Provocation of latent left ventricular outflow tract gradients with amyl nitrite and exercise in hypertrophic cardiomyopathy

Provocation of latent left Ventricular Outflow Tract Gradients With Amy1 Nitrite and Exercise in Hypertrophic Cardiomyopathy Thomas

H. Marwick, MD, PhD, Satoshi Nakatani, MD, Brian James D.‘Thomas, ‘MD, and Harry M.’ Lever, MD

Haluska,

Amyl nitrite ma be used to provoke latent gradients tients wi x hypertrophic cardiomyopathy (HC) in wi tr out significant resting outflow tract radients, but afterload reduction may not be cornpam ?I le to a more ic stressor such as s ptom-limited exercise physiol testing. ?ll is study compared tr e ability of amyl nitrite and exercise testing to provoke outflow tract gmdients in 57 Patients (40 men and 17 women, mean age + SD 49 r 16 years) with HC (septal thickness 19 f 5 mm, average resting gmdient 13 f 10 mm H ) who underwent echocardiography at rest, after amy P nitrite inhalation, and after maximal exercise. No significant gradient (<50 mm Hg) was induced after either provocation in 26 patients (46%); in 15 patients (260/o), inducibility was achieved after both stressors, in 6 (11%) after exercise only, and in 10 (18%) after amyl only. Patients with amyl-induced gradients differed from those in whom gradients were noninducible on the basis of smaller outflow tract dimensions (p
larger restin gradients (p
atients with the classic morphologic features of hypertrophic cardiomyopathy (HC) in the absence of a resting gradient were reported as a forme fruste of the syndrome within a few years of its original description.’ Subsequently, patients with nonobstructive HC were differentiated from a group with latent obstruction, in which the obstruction could be induced by various intcrventions. This group with latent obstruction typically develops symptoms later in life than those with resting obstruction, and are characterized by milder symptoms, less severe hypertrophy, and a more benign prognosis. Despite the better prognosis of the group of patients without resting outflow tract gradients, in individual patients, the symptoms associated with intermittent left ventricular outflow tract obstruction (dizziness, chest pain, and dyspnea) may be extremely troublesome. Proof that these nonspecific symptoms are due to outflow tract obstruction is dependent on inducing the gradient in the echocardiography laboratory. Various physical and pharmacologic maneuvers have been used for the induction of latent gradients.* but have previously been distinguished as being relatively nonphysiologic. In this study, WCsought to determine the concordance and associated

features of amyl nitrite and exercise for the induction of outflow tract gradients.

P

From .he Dqxrtment 0’ Cardiology Clevclard Clinic Fcbqdction, Clevctand, Ohlc. Mawscript received Iecemtxr 5, 199L; revised rawscript received and accept& Jcnuary 4, i 995 Address for reprints: Thomas H Maw& MD. ?hD, Departmelt oi Ccrdiology, F15 Clevelarld Cllnlc Foundatior, 9.500 Cucld Avenue, Clevctana, &a 44 195.

CARDIOMYOPA-hY/

METHODS Patient selection: Fifty-seven consecutive patients (mean age f SD 49 f 16 years) with nonobstructive HC who were examined with echocardiography at rest after administration of amyl nitrite and cxercisc from August 1990 to October 1993 were enrolled in the study and followed for a period of at least I year. Patients were selected to undergo provocative testing if they had anatomic features of HC with clinical suspicion of intermittent obstruction, but without significant obstruction at rest (resting gradient ~50 mm Hg). This group comprised 40 men and 17 women; 32 (56%) were receiving medical therapy with either a p blocker or a calcium antagonist. Echocardiogmphy: Left ventricular dimensions, including outflow tract dimension, were measured from the parastcrnal view, and the pattern of hypertrophy was classified into concentric, asymmetric septal. and proximal “scptal bulge” patterns.’ After adjusting the gain and filter to optimize the spectral display, outflow tract velocity was measured using continuous-wave Doppler from the apex, and the modified Bernoulli equation was used to calculate the outflow tract gradient. Mitral regurgitation was assessedusing color flow mapping, and cdre was taken at all stages of testing to align the continuous-wave Doppler in the outflow tract and not in the regurgitant jet. After completion of the resting echocardiagram. patients inhaled amyl nitrite over a period of 1

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TABLE I Clinical, Without

Morphologic, and Functional Characteristics in Patients With and Left Ventricular Outflow Tract Obstruction Induced by Amy1 Nitrite Inducible (n = 25)

