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Coronary artery dimensions in primary and secondary left ventricular hypertrophy
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Buckground.Coronaryartery enlargementhas beenpreviously described::, left venbirular hyprtrophy. Obj&ves. We soughtto assesscoronaryarterydimeusionsand their relation to left sentricular muscle mass in primary 3rd secondaryhypertrophy. Methfs. Cross-sectionalarea of the left and right coronary arteries wasdetermined hy quantitative corouaryangiographyin 52 patients: 12 control subjectsand 10 patients (13 with hypertrophic cardiomyopathy,12 with dilated cardiomyopathyand 15 with aortic valve disease).As a measure of let%ventricular hypertrophy, angiographic left ventricular massand equatorial cross-sectionalmusclearea were determined. Res;r&s. Cross-sectionalarea of both the left and right coronary arteriesis increasedin left ventricular hypertrophy(a, < 0.05 vs. valuesin control subjects).There is a curviiinearrelation between .---ll_--_l_--
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Enlargement of the coronary arteries has been reported in patients with left ventricular hypestrophyat necropsy(1.2) and in clinical studies (3-5). Increased dimensions of the left anterior descending and circumflex coronary arteries were found in patients with left ventricular hypertrophy secondary to aorric or mitral valve disease as well as in patients with hypertension (3-14). In severeleft ventricular hypertrophy the coronary arteries have Iimited ability to grow (3,s) and thus carry the riskof underperfusion during high demand situations suchas physicalexercise.However, the regulatory mechanisms are largely unknown and may be different in primary and secondary as well as eccentric and concentric hypertrophy. Thus, the purpose of the present study wasto analyzecoronary artery sizein patients with dilated and hypertrophic cardiomyopathy, and to compare the results with previously reported data in patients with secondary:eft ventricularhypertrophy (4).
Patients. Twelve patients with atypical chest pain and normal coronary arteries served as control subjects(group 2, From the Department of Internal Medicine, University Hospital, Zurich, Switzerland. Manu&pt received October 31,199S; revised manuscript received April 22, 1996, accepted April 24. 1996. Address for currespond~g: Dr. Otto M. Hess, Department of Internal Medicine, University Hospit& Raemistrasse 100; CH-8091 Zurich, Switzerland. 0106 by the American College of Cardiology Published by Elsevier Science Inc.
left coronaryarteq sizeand left ventricular musclemass [r = 0.76) or cross-sectionalmusclearea fr = U.75) However?normatkation of coronarycross-sectional area for left ventricuiarmuscle massor musclearea showsinsufficientenlargementof the coronary arteries In both primary and secondau hypertrophy. Coucbdsions. I) Coronaryartery sizeincreasesas left ventric= ular massincreasesin both primary and secondaryhypertrophy. 2) The enlargementof left coronarycross-sectional area is independent of the causeof the increasein left ventricular mass.3) The sizeof the coronaryarteriesis inapprogriate with regard to left ventrientar $pertrophy. Thus, the stimulusfor growth of the coronaryarteries is not iuflnencedby the underlyingdiseasebut appearsto dependon the degreeof left ventricuiar hypertrophy,
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mean age 2 SD 52 c S years, nine men and three women). These patients had no valvular or coronary artery diseaseor left ventricular hypertrophy. The remaining 40 patients comprised 13 patients with hypertrophic cardiomyopathy (group 2, mean age 43 + 9 years,10 men and 3 women), 12 patients with dilated cardiomyopathy (group 3, mean age 52 t 9 years, 7 men and 5 women) and 15 patients with aortic valve disease (group 4, mean age 55 2 7 years, 12 men and 3 women). Functional classificationwas assessedaccording ta New York Heart Associationcriteria. Cardiac catheterization. patients underwent right and left heart catheterization for diagnostic purposes. Informed consent wasobtained from all patients, Premeditation consistedof chlordiazepoxide, 10 