 |
Extreme
left ventricular hypertrophy complicating hypertension
without evidence of myocardial disarray
1Jonathan Hill,2 David
Begley
1London Chest Hospital, London, UK; 2Western
General Hospital, Edinburgh, UK
Correpondence: Dr Jonathan Hill, London Chest Hospital, London, UK, e-mail: jono@nih.gov
Introduction
A case is presented of a 67-year-old woman with a history of mild hypertension
who presented to our hospital with chest pain and shortness of breath following
a holiday in the Caribbean. She was referred with a diagnosis of severe aortic
stenosis requiring urgent valve replacement. Subsequent investigation showed
that she had gross left ventricular hypertrophy with features of hypertrophic
cardiomyopathy (HCM). Her clinical course deteriorated and she developed
signs of cardiac failure and required inotropic support and ventilation.
She died after 3 days of ventilation. Autopsy findings were not consistent
with the clinical diagnosis.
This case illustrates an extreme presentation of hypertensive heart disease
and highlights important considerations required for accurate diagnosis and
targeted treatment for patients with hypertension.
Case
This 67-year-old patient of Afro-Caribbean origin first became unwell in St
Lucia where, following an episode of shortness of breath and angina, a diagnosis
was made of critical aortic stenosis. She was commenced on a beta-blocker,
aspirin and digoxin. On return from her holiday she presented to the emergency
department of our hospital following a further episode of severe pain and markedly
reduced exercise tolerance. She had been experiencing pain at rest and on slight
exertion.
Her medical history was unremarkable and she had no risk factors for coronary
artery disease although at one routine medical visit 6 years previously she
was noted to have mild systolic hypertension and was commenced on furosemide.
On initial examination her heart rate was normal, blood pressure 100/50 mmHg,
apex beat was prominent with a double impulse. Her venous pressure wave was
noted at 4 cm above the aortic area. The murmur radiated to the carotids. An
ECG showed large voltage complexes with marked lateral ST repolarization abnormalities
(Figure 1).
 Left ventricular hypertrophy ECG: 12-lead
electrocardiogram taken on admission to hospital showing gross
changes consistent with voltage criteria for left ventricular
hypertrophy with lateral repolarization abnormalities.
A provisional diagnosis of severe aortic stenosis
with myocardial ischaemia was made. She was commenced on a low
dose of a beta-blocker; intravenous heparin and intravenous nitrate
were given as blood pressure allowed.
Initial biochemistry revealed normal liver and renal function and no elevation
in cardiac enzymes. She was found to be mildly anaemic with a haemoglobin of
10.5 g/dl and a normocytic picture. ESR was markedly abnormal at 105 mm/h.
CRP was also increased.
An echocardiogram showed gross biventricular hypertrophy with systolic anterior
motion of the mitral valve and left ventricular outflow tract obstruction.
Within 24 h of admission the patient was symptomatically much improved with
complete resolution of chest pain and dyspnoea. Arrangements were made for
further invasive cardiological investigation including left and right heart
catheterization. Unfortunately she developed further severe chest pain associated
with profound dyspnoea. Examination revealed bilateral coarse crepitations
at the lung bases. Nitrates were recommenced and she was given diamorphine.
There were no new changes on her ECG. She continued to develop further pain
despite intravenous therapy and became dramatically more unwell, with hypotension
and pulmonary oedema. Arterial blood gases revealed severe respiratory failure
with PCO2 of 7.7 kPa and PO2 of 5.0 kPa despite high flow oxygen. There was
a severe acidosis with pH of 7.16. She was intubated and ventilated and adrenaline
infusion was started. She did not respond and died despite inotropic support
and ventilation with 100% oxygen. The cause of death was recorded as cardiac
failure secondary to severe HCM. The possibility of massive pulmonary embolus
had been considered. No explanation at that time could be given for the raised
ESR and mild anaemia. A postmortem examination was carried out.
Autopsy findings revealed gross macroscopic changes in the heart consistent
with HCM (Figure 2).
 Figure
2. Hypertrophy: a transverse section at mid-cavity level
showing extreme left and right ventricular hypertrophy with
visible areas of myocardial fibrosis.
