evaluation, y
70±7 (60–91)
71±7 (60–84)
0.21
176 (47)
27 (48)
0.90
20.6±4 (15–33)
20.4±3.6 (15–33)
0.72
Patients, n (%)
Male, n (%)
Maximum LV thickness, mm
P Value
Atrial fibrillation, n (%)
167 (45)
23 (41)
0.59
LVOT gradient ≥30 mm Hg at rest,
n (%)
150 (40)
18 (32)
0.24
1
161 (43)
25 (45)
2
113 (30)
18 (32)
¾
98 (26)
13 (23)
1
180 (48)
27 (48)
2
115 (31)
16 (29)
¾
77 (21)
13 (23)
HCM-related
13/119 (11)
3/30 (10)
Non HCM-related
106/119 (89)
27/30 (90)
NYHA, initial evaluation, n (%)
0.88
NYHA, last evaluation, n (%)
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0.89
Mortality, n (%)
0.88
HCM indicates hypertrophic cardiomyopathy; LV, left ventricle; LVOT, left ventricular outflow tract; and NYHA, New York Heart
Association functional class.
involvement and was insufficient to incriminate HCM as the
cause of (or a significant contributor to) demise. Even with
these patients considered HCM-related deaths, the calculated
mortality rate was only 1.7%/y.
In this study population with relatively low HCM-related
mortality, we nevertheless identified a substantial proportion
of patients with those risk factors conventionally associated
with susceptibility to life-threatening arrhythmias.1–3,15 About
50% of our overall cohort had ≥1 risk markers, including about
one half of those patients surviving to the end of the follow-up
period (achieving 73 years of age on average). These findings
underscore the important principle that clinical markers that
convey predictive power for SD in younger HCM patients do
not necessarily assume the same significance in patients who
have achieved more advanced ages.
We should emphasize that the weight afforded syncope
in risk stratification of older HCM patients remains a difficult area.7 In the present cohort, unexplained syncope (ie,
judged likely nonneurocardiogenic in origin) was particularly
common, affecting ≈50% of those patients with risk factors
(including one third in whom syncope was the sole potential
marker). Massive LV hypertrophy (wall thickness ≥30 mm), a
SD risk marker in younger patients,4,19 was uncommon (<3%)
in our present cohort but nevertheless demonstrated compatibility with advanced age.4 Similarly, ≈40% of our patients
achieved advanced age despite LV outflow gradients (average,
73 mm Hg), underscoring that many patients tolerate these
gradients for extensive periods of time.
LGE on contrast CMR (presumably a marker for myocardial fibrosis) has been advanced as a potential predictor of SD
events and progressive heart failure.18,20–22 However, a large
proportion (ie, almost 40%) of our surviving patients had
areas of LGE, including some with substantial hyperenhancement. Although the time at which LGE developed in these
patients is unknown, recognition that many HCM patients
survive to normal or near-normal longevity with myocardial
fibrosis raises some skepticism concerning LGE as a risk
marker in this age group.
In the present cohort, the HCM-related death/event rate
owing to progressive heart failure, embolic stroke, or SD
(0.64%/y) was less than reported in other HCM cohorts
encompassing a broader age range,23 as well as the estimated
annual mortality risk in the general population >60 years of
age (ie, ≈2%).16 Furthermore, the study cohort demonstrated
a large measure of stability over the follow-up period with
only 2 deaths (and 1 heart transplantation) and with almost
80% of the surviving patients reporting no or only mild heart
failure symptoms at their most recent evaluation. Finally, our
observation that 47 survivors benefited from septal reduction
procedures with relief of severe symptoms and achieved the
advanced age of >70 years on average is consistent with the
principles that myectomy is associated with extended survival
indistinguishable from that expected in the general population24 and that both surgery and ablation are effective in reducing heart failure symptoms.1,2,15,24–26
Notably, Kaplan-Meier analysis showed that total mortality in these HCM patients exceeded that expected in the
general population but was due largely to other associated
cardiovascular diseases (particularly CAD), and noncardiac
conditions (eg, cancer) that are prevalent at the advanced
592 Circulation February 5, 2013
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ages achieved by these patients. Indeed, such comorbidity
posed a greater threat to survival than long-standing HCM
itself. This observation that prognosis in older HCM patients
may be based largely on comorbidities has the effect of
shifting the clinical focus at advanced ages to non-HCM diseases. Whether HCM is a passive bystander or has a potentially deleterious interaction with other diseases in this age
group is unresolved.8,27 Alternatively, this relationship may
have been influenced by selection bias, with HCM patients
having significant comorbidities more likely to come to clinical recognition.
