ORIGINAL ARTICLE

Right Ventricular Enlargement and

Dysfunction Are Associated With Increased
All-Cause Mortality in Hypertrophic
Cardiomyopathy
Songnan Wen, MD; Cristina Pislaru, MD; Steve R. Ommen, MD;
Michael J. Ackerman, MD, PhD; Sorin V. Pislaru, MD; and Jeffrey B. Geske, MD

Abstract

Objective: To assess whether right ventricular enlargement (RVE) and right ventricular dysfunction
(RVD) adversely affect prognosis in hypertrophic cardiomyopathy (HCM).
Patients and Methods: Data were retrieved from Mayo Clinic’s prospectively collected HCM registry
between January 1, 2000, and September 30, 2012. Right ventricle (RV) size and function were
semiquantitatively categorized via echocardiography as normal (RV-Norm) versus abnormal (RV-Abn)
(RVE or RVD). All-cause mortality was the primary endpoint.
Results: Of 1878 HCM patients studied (mean age 53
15 years; 41.6% female), only 71 (3.8%) had
RV-Abn (24 RVE, 28 RVD, 19 combined RVE and RVD). Compared with HCM patients with RV-
Norm, RV-Abn patients were older (57
14 vs 53
15 years, P¼.02), more symptomatic (New York
Heart Association functional class III-IV in 62.0% vs 48.6%, P¼.03), had more atrial fibrillation (53.5%
vs 17.3%, P<.001), and more prior implantable cardioverter-defibrillator implantation (23.9% vs
11.3%, P¼.02). Median follow-up was 9.4 years with 311 deaths. Patients who were RV-Abn had
higher all-cause mortality compared with RV-Norm (log-rank P<.001); 24.1% (95% CI, 15.5% to
35.3%) vs 6.1% (95% CI, 5.1% to 7.3%) at 5 years. In multivariable Cox modeling, RV-Abn (hazard
ratio, 1.89; 95% CI, 1.18 to 3.03; P¼.008) was associated independently with all-cause mortality after
adjusting for age, female sex, New York Heart Association functional class, atrial fibrillation, hyper-
tension, coronary artery disease, implantable cardioverter-defibrillator implantation, beta blocker use,
prior septal reduction therapy, resting LV outflow tract gradient, maximal LV wall thickness, and
moderate or greater tricuspid regurgitation.
Conclusion: Although perturbations in RV size and function were observed in fewer than 5% of pa-
tients with HCM, they were associated with nearly two-fold higher all-cause mortality at long-term
follow-up.
ª 2021 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2022;97(6):1123-1133

H
ypertrophic cardiomyopathy Unlike the large amount of literature on SCD
(HCM) is the most common in HCM, data assessing all-cause mortality in
inherited cardiomyopathy, with patients with HCM are more limited. From the Department of
Cardiovascular Medicine
prevalence of 0.2% in the general population Hypertrophic cardiomyopathy has often (S.W., C.P., S.R.O., M.J.A.,
and annual mortality rate of 1% to 2%.1,2 been considered a disease of the left ventricle S.V.P., J.B.G.); the Depart-
ment of Pediatric and
Although a leading cause of sudden cardiac (LV), although this concept has been
Adolescent Medicine, Di-
death (SCD) in young adults,3 SCD occurs recently challenged.7,8 Global and regional vision of Pediatric Cardi-
in only a small subset of patients with right ventricular (RV) systolic dysfunction, ology, Windland Smith
Rice Genetic Heart
HCM.4 Nonarrhythmic causes of death are as well as diastolic dysfunction, have been
common in HCM, especially in the elderly reported in HCM in the absence of RV hy- Affiliations continued at
and those with nonobstructive physiology.5,6 pertrophy.9,10 The importance of RV the end of this article.

Mayo Clin Proc. n June 2022;97(6):1123-1133 n https://doi.org/10.1016/j.mayocp.2021.12.005 1123