There was striking massive hypertrophy of the
left ventricle virtually obliterating the chamber. The right
ventricle was also hypertrophic. Both atria were dilated. There
were numerous areas of ischaemic fibrosis particularly in the
interventricular septum. The coronary vasculature was normal
and there was no evidence of atheroma. The thoracic and abdominal
aortae were also notably free of atheromatous change. There was
dilatation of the pulmonary outflow tract and vasculature in
the lung peripheries, indicative of long-standing pulmonary hypertension.
There was no evidence of pulmonary thromboembolism, but there
was intense pulmonary oedema. Histological examination of the
heart did not show myocardial disarray, which was an unexpected
finding. There was severe myocyte hypertrophy and fibrosis alone.
Discussion
In view of the finding of no myocardial disarray the diagnosis of classical
HCM becomes less certain. It is well known that patients of Afro-Caribbean
origin do develop left ventricular thickening, which can simulate HCM, including
the development of left ventricular outflow tract obstruction, in response
to a mild hypertensive stimulus. This case appeared to be an extreme form of
this. The exaggerated hypertrophic response may be genetically determined but
the gene is not known. The alternative explanation is that there are cases
of HCM due to one of the eight genes known to cause HCM (beta-myosin heavy
chain, troponins T[1] and I, alpha-tropomyosin, myosin binding
protein-C, essential and regulatory light chains of myosin and cardiac actin)
that do not develop disarray. This is thought to be unlikely as the pathogenesis
of HCM results from the mutant gene product interfering with myofibril alignment.
Considerable interest has focused on the importance of modifying factors in
explaining the variability of phenotypic expression in HCM.[2] Similar
modifying factors may play a role in the development of myocyte hypertrophy
in response to hypertension. Modifying factors could be variety of possibilities
including growth factors, or vascular hormones such as angiotensin II and endothelin-1.
Alternatively, polymorphisms in the genes encoding for these hormones may affect
function, or the polymorphism may be in a regulatory site affecting transcription.
The simple insertion/deletion I/D polymorphism in intron 16 of the angiotensin-I
converting enzyme (ACE) gene consists of a 287 bp repeat.[3] The
DD genotype is associated with elevated levels of circulating ACE and accounts
for a small but significant proportion of the phenotypic variability observed
in HCM. Other genetic polymorphisms have similarly been shown to account for
phenotypic variability.[4] It is likely that a combination
of these polymorphisms will increase the risk of developing left ventricular
hypertrophy in response to increased afterload.
The mechanism of cardiac failure was profound diastolic dysfunction[5] of
the grossly thickened left ventricle, leading to severely impaired filling.[6,7] The
use of nitrates may also have increased the left ventricular outflow tract
obstruction, interfering with coronary flow, leading to more ischaemia and
worsening diastolic function.[8,9] The left ventricle’s reduced
compliance was caused by replacement of myocardium with non-distensible fibrous
scar tissue.[10] With the added insult of myocardial ischaemia[11] caused
by outflow tract obstruction and reduced coronary flow the failing ventricle
is unable to compensate.
Conclusions
This patient had extreme hypertrophy without the typical histological features
of myocardial disarray found in HCM. The cycle of events which resulted in
her rapid clinical demise may not have been preventable but led to questions
regarding the use of inotropes and vasodilator drugs in a patient with severe
diastolic heart failure. The genetic implication for the families of patients
with this pattern of cardiac hypertrophy is not clear but suggests the existence
of further as yet undiscovered cardiac mass-modifying genes.
REFERENCES
-
Alpha-tropomyosin and cardiac troponin
T mutations cause familial hypertrophic cardiomyopathy: a
disease of the sarcomere.
Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna
W, Vosberg HP, Seidman JG, Seidman CE.
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115.