mg, administered orally 3 h before the psocedure. Vasoactive substanceswere withheld for 24 h before cathererization, Aortic pressurewas measured with an SF pigtail catheter introduced retrogradely from the right femoral artery and pulmonary artery pressure with a 7F Cournand catheter from the right femoral vein. After Ieft ventricular angiography,diagnosticcoronaryarteriography was carried out by the Judkins technique. A nonionic contrast material (iopamidoltrometamol; Lopamiro 370) MS used for quantitative coronary angiography to minimize h-yperemic reactions with transient changesin coronary blood flow (1.5). Cine film was used as a data carrier (filming rate 50 frames/s). Left ventricular voiume and ejection fraction were caiculated according to the area-length method (16). Left ventricu-
lar n~trscfemm wasdetermined with the formula of Kackleyet al. (17). III patients with hypertrophic cardiomyopathy and asymmetrichy~~rtropl~y,cross-sectionalmusciearea at the Ml ventricular equator {LVMA [cm’]) was used as a measure of left ventricular hypertrophy
wflerc h4 = left vcntricutar a~~gi~~~ra~hic short-&& diameter; a& 11= left ventricular angiographicwail thickilessmeasured ifi the right ,tnti&r oblique projection. I+( comparison purposts, this variable wasalso calculatedin all other patients. In patients with hypertrophic cardiomyopathy,~a!1 tl~i~kt~% (!I,.) was calculatedfrom the angiographic thicknessmultiplied by the echocardiographic septal/postcrior wall thickness ratio (s/p) to correct for asymmetricseptal hypertrophy: h, = [lx -i (h * s/p)@
~ua~~t~ta~~~e coronary arteriography. Quantitative evaluation of coronaryarteriograms was p~rfommedwith a scmiautomatic computer system(18). For each vcssc!segment, two to three end-diastolicmeasurementsin different projections we:e carried out and averaged to correct for bio!ogic variations in coronar] artery dimensions (19,20). The computer system is based on a ?&mm film projector (Tagarno AIS, Horserti, Denmark), a slow scan charged coupled device camera (for image digitation) developed at the Institute for Biomedical Engineering in Zurich, and a computer workstation (Apollo DN 3000, Apollo Computer AG, W:‘s&n, Switzeriand) for image storage and processing.Co,*tour detection was carried out by using a geometric-densitometricedge detection algorithm (Z-24). The methodology for computerized analysisof coronary arteriograms has been described elsewhere (18). Briefly, a three-dimensional model of the vessel was constructed by matching center lines of the individual biplane tracings+By digitizing the angiogramswith a resolution of 1,024 by 1,368 pixels, a spatiai resolution of 0.1 mm in the heart can be obtained. The gray scalerange of 12 bits corresponds to the dynamic range of the X-ray film, allowing for a highly reproducible and accuratelumen identification even on low contrast images. Phantom measurements with a Plexiglas model showed excellent correlations between the true and the measured diameter (r = 0.99). The mean difference (= accuracy) amounted to 0.02 mm for both planes and the standard deviation of difference (= precision)was0.09 mm for plane A and 0.12 mm for plane B, respectively.Intraobserver and interobservervariability were small (SEE [biplane data] 0.072 mm” [2.1% of the mean vesselarea] and 0.14 mm’ [4.1% of the mean vesselarea] for intraobserverand interobservervariability) (lb). The proximal cross-sectionalarea of the three major coronary vessels(left anterior descending,left circumflexand right coronary artery) was measured in all patients. The ptoximal cross-sectionalarea of the left anterior descending and left circumflex arterieswas defined as the vesselsegment immcdiateiy beyond the bifurcation of the left main coronary artery
*p -< b.05,i-p < U.Ut~@I< UK>!vxs~~scontrorsubje&: $P < 0.01,lip< 0.001 versuspatients with tiypertrophir cariiorqoyail~y. Data presentedSC mean value i SD.EDV = errd-diastolicvohm~; EF = ejectionfraction; LMM = left ventriculx muscle mass:LVEDP = left ventrictllar end-diastolic pressure: LVMA = cross-sectional muscleareaat the tef vcntricula equator;L.VSP = i& vont&xler systolicpressarc;MPAP = mean pulmonaryartcry pressure.