Agebrl Presyncope Major events (death, HC surgery) Septal bulge morphology LVOT diameter (mm) Septal wall thickness (mm) Posterior wall thickness (mm) Enddiastolic volume (ml) End-systolic volume (ml) Ejection fraction (%) Resting outflow gradient (mm Hg) Amyl heart rate (beats/min) Exercise outflow gradient (mm Hg)

Noninducible (n = 32)

52+ 15 8 (32%) 7/23 (30%)* 12 (48%) 1.7 * 0.3 19*5 15 f 2 106 + 27

462 58+ 19+

19 10 12

92 zt 20 71 f 41

47*

18

11 (34%)

2/28

(7%)* 6 (19%) 2.1 It 0.3 19r5 14 f 3

100 f 29

44~ 57* 8*5 88 i 29 f

18 10 22 26

p Value

NS NS 0.07 0.02 0.001 NS NS NS NS NS
*Follow-up completed in 5 1 patients. Values are expressed as mecm + SD. HC = hypertrophic cardiomyopathy; LVOT = left ventricular outflow tract

to 2 minutes until there was a significant increment of heart rate (>lO beats/min) or the patient became symptomatic from flushing or dizziness. Left ventricular outflow tract velocity was evaluated after amyl inhalation. Exercise echocardiography: After resolution of the hemodynamic effects of the amyl, and 25 minutes after this provocative maneuver, patients were prepared for treadmill exercise testing in the standard fashion. Resting images were repeatedin 4 standard views (parasternal long- and short-axis, and apical 2- and 4-chamber), which were recorded on videotape and digital format. Patients then exercisedusing a protocol selectedaccording to their level of fitness. Standardmonitoring was performed during exercise,which was terminated for severe chest pain, >2 mm of ST-segment elevation or depression, systolic or diastdlic blood pressuresof >250 and >130 mm Hg, severefatigue, or a decreaseof >20 mm Hg on 2 readings. Within 1 minute after exercise, with the patient in the supine position, outflow tract velocities were again measured. Follow-up: Patients were followed up over a period of at least 1 year (mean 27 f 12 months) by either clinic

review or telephone contact. Data were collected regarding the occurrence of major cardiac events (death, myocardial infarction) or worsening symptoms. Data analysis: Results are expressedas mean + SD. The relations between inducible gradients, symptom status, and outcome were examined using paired t testsfor continuous variables and chi-square tests for noncontinuous variables. Outflow tract gradients induced by amyl and exercise were comparedby paired t tests and linear regression. The group with concordant gradients measured by exercise and amyl was compared with those among whom the amyl-induced gradient, and those among whom the exercise-induced gradient were greatest. These groups were compared using t tests for continuous variables, and chi-square tests (including Yates’ correction when necessitatedby sample size) for noncontinuous variables.

RESULTS

FIGURE 1. Proportion of 57 Patients with nonobstructive hypertro hit cardiomyopathy in whom obstruction could be induced wig amyl nitrite, exercise (Ex], or both.

Clinical features: Provocation was performed in all patients becauseof clinical concern regarding latent outflow tract obstruction, but a high clinical suspicion of obstruction was present in 20 patients (35%) due to presyncope or syncope. Chest pain was present in 12 patients and dyspnea and fatigue were the predominant symptoms in the remaining patients. Septal wall thickness was 19 & 5 mm, and the posterior wall was 14 I!Z3 mm. The average resting outflow tract gradient was 13 f 10 mm Hg. No patient had significant resting obstruction, defined as a left ventricular outflow tract velocity >3.5 m/s (corresponding to a gradient >50 mm Hg). Outcome: Six patients,3 of whom lived overseas,could not be contactedfor follow-up. The other 51 patientswere followed over 27 + 12 months, during which time 1 patient died from ventricular tachycardia. Eight patients underwent septal myectomy or mitral valve replacement for the treatment of ongoing symptoms despite medical therapy; these subjectswere asymptomatic at follow-up. Four patients complained of significant ongoing problems (with presyncope,syncope,and chest pain), and the conditions of the remaining patients remained stablewith medical therapy.