We demonstrate that missense mutations (Asp175Asn; Glu180Gly) in the alpha-tropomyosin
gene cause familial hypertrophic cardiomyopathy (FHC) linked to chromosome
15q2. These findings implicated components of the troponin complex as candidate
genes at other FHC loci, particularly cardiac troponin T, which was mapped
in this study to chromosome 1q. Missense mutations (Ile79Asn; Arg92Gln) and
a mutation in the splice donor sequence of intron 15 of the cardiac troponin
T gene are also shown to cause FHC. Because alpha-tropomyosin and cardiac
troponin T as well as beta myosin heavy chain mutations cause the same phenotype,
we conclude that FHC is a disease of the sarcomere. Further, because the
splice site mutation is predicted to function as a null allele, we suggest
that abnormal stoichiometry of sarcomeric proteins can cause cardiac hypertrophy.
PMID: 8205619 [PubMed - indexed for MEDLINE]
-
Role of candidate modifier genes on the
phenotypic expression of hypertrophy in patients with hypertrophic
cardiomyopathy.
Brugada R, Kelsey W, Lechin M, Zhao G, Yu QT, Zoghbi
W, Quinones M, Elstein E, Omran A, Rakowski H, Wigle D,
Liew CC, Sole M, Roberts R, Marian AJ.
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
BACKGROUND: The phenotypic expression of left ventricular hypertrophy (LVH)
in patients with hypertrophic cardiomyopathy (HCM) is variable. This phenotypic
variability is not completely explained by the responsible mutations or other
known factors. Recent data denote a role for the modifier genes and environmental
factors. We studied the role of 3 potential modifier genes, i.e., angiotensinogen
(AGT), angiotensin II receptor 1a (AT1a), and endothelin-1 (END1) on the
phenotypic expression of LVH in patients with hypertrophic cardiomyopathy
(HCM). METHODS: The study population was comprised of 108 genetically independent
patients with HCM. Left ventricular mass index (LVMI) and LVH score were
determined per published protocols. The genotypes of AGT (M235T, T174M, and
G-6A), AT1a, and END1 were determined by polymerase chain reaction-restriction
fragment length polymorphism (PCR-RFLP) or mutation-specific PCR (MS-PCR).
RESULTS: Male patients had higher mean LVMI and LVH score than female patients
(146.0 +/- 33.5 vs 129.4 +/- 33.6, p = 0.01 and 6.0 vs 5.0, p = 0.010, respectively).
Gender accounted for 4.8% and 5.4% of the variability of LVMI and LVH score,
respectively. The END1 genotypes also had a significant influence on LVH
scores accounting for 2.9% of their variability (p = 0.042). The median LVH
score was greater in patients with the AA and AG genotypes, as compared to
patients with the GG genotype (7.0 vs 5.0, p = 0.034). Neither the AGT nor
the AT1 genotypes had a significant influence on the expression of LVH. In
multivariate regression analysis, END1 and gender accounted for 7.3% of the
variability of the LVH score (p = 0.007). CONCLUSIONS: Our results show that
gender and the END1 gene modify the phenotypic expression of hypertrophy
in patients with HCM.
PMID: 9444881 [PubMed - indexed for MEDLINE]
-
Angiotensin-I converting enzyme genotypes
and left ventricular hypertrophy in patients with hypertrophic
cardiomyopathy.
Lechin M, Quinones MA, Omran A, Hill R, Yu QT, Rakowski
H, Wigle D, Liew CC, Sole M, Roberts R, et al.
Department of Medicine, Baylor College of Medicine, Houston, Tex, USA.
BACKGROUND: The variability of the phenotypic expression of left ventricular
hypertrophy (LVH) in patients with hypertrophic cardiomyopathy (HCM) indicates
a potential role for additional modifying genes. Variants of angiotensin-I
converting enzyme (ACE) gene have been implicated in cardiac hypertrophy.
To assess whether ACE genotypes influence the phenotypic expression of hypertrophy,
we determined the left ventricular mass index (LVMI) and extent of hypertrophy
in 183 patients with HCM. METHODS AND RESULTS: LVMI was derived by the area-length
method using two-dimensional echocardiograms. Extent of LVH was determined
by a point score method (1 to 10 points). DNA was extracted from blood, and
ACE genotyping was performed by polymerase chain reaction (PCR) with an established
protocol. Amplification of DNA in the region of polymorphism by PCR of alleles
I and D showed 490- and 190-bp products, respectively. ACE genotypes DD,
ID, and II were present in 60, 90, and 33 patients with HCM, respectively.