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assessment in cardiac11,12 and noncardiac
diseases has become increasingly recog-
nized.13,14 We hypothesized that right ven-
tricular enlargement (RVE) and right
ventricular dysfunction (RVD) would
adversely affect prognosis in HCM. We char-
acterized prevalence of RV structural and
functional changes in a large, single-center
HCM referral population and correlated
with all-cause mortality.
PATIENTS AND METHODS
Patient Selection and Data Collection
The study population consisted of adult pa-
tients (age 18 years) with HCM. Diagnostic
and echocardiographic criteria used are as
previously published,15 with patients under-
going index evaluation at the Mayo Clinic in
Rochester, Minnesota, USA, between January
1, 2000, and September 30, 2012. The diag-
nosis of HCM was established by cardiolo-
gists with established expertise in HCM
considering all available clinical evidence.
Echocardiographic data were collected at
the time of index visit. For study inclusion,
RV size and function assessment needed to
have been included in the index echocardio-
gram report. When clinically appropriate,
symptom-limited graded exercise testing
was performed using an institutionally
designed incremental exercise testing proto-
col as described previously.16 All patients
provided consent to use of their medical re-
cords for research purposes. The study was
approved by the Mayo Clinic Institutional
Review Board.
Echocardiographic Evaluation
Comprehensive transthoracic echocardiogra-
phy was performed using commercially
available ultrasound equipment and
following contemporary American Society
of Echocardiography (ASE) guidelines.
Echocardiographic RV evaluation comprised
assessment of global RV systolic function
and RV size on a semiquantitative scale. In
brief, dedicated RV imaging was obtained
from different views including the RV inflow
view, short-axis imaging at the cardiac base
to visualize the RV outflow tract, and
n n
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MAYO CLINIC PROCEEDINGS
RV-focused imaging from the apex. Right
ventricular systolic function was determined
visually, incorporating additional objective
parameters whenever available. The systolic
excursion velocity (s’) of the tricuspid lateral
annulus was measured by tissue Doppler in
the four-chamber view.17 The percentage
RV fractional area change (FAC) was defined
as (end-diastolic area - end-systolic area)/
end-diastolic area  100. The RV index of
myocardial performance (RIMP) was deter-
mined from pulsed Doppler tracings as
(tricuspid valve opening time - RV ejection
time)/RV ejection time. Tricuspid annular
plane systolic excursion (TAPSE) was
measured in apical four-chamber view.
A semiquantitative approach was applied
to assess RV size and function based on the
Mayo Clinic echocardiographic protocol18
and ASE recommendations.17,19 Right ven-
tricular systolic function was classified as
normal, mild RVD, or moderate-severe
RVD. Right ventricular size was categorized
semiquantitatively as normal (two-thirds or
less of the LV size) or as mild (RV similar
to the LV size), moderate (RV larger than
the LV), or severe (RV much larger than
the LV) enlargement. Right ventricular
linear dimensions and areas were used
when clinically indicated and when appro-
priate image quality was present. Patients
with RVE, RVD, or both were defined as hav-
ing abnormal RV (RV-Abn). All other pa-
tients comprised the normal RV group
(RV-Norm). All RV quantitative measure-
ments in patients with RV-Abn were verified
by an experienced investigator (S.W.) in
accordance with current guidelines.17 As an
additional analysis for reliability of the semi-
quantitative approach, a comparative review
of RV measurements of 100 randomly
selected cases (50 from each group) was per-
formed by the same investigator.
Estimation of right atrial (RA) pressure
(5, 10, 15, and 20 mm Hg) was based on
inferior vena cava size and collapsibility.20
Right ventricular systolic pressure (RVSP)
was estimated in standard fashion; cutoffs
of 35 and 50 mm Hg were considered for
assessment of pulmonary hypertension
(PH) as previously used.21 Detection and
June 2022;97(6):1123-1133 https://doi.org/10.1016/j.mayocp.2021.12.005
www.mayoclinicproceedings.org
RV ENLARGEMENT AND DYSFUNCTION AND ALL-CAUSE MORTALITY IN HCM

TABLE 1. Baseline Characteristicsa,b

Characteristics RV-Abn (n¼71) RV-Norm (n¼1807) P All patients (n¼1878)
Age, y 57
14 53
15 .02 53
15
Female, n (%) 29 (40.8) 753 (41.7) .89 782 (41.6)
Systolic blood pressure, mm Hg 117
19 122
18 .04 121
18
Diastolic blood pressure, mm Hg 70
12 71
11 .38 71
11
Heart rate, beats/min 68
11 65
12 .02 65
12
Body mass index, kg/m2 30.2
7.1 29.9
5.8 .72 29.9
5.9
Body surface area, m2 2.02
0.27 2.01
0.26 .78 2.01
0.26
NYHA functional class III-IV 44 (62.0) 879 (48.6) .03 923 (49.1)
Coronary artery disease 13 (18.3) 362 (20.0) .72 375 (20.0)
Systemic hypertension 34 (47.9) 954 (52.8) .42 988 (52.6)
Syncope 16 (22.5) 358 (19.8) .52 374 (19.9)
Atrial fibrillation 38 (53.5) 312 (17.3) <.001 350 (18.6)
PPM implantation 21 (29.6) 221 (12.2) .001 242 (12.9)
ICD implantation 17 (23.9) 205 (11.3) .02 222 (11.8)
Family history of HCM 31 (43.7) 494 (27.3) .008 525 (28.0)
Family history of SCD 20 (28.2) 322 (17.8) .07 342 (18.2)
BNP, pg/mLc 449 (281-996) 161 (68-367) <.001 168 (69-381)
VO2, mL/kg/mind 16.2
7.8 20.1
6.5 .007 20.0
6.5
Percentage VO2 predicted, %d 54.8
20.1 65.4
19.1 .005 65.0
19.2
Medications
Beta receptor antagonist 61 (85.9) 1477 (81.7) .37 1538 (81.9)
Calcium channel antagonist 26 (36.6) 781 (43.2) .27 807 (43.0)
Amiodarone 18 (25.4) 119 (6.6) <.001 137 (7.3)
ACE-inhibitor/ARB 13 (18.3) 396 (21.9) .47 409 (21.8)
Disopyramide 10 (14.1) 165 (9.1) .16 175 (9.3)
Warfarin 32 (45.1) 203 (11.2) <.001 235 (12.5)
Diuretic 32 (45.1) 437 (24.2) <.001 469 (25.0)
History of septal reduction therapy 12 (16.9) 113 (6.3) .02 125 (6.7)
a
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; HCM, hypertrophic cardio-
myopathy; ICD, implantable cardioverter-defibrillator; NYHA, New York Heart Association; PPM, permanent pacemaker; RV-Abn,
abnormal right ventricle; RV-Norm, normal right ventricle; SCD, sudden cardiac death.
b
Continuous variables expressed as mean
SD, n (%),or median and interquartile range.
c
BNP assessed in n¼755 (40.2%).
d
Cardiopulmonary exercise testing performed in n¼1037 (55.2%).
Bold = P < .05