over a length of -1 cm. The computer traced this segment automatically and calculated the mean area over this segment. The proximal cross-sectionalarea of the right coronary artery was defined as the vessel segment 1 to 2 cm distal to the coronary ostimn. A vesselsegment was analyzedover 2 length of 1 cm, and the mean cross-sectionalarea was calculated as for the left coronay artery. Calibration wa.sperformed automatically by usingthe proximal part of the SFJudkinscatheter as a scalingdevice (2&Z). As index of the enisrgement of the coronary arieries with respect to muscle mass, the crosssectionalarea of the left coronary artery (Ir.it anterior descending artery plus left circumflexartery) per 100 g of angiogtaphic masswas calculated. In patients with hypertrophic catdiomyapathy (and in all others) coronary artery dimensions were normalized to cross-sectionalmuscle area at the left ventricular equator. Statistical analysis. Hemodynamic and angiographic data were compared by a one-way analysisof variamze.When the analysiswas significant, the Tukey zest was applied. Linear regressionanalysiswas performed by using the least squares technique. Data are reported as mean value +- 1 SD. Resultits Hemadynemic, ciirical arnd angiographic data. Of the I3 patients with hypertrophic cardiomyopathy, 10 were classified preoperativelyin tinctional classII and 3 in classIII. Six of the 12 patients with dilated cardiomyopathy were in functional class11,4 in ciassIII and 2 in class IV. Hemodynamic and angiographic data in control subjectsand patients with primary hypertrophy are reported in Table I. Data from patients with secondary hypertrophy are not included because they have been reported previously (4). In patients with hypertrophic cardiomyopathy,the peak systolicpressuregradient was 33 I 25 mm Hg at rest, 107 ? 381mm Hg during postextrasystolic beats and 78 t 28 during the Valsalva mane.uver. Mitral regurgitation fraction as assessedby the angio-Fick method was 19 t 9%. Left ventricular ejection fraction was 75% and
29%, respectivc!y, in patients with hypertrophio or dilated cardiomyopathy (p < 0.001). Left ventricular end-diastolic pressurewassignificantlyhigher than con&o1valcesin paGents with hypertrophic cardiomyopathy, but not in those with dilated cardiomyopathy. Left ventricular muscle mass was increasedto 318 2 189 g in patients with dilated cardiom;yopathy and to 307 ? 72 g in those with aortic valve disease.Left ventricular mass was 125 t 29 g in control subjects(p < 0.01 vs. patients with dilated cardiomyopathy and those with aortic valve disease).Cross-sectionamusclearea was33.0 -C6.6 cm’ in patients with hypertrophic cardiomyopathy, 28.4 I 8.2 cm* in those with dilated cardiomyopathy, 29.8 rt 6.5 in those with aortic valvediseaseand 17.7 t- 6.3 cm2 in control wbju%s fall p < 0.001 vs. control subjects) Coronary artery dimensions. Coronary an&graphic data are summarized in Table 2. In patients with dilated and hypertrophic cardiomyopnthy~ the left and right coronary arteries w*:re larger than those in control subjects (Fig. 1). However, noimalized coronary cross-sectionaldrea per 100 g muscle mass (left anterior descending plus left circumflex coronary artery) was significantlylower (Fig 2) in patients with Figure 1. Cross-sectional areaof the left cnronav arteryin patients with @nary and secondaryhypertrophy. AI = pat&& v&h a&c insuticiency;AS = patientswith aorticstenosis;C = controlsubjects; DCM and HCM = patients with dilated and hy~ertro~hi~ cardiomyopathy, respectively; LCA = sm of the I& anterior descending and circumRes coronary arteries. Data for patients with aortk stenosis aud aortic insutkiency ax kern Villari et al. (4). *p c tI.05 versus controi subjects. secondary
c
UCM
HCM
AS
hypertrophy
Al
Figure 2. Plot of the left coronaryarteq dimensions(LCA, mm”) versus(top panel)left ventricularmusclemass(LMM) and (buttom panef) ieft ventricularequatorialmusclearea (LVMrt). There is en inappropriateincreasein icft coronaryarterydimensionsin patienfs with severeieft ventricukrhypWrophy;that is,a relativedccteilsein coronaryartery size wit37 an increase in mass. Abbreviations as in Figure 1. Data for patienls with aortic stenosis and aortic inadliciency are from Vi& et A
dilated cardiomyopathy (7.1 I 1.5 mm2/100g) and aortic valve diseaset7.9 f 2.1 mm*!100 g) than in control subjects(II.5 t 5.8 mm*/100 g, p < 0.05). Similarly, normalized coronary cross-sectiona!area/l cm’ cross-sectionalmuscle area was smaller in patients with hypertrophic cardiomyopathy (0.83 4 0.13 mm*/cm’, p < 0.05) than in control subjects (0.92 + 0.63 mm%m2). Correfations. A significant correlation was found bchveen left coronary artery size and left ventricular end-diastolic volume, kf ventricular muscle massand cross-seectitwai muscle area (Table 3, Fig. 3). However, left coronav afiev size was not correlated with ejection fraction. A correlation was aiso found between right coronary artery size and mean pnlmonaty artery pressure (Fig. 4) or left ventricular enddiastoiic volume but not vvithcross-sectiona:musk area.