In genetically independent patients (n = 108), the mean LVMI (g/m2) was 148
+/- 35.3 in those with DD (n = 35) and 134.2 +/- 33.3 in those with ID and
II (n = 73) genotypes (P = .046). LVH score was 6.69 +/- 1.71 in patients
with DD and 5.55 +/- 2.19 in those with ID and II genotypes (P = .004). Regression
analysis showed that ACE genotypes accounted for 3.7% and 6.5% of the variability
of LVMI and LVH score (P = .046 and P = .008, respectively). In 26 patients
from a single family, LVMI and LVH score were also greater in patients with
DD than in those with ID and II genotypes. ACE genotypes accounted for 14.7%
and 10.4% of the variability of the LVMI and extent of hypertrophy, respectively.
CONCLUSIONS: ACE genotypes influence the phenotypic expression of hypertrophy
in HCM.
PMID: 7671365 [PubMed - indexed for MEDLINE]
-
Angiotensinogen gene polymorphism in Japanese
patients with hypertrophic cardiomyopathy.
Ishanov A, Okamoto H, Yoneya K, Watanabe M, Nakagawa
I, Machida M, Onozuka H, Mikami T, Kawaguchi H, Hata A,
Kondo K, Kitabatake A.
Department of Cardiovascular Medicine, Hokkaido University School of Medicine,
Kita-ku, Sapporo, Japan.
To examine the contribution of the renin-angiotensin system to hypertrophic
cardiomyopathy (HCM), we studied 96 patients with HCM (mean age 50 years,
55% male), 105 of their unaffected siblings and offspring, and 160 healthy
subjects without known hypertension and left ventricular hypertrophy (LVH)
who were frequency matched to cases by age and sex. Patients were divided
into familial or sporadic HCM (FHCM or SHCM) groups with or without affected
members of their family. The region of interest in the angiotensinogen (AGT)
gene, the missense mutation with methione-to-threonine amino acid substitution
at codon 235 in angiotensinogen (M235T), was amplified by polymerase chain
reaction with the use of allele-specific oligonucleotide primers flanking
the polymorphic region of the AGT gene to amplify template deoxyribonucleic
acid prepared from peripheral leukocytes. The T allele frequency was higher
in the SHCM group than in unaffected siblings and offspring (88% vs 78%,
X2 = 4.6, p < 0.05). The M allele frequency was higher in unaffected siblings
and offspring than in patients with SHCM (23% vs 12%, X2 = 4.6, p < 0.05).
The T allele frequency among unaffected siblings and offspring was similar
to that observed in healthy subjects (78% vs 78%). We conclude that HCM,
especially in sporadic cases, is partially determined by genetic disposition.
The molecular variant of angiotensinogen T235 seems to be a predisposing
factor for cardiac hypertrophy in HCM and carries an approximately twofold
increased risk.
PMID: 9023164 [PubMed - indexed for MEDLINE]
-
Diastolic abnormalities in patients with
hypertrophic cardiomyopathy: relation to magnitude of left
ventricular hypertrophy.
Spirito P, Maron BJ, Chiarella F, Bellotti P, Tramarin
R, Pozzoli M, Vecchio C.
To investigate the relationship between diastolic abnormalities and left
ventricular hypertrophy, 52 patients with hypertrophic cardiomyopathy (HCM)
and 22 normal subjects were studied with digitized M mode echocardiography
and two-dimensional echocardiography. Echocardiographic indexes of diastolic
function were compared in patients with different extent of left ventricular
hypertrophy. Time interval from minimum left ventricular internal dimension
to mitral valve opening and time to peak rate of increase in left ventricular
internal dimension were significantly prolonged (80 +/- 31 and 100 +/- 37
msec, respectively) in patients with HCM and the most extensive left ventricular
hypertrophy compared with those in patients with mild left ventricular hypertrophy
(59 +/- 25 and 74 +/- 34 msec, respectively; p less than .01). Furthermore,
peak rate of posterior wall diastolic excursion was significantly reduced
in those patients with HCM and posterior wall hypertrophy (8.3 +/- 4.0 cm/sec)
compared with that in patients with HCM but normal posterior wall thickness
(11.2 +/- 3.4 cm/sec; p less than .002). However, abnormal M mode echocardiographic
indexes of diastolic function were also identified in a substantial proportion
of patients (i.e., 73%) with HCM and only mild left ventricular hypertrophy.