gradation of tricuspid regurgitation (TR)
severity was visually assessed using an inte-
grative, semiquantitative approach (none,
mild, mild-moderate, moderate, moderate-
severe, and severe), including assessment of
color Doppler jet area, tricuspid valve
morphology, RA and RV size, inferior vena
cava size, jet density, and color Doppler
contour.
beginning from the index clinical visit,
with patients censored at the date of death
or a date of last medical contact in January
2017 was used for survival analysis in those
patients still assumed to be alive. All vital
status data were collected from the elec-
tronic health records and the national death
and location database (Accurint, Lexisnexis
for Mayo Clinic patients).

Study Endpoints Statistical Analysis

The endpoint of present study was all-cause Continuous variables are expressed as mean
mortality. Survival time was calculated
SD when normally distributed and median
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 MAYO CLINIC PROCEEDINGS

TABLE 2. Baseline Echocardiographic Characteristicsa,b

Characteristics RV- Abn (n¼71) RV-Norm (n¼1807) P All patients (n¼1878)
Anteroseptal wall thickness, mm 17.0
4.7 18.1
5.5 .07 18.0
5.5
Posterior wall thickness, mm 13.2
2.8 13.1
3.0 .82 13.1
3.0
Resting obstruction 36 (50.7) 1056 (58.4) .21 1092 (58.1)
Labile obstruction 7 (9.9) 370 (20.5) .005 377 (20.1)
Non-obstructive 28 (39.4) 381 (21.1) .003 409 (21.8)
LV outflow tract gradient, mm Hg 4 (4-55) 26 (4-69) .04 25 (4-67)
LV end diastolic dimension, mm 49
7 46
6 <.001 46
6
LV end systolic dimension, mm 32
8 26
5 <.001 27
5
LV ejection fraction, % 61
15 70
7 <.001 69
8
LV ejection fraction <50% 14 (19.7) 22 (1.2) <.001 36 (1.9)
LV mass index, g/m2 158
57 150
51 .26 151
51
Left atrial volume index, mL/m2c 66
26 48
22 <.001 48
23
Moderate or greater MRd 26 (40.0) 339 (20.1) .002 365 (20.8)
Mitral E velocity, m/se 0.92
0.37 0.87
0.29 .29 0.87
0.29
Mitral A velocity, m/se 0.57
0.30 0.75
0.31 <.001 0.75
0.31
E/A ratio e
1.87
0.96 1.33
0.72 <.001 1.34
0.73
Medial e’, m/sf 0.05
0.02 0.06
0.03 <.001 0.06
0.03
Lateral e’, m/sf 0.08
0.03 0.07
0.04 .37 0.07
0.04
Medial E/e’ ratiof 21.3
10.1 17.5
8.5 .007 17.6
8.5
f
Lateral E/e’ ratio 13.2
8.4 13.9
7.5 .67 13.9
7.5
Deceleration time, msf 192
55 227
62 <.001 226
63
Lateral tricuspid annular s’ velocity, cm/sg 10.2
3.0 13.0
3.2 <.001 12.9
3.2
PV systolic velocity, m/sh 0.93
0.24 1.06
0.23 .001 1.06
0.23
TR velocity, m/s i
3.36
0.70 2.67
0.43 <.001 2.70
0.47
Moderate or greater TRj 19 (27.9) 42 (2.6) <.001 61 (3.6)
Estimated RA pressure, mm Hgk 10.9
4.6 6.3
2.6 <.001 6.5
2.8
Estimated RVSP, mm Hgl 59
22 36
12 <.001 37
13
RVSP 35 mm Hg 56 (87.5) 569 (40.8) <.001 625 (42.8)
RVSP 50 mm Hg 38 (59.4) 155 (11.1) <.001 193 (13.2)
a
A, peak late diastolic mitral flow velocity; E, peak early diastolic mitral flow velocity; LV, left ventricle; MR, mitral regurgitation; PV,
pulmonary valve; RA, right atrium; RV-Abn, abnormal right ventricle; RV-Norm, normal right ventricle; RVSP, right ventricular systolic
pressure; TR, tricuspid regurgitation.
b
Continuous variables expressed as mean
SD or median and interquartile range.
c
Left atrial volume index available in n¼1710 (91.1%).
d
Semiquantitative assessment of MR severity available in n¼1754 (93.4%).
e
Mitral inflow assessment available in n¼1811 (96.4%).
f
Mitral annular tissue Doppler assessment available in n¼1663 (88.6%).
g
Lateral tricuspid annular s’ velocity in n¼736 (39.2%).
h
PV systolic velocity in n¼1052 (56.0%).
i
TR velocity available in n¼1467 (78.1%).
j
Semiquantitative assessment of TR severity available in n¼1701 (90.6%).
k
RA pressure available in n¼1673 (89.1%).
l
Right ventricular systolic pressure available in n¼1460 (77.7%).
Bold = P < .05

