Unexplained Hypertrophy - Assessing the Risk (From the 8th ...

VOLUME 24, NO. 2 SUMMER 1992

UNEXPLAINEDVENTRICULAR HYPERTROPHY

Board of Insurance Medicine Teaching Case

UNEXPLAINED HYPERTROPHY - ASSESSING THE RISK (From the 8th Triennial

Board of Insurance Medicine Course)

B. Ross MacKenzie, MD, FRCP(C), FACC

Presentation of Case

of increased ventricular mass and may in general be

identifying patients with severe hypertrophy that is

A 35 YEAR old male geologist is applying for a $200,000 often accompanied by interstitial fibrosis, impaired

term policy. His beneficiary is his wife. He is a non- coronary-artery reserve, and myocardial dysfunction.

smoker and has no symptoms. He jogs three nights per The Framingham Study has shown that the prevalence

week. He has a past history of mild hypertension, not of electrocardiographically determined LVH in the

requiring treatment. His father died suddenly and un- adult population is about 2%. Quantitative echo-

expectedly at age 52. Mother and siblings are alive and cardiography; which estimates left ventricular mass,

well.

not only is a more precise noninvasive tool for deter-

mining the presence of LVH but also permits the evalu-

The Attending Physician's Statement (APS) reveals a ation of serial changes in the mass and function of the

normal build, and his most recent BP is 130/90 (range left ventricle.

over past three years 140/90 - 160/100). 1991 chest x-ray

(APS) was normal. 1991 ECG (APS): borderline QRSWhen both ECG and echocardiographic studies were

voltage for left ventricular hypertrophy (LVH) and mi- performed in a large cohort of the Framingham Study; nor T-wave changes. 1991 echocardiogram: left ven- LVH was detected in 2.1% on the basis of ECG criteria

tricular cavity dimensions were at lower limits of and in 16% on the basis of echocardiographic criteria.

normal. There was asymmetrical septal hypertrophy Although the prevalence of LVH detected in people

(ASH) with a septum to free wall ratio of 1.5:1.0. Maxi- with hypertension with use of the two methods is mal wall thickness was 16 mm. There was no evidence higher (3 to 5% for ECG and 20 to 50% for echocardiog-

of left ventricular outflow tract obstruction.

raphy) than that for the general population, echo-

Left Ventricular Hypertrophy - Recent Advances

cardiography still identifies 7 to 10 times more persons with an abnormal cardiac mass than does ECG. In view

of this marked disparity in results, the prognostic infor-

It has been recognized for many years that the heart has mation obtained over decades of observation of popu-

an inherent capacity to adjust its mass and shape in lations with LVH detected by ECG cannot simply be

response to a sustained alteration in workload. In this assumed to apply to those with LVH determined by

respect, the hypertrophic response can be viewed as echocardiography. Only recently has echocardiography

adaptive, since the remodeled ventricular chamber is been shown to convey important prognostic informa-

capable of maintaining workloads in excess of normal. tion about cardiovascular events associated with LVH

Once recognized clinicall},, however, LVH in pathologic in both the general population and hypertensive popu-

conditions is strongly associated with a poor prognosis, lation. The independent risk of subsequent adverse

irrespective of the cause.

cardiovascular events in relation to the magnitude of

LVH detected echocardiographically underscores the In most epidemiologic studies and clinical trials, the use usefulness of this measurement and has raised impor-

of electrocardiography (ECG) to define LVH has iden- tant questions about the potential benefits of reducing tified only the most severe abnormalities of left veno the abnormal cardiac mass. Recent observations that tricular mass and shape and has reinforced to some similar reductions of blood pressure by various antihy-

extent the exaggerated association between LVH and pertensive agents have different effects on left ventricu-

adverse clinical events. Although highly specific, the lar mass has raised questions about the appropriateness

ECG criteria are notoriously insensitive to the presence of agents that do not lower left ventricular mass and by

V~ce President and Chief Medical Director, Sun Life Assurance Company

inference improve prognosis.

of Canada, 150 King St. W., Toronto, Ontario MSH 2J9, Canada. Attending Cardiologist, The Toronto Hospital (Toronto General Hospital Division), Toronto, Ontario, Canada.