In these patients, time interval from minimum left ventricular internal dimension
to mitral valve opening (59 +/- 25 msec), peak rate (12 +/- 4 cm/sec), and
time to peak rate of increase in left ventricular internal dimension (74
+/- 34 msec) were significantly different from normal (25 +/- 12 msec, 21
+/- 3 cm/sec, and 49 +/- 12 msec, respectively; p less than .01).(ABSTRACT
TRUNCATED AT 250 WORDS)
PMID: 3159509 [PubMed - indexed for MEDLINE]
-
Hypertrophic cardiomyopathy. Interrelations
of clinical manifestations, pathophysiology, and therapy
(1).
Maron BJ, Bonow RO, Cannon RO 3rd, Leon MB, Epstein
SE.
Publication Types:
PMID: 3547130 [PubMed - indexed for MEDLINE]
-
Hypertrophic cardiomyopathy. Interrelations
of clinical manifestations, pathophysiology, and therapy
(2).
Maron BJ, Bonow RO, Cannon RO 3rd, Leon MB, Epstein
SE.
Publication Types:
PMID: 3547135 [PubMed - indexed for MEDLINE]
-
Erratum in:
- Circulation 1998 Mar 17;97(10):1026
Mechanism of benefit of negative inotropes in obstructive
hypertrophic cardiomyopathy.
Sherrid MV, Pearle G, Gunsburg DZ.
Division of Cardiology, St. Luke's-Roosevelt Hospital Center, Columbia University,
College of Physicians and Surgeons, New York, NY 10019, USA. m.sherrid@mindspring.com
BACKGROUND: Drugs with negative inotropic effect are widely used to decrease
obstruction in hypertrophic cardiomyopathy (HCM). However, the mechanism
of therapeutic benefit has not been studied. METHODS AND RESULTS: We used
M-mode, two-dimensional, and pulsed Doppler echocardiography to study 11
patients with obstructive HCM before and after medical elimination of left
ventricular outflow tract obstruction. We measured 148 digitized pulsed Doppler
tracings recorded in the left ventricular cavity 2.5 cm apical of the mitral
valve. Successful treatment slowed average acceleration of left ventricular
ejection by 34% (P=.001). Mean time to peak velocity in the left ventricle
was prolonged 31% (P=.001). Mean time to an ejection velocity of 60 cm/s
was prolonged 91% (P=.001). Before treatment, left ventricular ejection velocity
peaked in the first half of systole; after successful treatment, it peaked
in the second half (P=.001). In contrast, after treatment, we found no change
in peak left ventricular ejection velocity. We also found no change in the
distance between the mitral coaptation point and the septum, as measured
in two planes, indicating no treatment-induced alteration of this anatomic
relationship. CONCLUSIONS: Medical treatment eliminates mitral-septal contact
and obstruction by decreasing left ventricular ejection acceleration. By
slowing acceleration, treatment reduces the hydrodynamic force on the protruding
mitral leaflet and delays mitral-septal contact. This, in turn, results in
a lower final pressure gradient.
PMID: 9443430 [PubMed - indexed for MEDLINE]
-
Dynamic Left Ventricular Outflow Obstruction
in Hypertrophic Cardiomyopathy Revisited: Significance, Pathogenesis,
and Treatment.
Sherrid MV.
St. Luke's-Roosevelt Hospital Center, New York, New York.