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APRIL 1.5, 1995

Non-inducible

26

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Both amyl and exercise 15

THE AMERICAN

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OF CARDIOLOGY@

VOL. 75

TABLE II out

Clinical,

Morphologic,

Left Ventricular

Outflow

and Tract

Exercise

Characteristics

Obstruction

Induced

in Patients

by

Inducible

Age lyd Presyncope Major

events

LVOT

diameter

Septal

bulge

Septal

wall

Posterior

(death,

Amy1

thickness volume

fraction outflow

15 108

(ml] [ml)

48+ 56

gradient

(mm

gradient

rate-pressure

Exercise

heart

Exercise

capacity

*Follow-up

(mm)

rate

(mm product

Hg)

17*

Hg)

(X 10”)

(% age-predicted)

4/34

-+ 0.4

completed

(12%)*

1.9 c 0.4 7 (19%) 19+5

*

3

t

27

100

18

43

2 7 11

69

+ 34

31.0 91

t 9.7 * 15

NS 0.08 NS NS co.01 NS

14*3

NS + 28 *

19

NS NS

58

+ ii

11

t8

0.02

38

* 38

0.003 0.04

25.7

NS

+ 9.3

82+

9*3

(METS)

With

p Value

17

9 (25%)

19-+6

(%)

outflow

Exercise

surgery)

(mm]

volume

Ejection

52*

16

1 1 (52%)

wall

End-systolic

(n = 36)

45+

1 .a

thickness

End-diastolic

Resting

HC

and

Noninducible

(n = 21)

10 (48%) 5/l 7 (29%)’

(mm]

With

Exercise

18

ai3

0.07 0.07

in 5 I patients.

Values are expressed 05 mec~n t SD. other abbreviations METS = metabolic equivalents;

Hemodynamic response to stresson: Heart rate at rest was 74 f 15 beats/min, increasing after amyl inhalation to 87 + 21 beats/min (p
gradients >50 mm Hg could not bc induced in response to either provocation. Fifteen (26%) became inducible after both stressors, 6 (11%) after exercise only, and 10 (18%) after amyl only (Figure 1). Patients who had an inducible gradient in response to either stress were characterized by a smaller lcfi ventricular outflow tract diametcr than the remaining patients (1.8 f 0.3 vs 2.1 f 0.3 mm, p ~0.01) and a greater resting gradient (I8 f 11 vs 7 f 3 mm Hg, p 50 mm Hg) with amyl, among whom the mean gradient was 87 + 22 mm Hg. The correlation of clinical, morphologic, and functional factors associated with a response to amyl nitrite is listed in Table I. Patients developing obstruction with amyl included 8 of the 19 patients whose main symptom was prcsyncope; the prevalence of this symptom was no diff‘ercnt from that in patients without amylinduced obstruction. Major subsequent events (death or surgery for symptoms refractive to medical therapy) were more prevalent in patients with amyl-induced graCARDIOM”rJ?AI

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as in Table

I.

dients than those without inducible gradients, although the association of intcrmittcnt obstructive symptoms with an inducible gradient may have influenced the decision to perform surgery on these patients. This group had a greater prevalence of septal bulge morphology, narrower left ventricular outflow tract diameter, and greater resting gradients than those who failed to develop obstruction with amyl. Finally, patients in whom obstmction was induced by amyl had higher exercise-induced gradients than those in whom gradients were not inducible. After cxercisc, the mean gradient for the group increased to 49 f 39 mm Hg (p 50 mm Hg developed in 21 patients, among whom the mean gradient was 93 f 25 mm Hg. Of 19 patients with obstructive symptoms, a gradient was provoked with exercise in 48%, compared with 32% with amyl. Patients with septal bulge morphology and higher resting gradients were more likely to develop obstruction with exercise, which also occurred in subjects who were able to perform a greater level of cardiac work (Table II). Patients developing significant obstruction with exercise also demonstrated more obstruction with amyl than those without inducible obstruction. Correlation of left ventricular outflow tract gradients with amyl and exercise: There was no significant diff’er-

cnce between the inducible gradients by each technique (mean dilrerence only 2 f 37 mm Hg). Figure 2 illustrates the variation between peak amyl- and exerciscinduced gradients (r = 0.54, p
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TABLE III Comporison

of Groups With Exercise-Induced Gradients Equivalent to Those Attainable With Amyf Inhalation, Those With Preponderant Exercise-Induced Gradients, and Those With Disproportionate Amyl-Induced Gradients Equivalent Gradients (n = 14) 38 LIZ 15’ 21 * 15t 14*3 83 t 20 72 * 21t 2 1.6 + 8.48 8.8 * 3.2 11 +9 35 _c 36 35 * 361