with interquartile range (IQR) when non- Wilcoxon rank sum tests as appropriate.
normally distributed. Comparison of vari- Kappa-statistics were used to validate the
ables between RV-Abn and RV-Norm groups variability and accuracy of RV echocardio-
were performed using Student t-tests and graphic measures. Survival was assessed
n n
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RV ENLARGEMENT AND DYSFUNCTION AND ALL-CAUSE MORTALITY IN HCM
using Kaplan-Meier survival curves with log
rank P values reported. Univariate and
multivariable Cox proportional hazard ana-
lyses were performed to determine the rela-
tion between RV-Abn and all-cause
mortality, with hazard ratios (HRs) and
95% CIs reported. Parameters were chosen
to enter the multivariate model depending
on their significance in the univariate ana-
lyses (P<.05) and/or their clinical relevance
to the study endpoint. The final model was
validated with a stepwise backward selection
method. A P less than .05 was considered
statistically significant. Analysis was per-
formed using the JMP software 14.0 (SAS
Institute, Cary, NC, USA).
RESULTS
Clinical Characteristics
A total of 1878 HCM patients were enrolled in
the study (mean age, 53
15 years; 782
[41.6%] female) (Supplemental Figure, avail-
able online at www.mayoclinicproceedings.
org). Among them, 71 (3.8%) patients were
classified as RV-Abn (24 RVE, 28 RVD, and
19 with both RVE and RVD). Compared
with the vast majority of HCM patients with
normal RV size and function (RV-Norm),
this small subset of patients with RV-Abn
were older (57
14 years vs 53
15 years,
P¼.02), more likely to have history of atrial
fibrillation (AF) (53.5% vs 17.3%, 38/71 vs
312/1807, P<.001), more symptomatic
(New York Heart Associated [NYHA] func-
tional class III-IV in 62.0% vs 48.6%, 44/71
vs 879/1807, P¼.03), and were more likely
to have undergone implantable cardioverter-
defibrillator (ICD) implantation (23.9% vs
11.3%, 17/71 vs 205/1807, P¼.02). Patients
in the RV-Abn group were more likely to
have a family history of HCM (43.7% vs
27.3%, 31/71 vs 494/1807, P¼.008). More pa-
tients in the RV-Abn group were taking amio-
darone (25.4% vs 6.6%, 18/71 vs 119/1807,
P<.001), diuretics (45.1% vs 24.2%, 32/71
vs 437/1807, P<.001), and warfarin (45.1%
vs 11.2%, 32/71 vs 203/1807, P<.001). Pa-
tients with RV-Abn were more likely to have
undergone septal reduction therapy (SRT)
preceding index visit (16.9% vs 6.3%, 12/71
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vs 113/1807, P¼.02). Clinical characteristics
stratified by RV status are described in
Table 1.
Echocardiographic Assessment
Echocardiographic measurements at index
visit are shown in Table 2. An independent
review of 100 randomly selected studies
(50 from each group) showed excellent
interobserver agreement, with Kappa coeffi-
cient 0.98 (95% CI, 0.93 to 1.00) for RVE
and 0.90 (95% CI, 0.81 to 0.98) for RVD.
Quantitative measurements of RV size and
function in RV-Abn patients are provided
in Table 3. No single parameter of RV sys-
tolic function clearly emerged as the best
parameter to assess RVD in this retrospective
cohort, noting heterogenous assessment.
Although some patients with semiquantita-
tively categorized RVD had quantitative as-
sessments that were in the normal range,
all echocardiographic measures of RV sys-
tolic function were lower in patients with
RVD versus RV-Norm (P<.001 for all).
Overall, RV-Abn patients had higher esti-
mated RA pressure (10.9
4.6 mm Hg vs
6.3
2.6 mm Hg, P<.001) and higher esti-
mated RVSP (59
22 mm Hg vs 36
12
mm Hg, P<.001). Differences remained sig-
nificant using RVSP cutoffs of greater than
or equal to 35 mm Hg or greater than or
equal to 50 mm Hg (P<.001 for both).
Patients in the RV-Abn group had larger
left-sided chambers (left atrial [LA] volume
index 66
26 mL/m2 vs 48
22 mL/m2,
P<.001 and LV-end diastolic dimension
49
7 mm vs. 46
6 mm, P<.001). Patients
with RV-Abn had lower LV ejection fraction
(LVEF) compared with RV-Norm subjects
(61
15% vs 70
7%, P<.001) and more
RV-Abn patients presented with LVEF <
50% at index visit (19.7% vs 1.2%, 14/71
vs 22/1807, P<.001). Patients with RV-Abn
had greater E/A ratio (1.87
0.96 vs
1.33
0.72, P<.001) and medial E/e’ ratio
(21.3
10.1 vs 17.5
8.5, P¼.007). More pa-
tients in the RV-Abn group had moderate or
greater mitral (40.0% vs 20.1%, 26/65 vs
339/1689, P¼.002) and tricuspid (27.9% vs
2.6%, 19/68 vs 42/1633, P<.001)
1127
 MAYO CLINIC PROCEEDINGS