In e~peri~en~i and clinical studies a direct rehtion between left ventricuiar muscle mass and coronary dimensions has been reported (6-&l&26-29), Blood ftow ,eiocity has been postulated as a regulatory mechanism. An increase in
Fable 3. Correlation Between Corcmq Acteq~ Dirrrensions and
Ilemnci,yt?anric Variables _I~^_I___ ._-. -
--.---~--
Lcfr Coronary Arteiy (0 =---35)
r CoeB --__ ii.075
Varia1blc l_l^ll___llWSP (mm 142) LVEDP jmn1Hgj MPM (mn, Hg) EF (%) LVEDV (in!) LMM (g) L?MA (d)
P Vaitrc ..-.- -111111 omi
(i.O:!
O.O!t7 0.07 5.42 0.012 0.0002 (n = 21)
ii.45
0.31 -0.14 5.42 0.72
c.75
_-1-_11--__-
Right Cor?mn!y Amy (11= 37) __-.____l_-r P vain: ’ Cock o.G-
0.i’) ci.?B -0.291
0.35 0.019 0.0s 0.524 5.037 5.117
0.371 0.44
0.0001(n = 26)
0.30
--
“Linear regressionanalysis.Coeff = coellicieni; other abbreviationsas in Table 1.
mean flow velocityhas hcen associatedwith a change in shear stress,which hasbeen shown to be a mediator for the release of the endothelium-derived relaxing factor, the putative nitric oxide. Endothelium-derived relaxing factor is a potent vasodi-
Figure
3.
Correlation between left coroilaq arteq cross-sectional area
(LCA) slndleft ventricularmusclemass(LMM) (ton panel)and left ventricularcross-sectional musclearea(LVMA) (bottompanel).The curvilinearrelation was better than the linear relation. Data for patientswithaorticstenosis arefromVillariet al. (4).Abbreviations as in Figure1. 40
linear
curvilinear
0.686
0.758
P eO.001
r
0 0
100
200
300
400
500
LMM (99
linear
0
10
20
30
40
so
LVMA (cm2) BC
0
A5
V DCM
A HCM
curvilinear
0.724
0.748
P
<0.001
r
--..1
T-----l-----I_TI_--?0 20
4
30
40
MPAP (mm tig)
5 AS V DCM b HCM mc Figure 4. Correlationbetweenright coronaryarterycress-sectional area (RCA) and mean pulmonaryartery pressure(MPAP).The curvilinearrelation was better than the linear relation. Data for patientswith aorticstencGsare from Villariet al.(4).Abbreviationsas in Figure1.