Age Ird Septal wall thickness (mm] Posterior wall thickness [mm] Amyf heart rate [beats/min) Exercise heart rate (% age-predicted) Exercise rate-pressure product (X 1 03) Exercise capacity (METS) Resting outffow gradient (mm Hg) Amyl outflow gradient (mm Hg) Exercise outffow gradient (mm Hg)

Exercise Predominant (n = 25)

Amyl Predominont (n = 18)

47* 20 14 94 96 33.7 9.4 12* 37 66

60 17 14 83 822 24.3 7.2 14 76 31

‘Age (equivalent vs omyl). p ~0.0001. ‘Septol thickness (equivalent VI omyl), p ~0.01 ‘Exercise heart rate (equivalent vs exercise), p
DISCUSSION The results of this study suggest that gradients induced by either stress are present in 54% of patients with symptomatic, nonobstructive HC, and that these patients have a greater prevalence of scptal bulge morphology and higher resting gradients than those whose gradients are noninducible. There was a limited correlation between the behavior of outflow tract gradients with exer-

E .w P b

T

.

.

. t 20

.

.

.2’ : .. . JI.

.

. .

FIGURE 2. Relation between maximal induced grad&k (mm Hg) provoked by amy( nitrite and exercise.

.

.

. . .. . .= . . ..

.

J

.

.. .

. .

.

8

.

.

I

0 0

20

40

w

80

Amythduced

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.

120

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cise and that during vasodilator stress, and significant fractions of patients with inducible gradients using one methodology did not demonstrate significant gradients with the other stress. Exercise-induced gradients exceedcd those obtained with amyl in patients who were able to attain higher cardiac workloads with stress. Amylinduced obstruction was more prevalent in patients with narrow left ventricular outflow tracts, and amyl-induced gradients exceeded those induced by exercise in older patients. Clinical relevance of inducible obstruction: Although initial reports of obstructive HC involved patients with asymmetric septal hypertrophy and a significant resting left ventricular outflow tract gradient, neither of these aspects are critical to the diagnosis. The dynamic nature of left ventricular outflow tract obstruction in HC has been recognized since the initial descriptions of the illness, which reported temporal variations of the outflow tract gradient4 as well as timing of obstruction.5 Outflow tract gradients may bc provoked by hemodynamic dis-

were characterized by older age (p 65 years old, whereas only 3 of the remaining 39 patients (8%) were in this age group (p = 0.01). In contrast, patients having disproportionate elevation of the left ventricular outtlow tract gradient with exercise were characterized by mom septal hypertrophy than the remaining patients (77% vs 50% p = 0.04), and had a higher heart rate (p
lw)

17 6 4 21 9t 7.85 1.7 10 t 33 * 42” e * f zt t r

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100

140

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turbances, providing that the substrate of outflow tract narrowing is present.6 A common clinical situation for patients with HC without resting obstruction is the intermittent occurrence of presyncope. Whereas this finding may have therapeutic implications in an otherwise asymptomatic patient, few data are available with respect to its prognostic implications, although this and previous studies suggest that latent obstruction is prognostically benign. To identify whether symptoms pertain to obstruction or other cardiac problems, the Valsalva maneuver, amyl nitrite, and isoprcnaline have been used to provoke obstruction. but each of these alternatives has disadvantages. Tsoprenalinc or other sympathomimetics’ are not favored in the outpatient setting because they are administered intravenously and may induce rhythm disturbances. The Valsatva maneuver is often difiicult to coordinate in elderly patients, and may impair echocardiographic imaging. Amy1 nitrite is usually used if the Valsalva maneuver is negative or is not perfonned satisfactorily. Provocative maneuvers that are used less often include augmentation of afterload, using methoxamine,’ or use of the Muller maneuver,H which increases left ventricular afterload through an increase of left ventricular transmural pressure. Finally, increased obstruction may bc observed during long cycle lengths’ and extrasystoles.tO Exercise testing in patients with hypertrophic cordioThe pharmacologic stresses previously dismyoplhy:

cussed bring out latent gradients by altering loading conditions. However, in the everyday clinical setting, patient symptoms are induced less often by sevcrc vasodilatation or hypovolemia, and may instead be produced by increasing inotropy with exercise. The response of outflow tract velocity to exercise has shown considerable heterogeneity in studies using invasive techniques as well as stress echocardiography. Using supine exercise and invasive monitoring, Klues et al” reported that no significant obstruction occurred during exercise in 10 patients, who then developed obstruction after exercise. These findings are concordant with those of Grbic et al,‘* who also used supine exercise. During upright bicycle

exercise, however, Schwammenthal et al” reported outflow tract gradients to increase during exercise-a difference that may reflect variations in patient selection and stress methodology. These studies are in agreement with ours to the extent that postexercise gradients may be increased in these patients. However, they have predominantly involved patients with resting obstruction, whereas WC believe that the benefit of exercise or other provocative maneuvers is to evaluate whether patients without resting gradients have inducible obstruction.

1. Whalen KE. Cohen Al. Sumner KG, Mclntoch HI). De:monsra!ion of rhe dynamic nature of Idiopathic hypertrophic suhaortic s~cno\i). Am J Cur&>/ 1963; I I:X- 17. 2. Wigle ED. Lenkei SC. Chrywhou A. Wilson DR. Muscular wbaonic stenosis: Ihc effect of pcriphcwl vacalilation. Can Mrrl A.~soc .I 1961:89:XW899. 3. Ixver IN, Kaclm RF. Curric PJ. Healy HP. Ilvpertrophlc cardmmyopathy in thr elderly: dictmction from the young based on card&c shape. ~‘rrcrrl~~nun 198979: %0-5X9. 4. Braunwald E. Oldham HK Jr, ROSL J Jr. Linhnn JW. Mawn DT, Fix-i L III. The circulaloty respnw of patxnts with idiopathic hypcnrophic whaon~c ctenoins IO ntuoglyccrin and to the Valsalva maneuver. Crr-mlufion 1964;29:422~31. 5. Wigle ED. C‘ardiovaaular drugs in muscular subaor~~c atenaG\. I.‘& Prw : 96.5: 24: ‘279 I286 6. Ji:mg L. Levine KA. Kinp ME, Weyman AI+. An integrated mechanism for systolic auterior motion of the mmal valve in hypcmophic cardiomyopathy based on echocardidiographic obsenationr. Am ilmrr .I 1987:113:633&4. 7. Braunwald E. Ebcn Ph. Hemodynamic aIrwaGon\ in Idiopathic hypavophic whaonic stenosis induced by sympathomirnelnc dmgs. /In! .I Corrliol 1962; IO: 4x9 4%. 8. Buda AJ. MacKenr.ic GW. W~glc ED. Effort of negative intrathor;uc pressure 011 left vcntncular outflow tract obstructmn in muscular wbaonic stenosis. C‘in-rrlorrou IYXI:67:87.5-XXI. 9. Come PC. Riley .LIF. Miklxk CL. Echocardiographic evidence of increased obarmchon following long cycle length\ m atria1 tihrill~~f~on in patients wuh hyper~roph~c cardiomyopathy. J C/in L’lwusounri 19x4; 12~2-4 I-243. 10. An&f GII. Wistran 1). Slon Ll. Markis JE. Come PC, %oll PM. Cohn PI;. Value of a noninvacively induced vcn~ricular exwabystole during echocardiographic and phonocxdiographic aswwncnt of paticnr~ with idmpathic hypertrophlc whaon~c stenocis. Am J (‘ardrol 1078:42:91%924. 11. Klucs IIG. Lcuncr C. Kuhn Il. lrff ventricular ou~flou tract obstruction in patienlb wth hypeflrophic cardiomyopathy: increase in gradient after excn‘ix. J Am Cdl C‘ardml I YY2; ‘9:527-S33. 12. Grhic X4, Si_ewut II. Hivier JL. P;~yot 41. Jargw M. Effct d’une effort dynamique sur I’hemcdynamique du ventricule gauche Ion d‘une cardiomyopathre obstructive. Sc/~wet: Mrd Wochemrhr ‘980; I IO: ‘602 ‘696. 13. Schwammenthal E. Schwanzkopff H. Block \4’, Johns I. I.oarc B. Engbcrding K. Borggrefe X4. Breilhw G. Doppler cchccardiographic aswwnent of Ihe pressure gradient durmg bicycle ergometry in hypenrophic cardiomyopathy. Am J Cordid ‘992:69:1623 ‘62X.

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