in the RV-Norm group. Median time to

TABLE 3. Right Ventricular Size and Functional
death was 6.0 (IQR, 3.5 to 9.1) years after in-
Measurements in HCM Patients With Abnormal
Right Ventricle (n¼71)a,b
dex evaluation. Survival was worse in RV-
Abn patients compared with RV-Norm
Measurement n Value
(log-rank P<.001) (Figure 1), with 5-year
RV basal dimension, mm 71 45
9
all-cause mortality estimates of 24.1% (95%
RV mid dimension, mm 71 35
8 CI, 15.5% to 35.3%) versus 6.1% (95% CI,
RV base-apex length, mm 71 73
13 5.1% to 7.3%) and 10-year all-cause mortal-
RV thickness, mm 71 7.6
1.8 ity estimates of 41.1% (95% CI, 28.6% to
RV diastolic area, cm2 71 21.7
6.5 54.7%) versus 14.2% (95% CI, 12.6% to
2
RV systolic area, cm 71 15.2
5.7 16.1%), respectively. There was no differ-
RV fractional area change, % 71 31
10 ence in rates of SRT after initial assessment
Lateral tricuspid annular s’ 36 10
3 between RV-Abn and RV-Norm patients
velocity, cm/s (log-rank P¼.30).
PV systolic velocity, m/s 44 0.93
0.24
TAPSE, mm 10 18
6
Hazard Modeling
RIMP 33 0.65
0.28
a
Univariate Cox regression analysis for
HCM, hypertrophic cardiomyopathy; PV, pulmonary valve;
RIMP, right ventricular index of myocardial performance; RV,
all-cause mortality was performed with
right ventricle; TAPSE, tricuspid annular plane systolic parameters chosen based on prior knowledge
excursion. or expected clinical relevance (Table 4). The
first multivariate model (model 1) was created
b
Continuous variables expressed as mean
SD.

by entering parameters that were significant in

regurgitation. Patients with RV-Abn were
also more likely to exhibit nonobstructive
HCM compared with RV-Norm (39.4% vs
21.1%, 28/71 vs 381/1807, P¼.003), with
resting LV outflow tract gradient 4 (IQR, 4
to 55) mm Hg versus 26 (IQR, 4 to 69)
mm Hg (P¼.04).
Biochemical and Cardiopulmonary
Assessment
Plasma B-type natriuretic peptide (BNP) was
higher in RV-Abn patients compared with
RV-Norm (449 [IQR, 281 to 996] pg/mL vs
161 [IQR, 68 to 367] pg/mL; P<.001). In pa-
tients with cardiopulmonary exercise testing
(n¼1037), RV-Abn patients (n¼33) had
worse exercise capacity, both with regards to
peak VO2 (16.2
7.8 mL/kg/min vs 20.1
6.5
mL/kg/min; P¼.007) and percent VO2 pre-
dicted (54.8
20.1% vs 65.4
19.1%;
P¼.005).
Outcomes
Median follow-up was 9.4 (IQR, 7.3 to 12.1)
years, encompassing 17,933 patient-years,
with 1859 patients (99.0%) followed-up
beyond 1 year. During follow-up, 311 deaths
occurred: 27 in the RV-Abn group and 284
n n
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the univariate analysis. This model showed
that RV-Abn was associated independently
with increased all-cause mortality (HR, 1.86;
95% CI, 1.20 to 2.89; P¼.006) (model 1 in
Table 4). A second model (model 2) added
ICD implantation preceding index evaluation,
beta receptor antagonist use, LV outflow tract
gradient, and maximal wall thickness. Here,
RV-Abn remained independently associated
with worse outcome (HR, 1.89; 95% CI, 1.18
to 3.03; P¼.008) (model 2 in Table 4). Back-
ward regression analysis confirmed that results
were similar to the multivariate analysis
(Supplemental Table, available online at
www.mayoclinicproceedings.org).
DISCUSSION
This is by far the most extensive study of the
RV phenotype in terms of echocardiographi-
cally assessed size and function in HCM
showing an independent association of the
RV with all-cause mortality. The principal
finding of the present study is that although
RV-Abn is uncommon (3.8%) in HCM, it
was independently associated with nearly
two-fold higher all-cause mortality at long-
term follow-up compared with the majority
having a normal RV phenotype.
June 2022;97(6):1123-1133 https://doi.org/10.1016/j.mayocp.2021.12.005
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RV ENLARGEMENT AND DYSFUNCTION AND ALL-CAUSE MORTALITY IN HCM