lator and is responsiblefor the regulatir?t of coronary artery size,during exercise,for example. In low and moderate grades of left ventricular hypertrophy an appropriate increase in coronary artery size has beer reported, whereas in severe left ventricular hypertrophy an inappropriate growth of the coronary arteries with a reduction in cross-sectional vessel area/l00 g muscie masshas been noted (4). Coronary artery dimensions in primary and secondary bypertrophy. In the present study, coronary artery dimensions in patients with primary hypertrophy were analyzed and compared with those in patients with secondaryhypertrophy due to aortic valve disease(Fig. 1). In both hypertrophic and dilated cardiomyopathy, we observed a large increase in coronary artery size that was independent of the cause and insufficient for the degree of left ventricular hypertrophy. There was a curvilinear relation between left coronary artery size and left ventricular hypertrophy (muscle mass and area, respectively) (Fig. 3); that is, the slope of this relation becomes asymptomatic with large masses and, thus, the ratio behveen crosssectional area and muscle mass decreases(Table 2). Thus, patients with primary and secondaryhypertrophy demonstrate an inadequate growth of the coronary artery with regard to the increasein left ventricular mass;that is, in severehypertrophy the coronary arteries are too small for the increase in left ventricular muscle mass. Pathophysiologicconsiderations. Although the sizeof the coronary arteries is not a limiting factor for myocatdial perfusion, functional adaptation by way of the release of endothelium-derived relaxing factor seemsto be inadequate in severe hypertrophy. An insufficient growth of the coronary arteries has been observed in severe left ventricular hypertrophy (5) and may explain the occurrenceof myocardial ischemia in high demand situations such as exercise. The exact mechanism of controlling the growth of the coronary arteries is co! understood but may involve several
factor” wh
as structural (vascular ren1odcljng)
md fi~nct~ollal
(e~dothe~al dys~~i~~tio~~) changes. For example, vasodilator response of the left ccwoaary artery co&i
be abnormal
in
patients wri1.hleft ventricular hypertrophy becausethe state of the artery at rest is ?nore dilated” than usual its a result oi increasedshear sl-ressdue to higher blood How; such changes would iead to enhanced releaseof endotllejium~derivedreiaxing factor, and, thus, to vascularsmooth made relaxation with increased medial circumference. Therefore, the release of endothelium-derived relaxing factor is chronically stimulated by the increase in left ventricular mass (30); thus, signal transduction mechanismsrelating left ventricular massto left coronary artery dimension are intact but perhaps maximally stimulated. In this regard, a reduced coronary vasodilator capacity has been reported after administration of sublingual nitroglycerin in patients with left ventricular pressureoverload hypertrophy due to aortic stenosis (31). In contrast, the increase in left ventricular mass may cause or be associated with a defect in the signal transduction mechanisms that relate blood flow to vesselcaliber. In this case: the defect in signal transduction mechanismswould inhibit the left coronary artery from responding appropriately to an increasein left ventricular mass. Although increased coronary blood flow has been postulated to be the major growth stimulus, enlargement of the coronary arteries may be related to other factors such as perfusion pressure, endothelium-derived relaxing factor (32.34), circulating neurohormones and local growth factors (34,35). As Lmg as coronary artery enlargement is “adequately” matched to left ventricular muscle mass, it allows mean flow velocityand shear stressto be kept normal despite the increase in absolute coronary blood 3ow (13,35,X). This mechanism depends largely on the capacity of the endothelium to sense shear stress and, thus, to release the endothelium-derived relaxing factor (38,39). However, an impaired coronary vasodilator response to intracoronary nitroglycerin has been reported in patients with dilated cardiomyopathy (40) and aortic valve disease(31). In agreement with previous reports from our group (4), different patterns of changes in coronary artery sizehave been observed for the right and left coronary artery. Whereas the left coronary artery seemsto follow changesin left ventricular mass, the right coronary artery does not. For instance, crosssectional area of the proximal right coronary artery was directly correlated with mean pulmonary artery pressure(Fig. 4), suggestingthat right coronary artery dimensions are it&renced by the extent of right ventricular pressureoverload and, hence, right ventricular muscle mass. Limitations of tIte study. Other determinants of coronary artery sizemust also be addressed,such as age, gender, body surfacearea and coronary basalvasomotor tone (I&41). In the present study, age, gender and body surface area were similar in patients with hypertrophic or dilated cardiomyopathy and control subjects. Heart rate was similar in all three groups, suggestingthat ‘“overall” autonomic nervous activity was sim-
Canchtsions, Coronay artery size is increased in patients with hypertrophic or dilater! ~~~rdicr~yo~~th~ to an extent skdar to that in pat&% with seconda? left ventricular ~~F3ertroFhy. The ~~nlarge~n~nt of the proximal left cSXra1y artery correlates directly with the increasein left v~~tr~~~~l~ musc!e mass, but coronary artery size remains in~~~ro~r~~t~e with reggardto the degreeof left ventricular hypertrophy. ‘Ihns: coronary arteries in patients with severeleft ventricular hypertrophy are relatively too small for the degree of hypertrophy and may contribute :o subendocardtalhypoperfusion in situations of high demand, causing angina pectoris, increased ventricular ectopic activity and sudden card& death. The main determinant of size seemsto be left ventricular hypertrophy for the left coronary artery and mean pulmonary artery pressure for the right coronary artery. Thus, the stimulus for growth of the coronary arteries seemsto be similar in primary and secondary left ventricular hypertrophy and probably is directly related to muscle massand flow.