Hypertrophic cardiomyopathy (HCM) may be defined ~o. I.VH ,nd/c)r RVH without identifiable c~io(- It i*

JOURNAL OF INSURANCEMEDICINE

VOLUME 24, NO. 2 SUMMER 1992

usuall3~ but not always, associated with microscopic hour ambulatory monitoring. Studies to date have not

evidence of myocardial fiber disarray. HCM is associ- indicated that a variety of therapeutic interventions

ated with asymmetric hypertrophy of the left ventricle including beta blockers, calcium antagonists, antiar-

in 95% of cases, with asymmetric septal hypertrophy rhythmic agents or surger34 have a positive effect on

being the most common form. Both the site and extent survival.

of hypertrophy are important in determining the dis-

ease manifestations and the prognosis. Basal (subaortic) In over half of the patients with HCM the disease is

septal hypertrophy typically results in obstructive familial, the pattern of transmission in classic, mende-

HCM, whereas, isolated apical hypertrophy does not. lian terms being autosomal dominant with variable

Extensive hypertrophy in HCM is associated with ECG expression, while the remaining cases appear to be

evidence of LVH, atrial arrhythrnias, septal perforator sporadic. In the short span of the last three years, the

artery compression, and a greater likelihood of obstruc- application of the techniques of molecular biology has

tion to left ventricular outflow and abnormal diastolic brought a new understanding of HCM. In approxi-

filling. Although echocardiographically detected asym- mately 50% of families with familial HCM, the disease

metrical septal hypertrophy has been emphasized in has been shown to be caused by missense mutations in

the diagnosis of HCM, it is not specific for HCM. ASH the beta cardiac myosin heavy-chain gene. A missense

has occasionally been demonstrated in patients with mutation is a single-based mutation that results in the

essential hypertension and valvular aortic stenosis, in insertion of a different amino acid into the protein for

patients undergoing hemodialysis and rarely in elite which the gene codes. Taking advantage of the ectopic

athletes.

expression of this gene in peripheral-blood lympho-

cytes, the evaluation of persons with suspected HCM

A potentially low risk group of individuals with HCM can now include genetic studies. Identification of the

are those with apical HCM which is characterized by precise mutation responsible for familial HCM in one

marked T- wave inversion on the ECG. The Japanese proband permits rapid, cost-effective evaluation of all

experience with this subgroup has been associated with family members by peripheral-bood aniayses. Genetic

a relatively normal natural history although the early testing will not only assist diagnosis when the clinical

reported experience with this subset in North America evaluation is complicated by concurrent hypertension

reveals a natural history between that of normal indi- or athletic training but also permit preclinical or prena-

viduals and those at the higher risk end of the spectrum. tal diagnosis. Equally important, genetic analyses also

allow the diagnosis of familial HCM to be unequivo-

The natural history of HCM has been documented in cally excluded in unaffected members of families with

several large series. The early series were based largely identified mutations. Final134 there is now preliminary

on hospital and treated populations and therefore bi- evidence that among patients with particular muta-

ased toward the more severe end of the disease spec- tions, the different missense mutations are associated

trum. More recent reports from nonspecialist centers with differences in survival, despite otherwise similar

utilizing more sensitive echocardiographic diagnostic clinical findings.

techniques, and the finding of HCM in the elderly,

suggest that HCM is a relatively more common disease Long-term athletic training produces the ECG changes,

with a more benign prognosis than has previously been the increases in diastolic dimensions of the left ventri-

appreciated.

cle, in the thickness of the left ventricular wall and in

the calculated left ventricular mass that make up what

The natural history of HCM is characterized by slow is commonly known as the "athletic heart syndrome."

progression of symptoms with a high incidence of sud- The increase in thickness of the left ventricular wall is

den death, often in patients with mild or no symptoms. usually mild, but it may be more substantial in some

The annual mortality is highest in infants and children, athletes and create the diagnostic problem of distin-

4-6%, and is 2-4% in adults.

guishing the physiologic hypertrophy of the athlete's

heart from pathologic forms of hypertrophy4 such as

In children, those at risk are distinguished by the fol- HCM. This is an important differential diagnosis, since

lowing risk factors: young age at diagnosis, syncope most instances of sudden death in young athletes are

and a family history of HCM and sudden death. In probably due to HCM. The distinction between these

adults, the predictive power of conventional clinical, two forms of hypertrophy depends largely on the

hemodynamic, echocardiographic and angiographic judgement of whether the magnitude of the left ven-

features and measurements is relatively poor. The most tricular wall thickness exceeds that expected as a result

discriminant marker of high risk in adults is the pres- of athletic training alone.

ence of nonsustained ventricular tachycardia on 24-

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VOLUME 24, NO. 2 SUMMER 1992