100

80
Mortality (%) Log-rank P<.001

60

40

20

0
0 2 4 6 8 10
Time (years)
No. at risk
1807 1777 1729 1555 1212 820
71 65 57 46 32 18
Normal RV Abnormal RV

FIGURE 1. All-cause mortality in patients with hypertrophic cardiomyopathy stratified by normal right
ventricle (RV-Norm) and abnormal right ventricle (RV-Abn). At median of 9.4 years follow-up, Kaplan-
Meier survival curves showed that all-cause mortality was significantly higher in the RV-Abn cohort
compared with the RV-Norm cohort (log-rank P<.001). RV, right ventricle.

Prevalence of Abnormal Anatomic/Func- between normal and abnormal global RV

tional RV Phenotype in HCM
There is a paucity of data on the prevalence
of an abnormal RV size and function in pa-
tients with HCM. In this large referral popu-
lation, RV-Abn was observed in 3.8% of
patients who were diagnosed with HCM.
This number is much lower than prior re-
ports of global RV dysfunction in 11% to
32% of HCM patients.9,10,22 However, those
studies were limited by the small sample
size with very selective patients using
different inclusion criteria. The current
study detected RV-Abn based on routine
echocardiographic assessment, similar to
how measurements would be performed at
the majority of centers worldwide (a “real-
world” approach), as opposed to limiting
definition to specific measurements (ie, RV
ejection fraction, TAPSE, RV strain) or
mandating cardiac magnetic resonance imag-
ing (MRI), which could result in selection
bias (such as eliminating patients with
ICDs) or reduced cohort size. An integrated
approach including assessment of RV size,
comprehensive visual assessment of contrac-
tility, and TAPSE allows the distinction
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systolic function with good accuracy.17,23
This integrated approach explains why
patients categorized as having RVD may
have had some measures of RV systolic func-
tion within the normal range. The ASE
guidelines have recommended using this
semiquantitative method and accuracy of
semiquantitative RV assessment has recently
been validated by our institution.13
Mechanisms Underlying an Abnormal RV
Phenotype in HCM
The underlying mechanism of RVD and RVE
in HCM patients is likely multifactorial
(Figure 2). Pulmonary hypertension in
HCM is common, and secondary adaptation
to an increased RV afterload is likely a
contributor to RV size and function. Once
RV remodeling has begun, a vicious cycle
can occur, with RVE producing tricuspid
annular distortion/dilatation and significant
resultant TR. The TR itself, whether initiated
by RV remodeling or occurring as a conse-
quence of device lead interference, exposes
the RV to increases in preload, which can
in turn exacerbate RV dilation. Among those
1129
 MAYO CLINIC PROCEEDINGS

TABLE 4. Univariate and Multivariable Cox Regression Analysis for Mortalitya

Univariate Model 1b Model 2c
Characteristic HR (95% CI) P HR (95% CI) P HR (95% CI) P
Age, per y 1.06 (1.05-1.07) <.001 1.05 (1.04-1.07) <.001 1.06 (1.04-1.07) <.001
Female 1.85 (1.48-2.31) <.001 1.12 (0.87-1.44) .38 1.08 (0.82-1.41) .60
Atrial fibrillation 2.14 (1.68-2.73) <.001 1.55 (1.19-2.02) .001 1.46 (1.09-1.94) .01
Hypertension 2.14 (1.69-2.71) <.001 1.43 (1.09-1.88) .01 1.44 (1.07-1.92) .01
Coronary artery disease 1.45 (1.12-1.88) .005 0.79 (0.60-1.05) .11 0.78 (0.57-1.06) .12
NYHA functional class III-IV 1.59 (1.27-1.99) <.001 1.27 (0.99-1.61) .06 1.27 (0.96-1.66) .09
ICD implantation 0.90 (0.61-1.29) .59 1.13 (0.73-1.74) .59
Baseline beta receptor antagonist use 1.16 (0.82-1.70) .42 0.96 (0.64-1.45) .84
History of septal reduction therapy 1.74 (1.16-2.51) .008 1.48 (1.00-2.19) .05 1.57 (1.02-2.40) .04
Resting LV outflow tract gradient, 1.00 (0.99-1.01) .07 1.00 (0.99-1.01) .93
per mm Hg
Obstructive physiology 0.93 (0.71-1.22) .63
Maximal LV wall thickness, per mm 0.99 (0.97-1.01) .38 1.02 (0.99-1.05) .14
LV ejection fraction 0.99 (0.98-1.00) .12
RV-Abn 3.42 (2.30-5.08) <.001 1.86 (1.20-2.89) .006 1.89 (1.18-3.03) .008
Moderate or greater TR 4.92 (3.43-7.05) <.001 2.28 (1.53-3.40) <.001 2.20 (1.45-3.34) <.001
a
HR, hazard ratio; ICD, implantable cardioverter-defibrillator; LV, left ventricle; NYHA, New York Heart Association; RV-Abn, abnormal right ventricle; TR, tricuspid
regurgitation.
b
Model 1 is adjusted for parameters that were significant in the univariate analysis.
c
Model 2 consists of variables in Model 1, ICD implantation preceding index evaluation, beta receptor antagonist use, LV outflow tract gradient, and maximal wall thickness.
Bold = P < .05