Systolic anterior motion of the mitral valve and mitral-septal contact is
the usual cause of dynamic left ventricular outflow obstruction in hypertrophic
cardiomyopathy. That true obstruction actually occurs is now established
based on cardiac catheterization and echocardiographic evidence. A mid-systolic
drop in left ventricular systolic ejection velocity because of obstruction
has been demonstrated recently. Echocardiographic data indicate that systolic
anterior motion of the mitral valve is initiated by flow drag; the mitral
valve is swept toward the septum by the pushing force of flow. After mitral-septal
contact, obstruction begets further obstruction as the pressure gradient
pushes the mitral valve into the septum. Most symptomatic patients with obstruction
can be treated successfully with negatively inotropic drugs. These medications
reduce systolic anterior motion and obstruction by decreasing early left
ventricular ejection acceleration, decreasing the early systolic pushing
force on the protruding mitral leaflet. Patients who do not improve on medication
generally benefit from surgery. Newer interventions to relieve obstruction,
such as dual-chamber pacing and percutaneous transluminal septal myocardial
ablation are under active investigation.
PMID: 10348935 [PubMed - as supplied by publisher]
10. Apstein CS. Diastolic dysfunction during ischemia role
of glycolytic ATP generation. In: Lorell BH GW, Grossman W ed. Diastolic
relaxation of the heart. Boston, Ma: Kluwer, 2000; 125–134.
-
Myocardial ischemia in patients with hypertrophic
cardiomyopathy: contribution of inadequate vasodilator reserve
and elevated left ventricular filling pressures.
Cannon RO 3rd, Rosing DR, Maron BJ, Leon MB, Bonow RO,
Watson RM, Epstein SE.
To study the mechanism and hemodynamic significance of myocardial ischemia
in hypertrophic cardiomyopathy, 20 patients (nine with resting left ventricular
outflow tract obstruction greater than or equal to 30 mm Hg) with a history
of angina pectoris and angiographically normal coronary arteries underwent
a pacing study with measurement of great cardiac vein flow, lactate and oxygen
content, and left ventricular filling pressure. Compared with 28 control
subjects without hypertrophic cardiomyopathy, their resting coronary blood
flow was higher (91 +/- 27 vs 66 +/- 17 ml/min; p less than .001) and their
coronary resistance was lower (1.13 +/- 0.38 vs 1.55 +/- 0.45 mm Hg/ml/min;
p less than .001). Left ventricular end-diastolic pressure (16 +/- 6 vs 11
+/- 3 mm Hg; p less than .001) and pulmonary arterial wedge pressure (13
+/- 5 vs 7 +/- 3 mm Hg; p less than .001) were significantly higher in patients
with hypertrophic cardiomyopathy. During pacing, coronary flow rose in both
groups, although coronary and myocardial hemodynamics differed greatly. In
contrast to the linear increase in flow in control subjects up to heart rate
of 150 beats/min (66 +/- 17 to 125 +/- 28 ml/min), patients with hypertrophic
cardiomyopathy demonstrated an initial rise in flow to 133 +/- 31 ml/min
at an intermediate heart rate of 130 beats/min. At this point, 12 of 20 patients
developed their typical chest pain. With continued pacing to a heart rate
of 150 beats/min, mean coronary flow fell to 114 +/- 29 ml/min (p less than
.002), with 18 of 20 patients experiencing their typical chest pain and metabolic
evidence of myocardial ischemia. This fall in coronary flow was associated
with a substantial rise in left ventricular end-diastolic pressure (30 +/-
9 mm Hg immediately after peak pacing). In the 14 patients whose coronary
flow actually fell from intermediate to peak pacing, the rise in left ventricular
end-diastolic pressure in the same interval was greater than that of the
six patients whose flow remained unchanged or increased (11 +/- 8 vs 2 +/-
2 mm Hg; p less than .01). In addition, despite metabolic and hemodynamic
evidence of myocardial ischemia, the arteriovenous O2 difference actually
narrowed at peak pacing. Thus most patients with hypertrophic cardiomyopathy
achieved maximum coronary vasodilation and flow at modest increases in heart
rate. Elevation in left ventricular filling pressure, probably related to
ischemia-induced changes in ventricular compliance, was associated with a
decline in coronary flow.(ABSTRACT TRUNCATED AT 400 WORDS)
PMID: 4038383 [PubMed - indexed for MEDLINE]
|
|