UNEXPLAINEDVENTRICULAR HYPERTROPHY

Precise definition of the physiologic limits on the extent of hypertrophy can be documented in the athlete but

to which cardiac dimensions can be altered by athletic not in someone with HCM.

conditioning, particularly left ventricular wall thick-

ness, has been hampered by a lack of echocardiographic Case Discussion

data obtained systematically in large groups of highly

trained athletes participating in a wide range of sports. This case presents the medical director with the prob-

A recent report by Pelliccia, et al, has addressed this lem of assessing the risk of an applicant with unex-

issue. These investigators concluded that a left ven- plained left ventricular hypertrophy. Analysis of the

tricular wall thickness of 13 mm is very uncommon in case reveals three potential explanations for the LVH:

highly trained athletes, virtually confined to athletes "the athletic heart syndrome," sustained hypertension,

training in rowing sports, and associated with an en- and HCM. The relatively low intensity of exercise train-

larged left ventricular cavil. In addition, the upper ing (versus a true athlete), the presence of ASH (rare in

limit to which the thickness of the left ventricular wall athletes), and the left ventricular cavity dimensions at

may be increased by athletic training appears to be 16 the lower limits of normal, argue against the athletic

ram. Therefore, athletes with a wall thickness of more heart syndrome. The degree of hypertension docu-

than 16 mm and a nondilated left ventricular cavity are mented is in the mild range and would be an unlikely

likely to have primary forms of pathologic hypertroph~ stimulus for this degree of LVH. More detailed docu-

such as HCM.

mentation of blood pressures or the use of an ambula-

Occasionall~ the borderline between a person who en-

gages in recreational sports and an athlete is indistinct. Training effects can be observed from aerobic exercise

tory blood pressure recorder would be necessary to confirm more severe hypertension. The family history of premature sudden death, the abnormal ECG, the presence of ASH, the left ventricular maximal wall

periods of thirty minutes duration performed three thickness of 16ram and left ventricular cavity dimen-

times a week. True athletes, however, engage in much sions in the lower limit of normal are strongly suggesmore rigorous training schedules involving several tive of HCM. For this reason, most participants at the

hours a da~ at least five days per week.

8th Triennial Course felt the mortality in 35 year old

males with HCM would exceed 500% of the mortality

In addition to the above echocardiographic charac- among underwritten, unimpaired 35 year old men. A

teristics, the essence of distinguishing between HCM few participants indicated that they might expect a

and physiologic adaption lies in the cavity dimensions mortality ratio as low as 300% of select mortality in a and diastolic function. In HCM the cavity dimensions group of similarly impaired individuals, if the constel-

tend to be at the lower limit of normal, particularly at lation of clinical and laboratory features were more

end-systole. Pulsed Doppler echocardiography is also toward the benign end of the spectrum of HCM such as

useful in demonstrating the alterations in flow pattern might be found with apical HCM.

across the mitral valve due to diastolic dysfunction. In HCM, the peak velocity during the initial diastolic flow

Suggested Reading

(E) is reduced, and the velocity following atrial systole Pfeffer MA, Pfeffer JM. Reversing cardiac hypertrophy in hyperten(A) is significantly increased. This is expressed as a sion. N Engl J Med 1990; 322:1388-1389.

reversal of the normal E to A ratio. In athletes, the McKenna WJ, Camm AJ. Sudden death in hypertrophic end-diastolic dimensions are at or slightly above the cardiomyopathy. Circulation 1989; 80:1489-1491.

upper limit of normal, with normal end-systolic dimen- Pellicia A, Maron BJ, Spataro A, Proschan MA, et al. The upper limit

sions. These individuals have an increased early rapid of physiologic cardiac hypertrophy in highly trained elite athletes. N

filling (E) and therefore, and increased E to A ratio.

Engl J Med 1990; 324:295-301.

Webb, JG, Sasson Z, Rakowski H, Liu P, Wigle ED. Apical hyper-tro-

When genuine doubt remains after comparing the pre- phic cardiomyopathy. JAm Coil Cardio11990; 15:83-90.

ceding diagnostic indices, two further alternatives remain: performing echocardiography on first degree relatives in whom the finding of ASH should arouse suspicion and as a last resort having the applicant undergo a period of detraining during which regression

Rosenzweig A, Watkins H, Dar-San H, Mohammed M, et al. Preclinical diagnosis of familial hypertrophic cardiomyopathy by genetic analysis of blood lymphocytes. N Engl J Med 1991; 325:1753-1759.

Watkins H, Rosenzweig A, Dar-San H, et al. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy, N Engl J Med 1992; 326:1108-1114.

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