with either an ICD or a pacemaker, RV pac-
ing (especially with lead implantation at the
RV apex) can result in interventricular dys-
synchrony and contribute to RVD.24 We
found substantially higher echocardiograph-
ically defined right-sided heart chamber
pressures, more TR, and more categorically
defined PH in the RV-Abn group. Previous
studies have shown that age-dependent
myocardial stiffening and time-dependent
exposure to abnormal hemodynamics
contribute to PH in elderly HCM pa-
tients,25,26 which may account for the
observed age difference between RV-Abn
and RV-Norm groups in our study. Never-
theless, RV-Abn remained predictive of out-
comes in multivariable analysis even when
age was included.
Intrinsic abnormalities of RV myocar-
dium must also be considered in the etiology
of or evolution towards an abnormal RV
phenotype. Right ventricular myocardium
is not spared in HCM7,27 and abnormalities
may present as RVE, RVD, and/or RV
n n
1130 Mayo Clin Proc.
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hypertrophy. The lower LV outflow tract
gradient in the RV-Abn patients suggests
some disconnect between obstruction and
RV abnormalities, possibly because of dia-
stolic dysfunction in nonobstructive patients
or those with LV systolic dysfunction. How-
ever, patients with RV-Abn were also more
likely to have undergone SRT before index
visit compared with RV-Norm, which may
contribute to lower LV outflow tract gradient
in this cohort. Although septal myectomy
has been shown to reduce PH in HCM
with enduring results,26 patients with RV-
Abn still exhibited a higher mortality despite
greater rates of septal reduction therapy at
baseline. This finding further supports that
RV-Abn is a manifestation of more severe
phenotypic disease. Other mechanisms in
development of RVD in HCM include
myocardial ischemia, systemic inflammation,
and noncardiac comorbidities such as
obstructive sleep apnea (which is common
in HCM),27 chronic obstructive pulmonary
disease, and pulmonary embolism. It is our
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RV ENLARGEMENT AND DYSFUNCTION AND ALL-CAUSE MORTALITY IN HCM

Proposed development and consequences of right ventricular

abnormality in hypertrophic cardiomyopathy

HCM with normal RV HCM with abnormal RV

Genetic expression
Neurohormonal activation
Dynamic
obstruction

Mitral regurgitation Pulmonary hypertension

Diastolic
dysfunction Tricuspid regurgitation

Left ventricular RV remodeling

remodeling RA dilation Arrhythmias
RV dysfunction

Myocardial disarray Heart failure

and fibrosis

Age and sex n Mortality

Sleep apnea

FIGURE 2. Proposed development and consequences of right ventricular (RV) abnormalities in hypertrophic cardiomyopathy (HCM).
Right ventricular abnormalities in HCM are a likely a consequence of various combinations of genetic, hemodynamic, and mechanical
mechanisms. Each of these contributes variably to the development of RV abnormalities at different stage of HCM, whereas
comorbidities act as moderators. RA, right atrium.