The patient cohort reported here constitutes the experience of 2 large HCM centers for which some patient referral selection bias was unavoidable. Therefore, typical of all
hospital-based cohort studies in HCM,28 we cannot be certain that our data are entirely representative of the general
HCM population. Nevertheless, we would anticipate that in
a purely unselected HCM cohort uncontaminated by referral
bias (and no longer accessible in this disease),28 susceptibility for SD would be similar to and certainly no higher
than that reported here. In addition, although survival to
older ages and normal longevity have been recognized in
HCM,9,28–30 prior data in this age group are encumbered by
limited study designs, relatively small cohorts, and selected
patient populations that did not specifically address risk
stratification.9,23,29,30
Conclusions
In a large HCM cohort, advanced age itself appears to mitigate disease-related complications, including death resulting
from progressive heart failure or SD even in the presence of
conventional risk markers and LGE. This represents a shift in
perception of HCM, once regarded as a progressive disorder at
any age (and throughout life), with aging in effect representing a negative risk factor for many patients.
The data presented here propose an inverse relationship between advanced age and disease-related risk in
HCM, inevitably affecting management decision making.
Recommendations for primary prevention ICDs in older HCM
patients should be made on a case-by-case basis with prudent
restraint. In such HCM patients, non--HCM-related cardiac
and noncardiac competing modes of death convey disproportionate impact on mortality and pose a greater threat to longterm survival than HCM alone. These observations underscore
the importance of attention to the overall clinical environment
with aggressive identification of coexistent disease.
Disclosures
Dr B.J. Maron serves as a consultant for GeneDx and has received
grant/research support from Medtronic. Dr M.S. Maron serves as a
consultant/is on the advisory board for PGx and GeneDx. The other
authors report no potential conflicts.
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Clinical Perspective
Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden death in the young and is responsible for heart
failure and stroke-related disability and death in adults of all ages. Although HCM is known to be compatible with normal longevity, a common perception also remains that this disease is ultimately associated with unrelenting progression
throughout a patient’s lifetime. Therefore, whether patients of more advanced ages harbor disease-related risks similar to
young patients is unresolved. By assembling and analyzing 428 HCM patients presenting at ≥60 years of age to 2 major
centers, we were able to clarify the natural history of this complex disease at more advanced ages. Over follow-up, 279
patients (65%) survived to 73±7 years of age, and 149 (35%) died at 80±8 years. Only 16 patients (3.7%) had HCM-related
mortality events (0.64%/y), including embolic stroke (n=6), progressive heart failure or transplantation (n=3), postoperative
complications (n=2), and arrhythmic sudden death events (n=5, including 2 who died; 0.2%/y). Notably, all-cause mortality
was increased compared with a matched US general population, predominantly resulting from non--HCM-related causes.
Consequently, these data suggest an inverse relationship between the inherent risks from HCM and achieving advanced age,
with survival itself generally declaring lower-risk status. Patients surviving into the seventh decade with this genetic disease
are at low risk for HCM-related mortality and morbidity, including sudden death (even when conventional risk factors are
present). These data do not support aggressive prophylactic defibrillator implantation at advanced ages for HCM patients.
Indeed, in such older patients, other cardiac or noncardiac comorbidities, as competing modes of death, pose a greater threat
to long-term survival.
Risk Stratification and Outcome of Patients With Hypertrophic Cardiomyopathy ≥60
Years of Age
Barry J. Maron, Ethan J. Rowin, Susan A. Casey, Tammy S. Haas, Raymond H.M. Chan, James
E. Udelson, Ross F. Garberich, John R. Lesser, Evan Appelbaum, Warren J. Manning and
Martin S. Maron
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Circulation. 2013;127:585-593; originally published online December 30, 2012;
doi: 10.1161/CIRCULATIONAHA.112.136085
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2012 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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