speculation that RV-Abn in HCM is likely additional marker of disease severity is not
multifactorial, with these comorbidities clear. Given these findings of greater pheno-
serving as moderators. typic severity, it is not surprising to see a
higher rate of ICD implantation in the
Associations Between an Abnormal RV RV-Abn group.
Phenotype and Clinical Presentation
Patients with RVE, RVD, or both had poorer An Abnormal RV Phenotype is a Novel Risk
LV systolic function, were more symptom- Factor for All-Cause Mortality in HCM
atic, and had higher BNP levels at index visit. We have previously shown within this HCM
In greater than 1000 patients (n¼1037, cohort that female sex is a strong predictor
55.2%), cardiopulmonary exercise testing of poor outcome15 and that PH is an inde-
showed lower absolute and predicted VO2 pendent predictor of all-cause mortality.21
in RV-Abn patients. Impaired RV function Although a much smaller study with shorter
likely contributes to exercise limitations follow-up previously correlated RV dysfunc-
when present; however the relative contribu- tion to death and heart transplantation in
tion of LV and RV performance to the low HCM,8 the present study is the first to reveal
VO2 cannot be determined in this retrospec- that both RVE and RVD are associated with
tive study. Furthermore, AF was more all-cause mortality in HCM, emphasizing
frequently detected in the RV-Abn group, the importance of multifaceted RV assess-
which may reflect atrial remodeling or ment for comprehensive HCM risk stratifica-
higher filling pressures.28 Pulmonary hyper- tion. Although patients with RV-Abn had
tension was also more likely to be found many differences from those with RV-
within the RV-Abn cohort, but whether Norm, RV-Abn remained significantly asso-
this is a primary driver of RV-Abn or an ciated with worse outcome in multivariable
Mayo Clin Proc. n June 2022;97(6):1123-1133 n https://doi.org/10.1016/j.mayocp.2021.12.005 1131
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analyses. Further quantitative analysis may
increase the detection of RV-Abn and would
be helpful to determine if there are specific
cutoffs for RV size or preferred echocardio-
graphic markers of systolic dysfunction
(such as TAPSE, RIMP, tricuspid annular tis-
sue Doppler, or RV strain) in predicting
mortality. Data herein show that HCM pa-
tients with semiquantitatively defined RVE
and/or RVD were at nearly two-fold higher
risk of all-cause mortality compared with
those with a normal RV.
Study Limitations
This is a retrospective study conducted in a
tertiary referral center and is subject to
inherent limitations associated with retro-
spective analyses and referral bias. However,
the large patient population herein includes
many patients with less symptomatic status
on index evaluation, which provides applica-
bility across a variety of HCM cohorts. Sam-
ple size difference of the two groups could
affect study results. Data on mortality were
obtained from institutional health records
and the national death database where the
specific cause of death was often unavailable.
Longitudinal changes in therapy during
follow-up might have potential to confound
results; however, baseline ICD implantation,
SRT, and antiadrenergic therapy with beta
blockers were evaluated and included in sta-
tistical modeling. Systematic, prospective RV
quantitative assessments of RVE, RVD, and
RV hypertrophy were not performed in this
large cohort as many of the currently recom-
mended indexes of RV function were not in
clinical use or not available for a significant
portion of the study population, including
RV strain. A systematic approach using mul-
tiple quantitative measures of RV function,
including RV strain, could identify addi-
tional RV systolic dysfunction; however,
the semiquantitative approach recommen-
ded by the ASE guidelines was used and pre-
sents a real-world approach to RV size and
global function assessment. Furthermore,
we were able to retrospectively quantitate
RV size and function on stored images in
all patients with RV-Abn. The present study
was limited to echocardiographic data;
n n
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MAYO CLINIC PROCEEDINGS
integration of cardiac MRI findings is a
promising area of future research.
CONCLUSION
Our study shows that although RVE and
RVD have low prevalence in patients with
HCM, an abnormal RV phenotype, as
defined by echocardiographically deter-
mined perturbations in either RV size or
RV function, is an independent predictor of
increased all-cause mortality at long-term
follow-up and should be considered in
HCM management and risk stratification.
POTENTIAL COMPETING INTERESTS
The authors report no potential competing
interests.
SUPPLEMENTAL ONLINE MATERIAL
Supplemental material can be found online
at http://www.mayoclinicproceedings.org.
Supplemental material attached to journal
articles has not been edited, and the authors
take responsibility for the accuracy of all
data.
Abbreviations and Acronyms: HCM, hypertrophic
cardiomyopathy; HR, hazard ratio; ICD, implantable
cardioverter-defibrillator; LA, left atrium; LV, left ventricle;
PH, pulmonary hypertension; RA, right atrium; RV, right
ventricle; RV-Abn, abnormal right ventricle; RVD, right
ventricular dysfunction; RVE, right ventricular enlargement;
RV-Norm, normal right ventricle; RVSP, right ventricular
systolic pressure; SCD, sudden cardiac death
Affiliations (Continued from the first page of this
article.): Rhythm Clinic (M.J.A); and the Department of Mo-
lecular Pharmacology & Experimental Therapeutics, Wind-
land Smith Rice Sudden Death Genomics Labotorary
(M.J.A.), Mayo Clinic, Rochester, MN, USA.
Correspondence: Address to Jeffrey B. Geske, MD, Mayo
Clinic, 200 First Street SW, Rochester, MN 55902 (geske.
jeffrey@mayo.edu; Twitter: @jeffreygeske).
ORCID
Songnan Wen: https://orcid.org/0000-0002-6256-3189;
Jeffrey B. Geske: https://orcid.org/0000-0003-1671-4262
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