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~ 1 1 1 - - - -
Buckground.Coronaryartery enlargementhas beenpreviously described::, left venbirular hyprtrophy. Obj&ves. We soughtto assesscoronaryarterydimeusionsand their relation to left sentricular muscle mass in primary 3rd secondaryhypertrophy. Methfs. Cross-sectionalarea of the left and right coronary arteries wasdetermined hy quantitative corouaryangiographyin 52 patients: 12 control subjectsand 10 patients (13 with hypertrophic cardiomyopathy,12 with dilated cardiomyopathyand 15 with aortic valve disease).As a measure of let%ventricular hypertrophy, angiographic left ventricular massand equatorial cross-sectionalmusclearea were determined. Res;r&s. Cross-sectionalarea of both the left and right coronary arteriesis increasedin left ventricular hypertrophy(a, < 0.05 vs. valuesin control subjects).There is a curviiinearrelation between .---ll_--_l_--
-
Enlargement of the coronary arteries has been reported in patients with left ventricular hypestrophyat necropsy(1.2) and in clinical studies (3-5). Increased dimensions of the left anterior descending and circumflex coronary arteries were found in patients with left ventricular hypertrophy secondary to aorric or mitral valve disease as well as in patients with hypertension (3-14). In severeleft ventricular hypertrophy the coronary arteries have Iimited ability to grow (3,s) and thus carry the riskof underperfusion during high demand situations suchas physicalexercise.However, the regulatory mechanisms are largely unknown and may be different in primary and secondary as well as eccentric and concentric hypertrophy. Thus, the purpose of the present study wasto analyzecoronary artery sizein patients with dilated and hypertrophic cardiomyopathy, and to compare the results with previously reported data in patients with secondary:eft ventricularhypertrophy (4).
Patients. Twelve patients with atypical chest pain and normal coronary arteries served as control subjects(group 2, From the Department of Internal Medicine, University Hospital, Zurich, Switzerland. Manu&pt received October 31,199S; revised manuscript received April 22, 1996, accepted April 24. 1996. Address for currespond~g: Dr. Otto M. Hess, Department of Internal Medicine, University Hospit& Raemistrasse 100; CH-8091 Zurich, Switzerland. 0106 by the American College of Cardiology Published by Elsevier Science Inc.
left coronaryarteq sizeand left ventricular musclemass [r = 0.76) or cross-sectionalmusclearea fr = U.75) However?normatkation of coronarycross-sectional area for left ventricuiarmuscle massor musclearea showsinsufficientenlargementof the coronary arteries In both primary and secondau hypertrophy. Coucbdsions. I) Coronaryartery sizeincreasesas left ventric= ular massincreasesin both primary and secondaryhypertrophy. 2) The enlargementof left coronarycross-sectional area is independent of the causeof the increasein left ventricular mass.3) The sizeof the coronaryarteriesis inapprogriate with regard to left ventrientar $pertrophy. Thus, the stimulusfor growth of the coronaryarteries is not iuflnencedby the underlyingdiseasebut appearsto dependon the degreeof left ventricuiar hypertrophy,
--1__-.--
mean age 2 SD 52 c S years, nine men and three women). These patients had no valvular or coronary artery diseaseor left ventricular hypertrophy. The remaining 40 patients comprised 13 patients with hypertrophic cardiomyopathy (group 2, mean age 43 + 9 years,10 men and 3 women), 12 patients with dilated cardiomyopathy (group 3, mean age 52 t 9 years, 7 men and 5 women) and 15 patients with aortic valve disease (group 4, mean age 55 2 7 years, 12 men and 3 women). Functional classificationwas assessedaccording ta New York Heart Associationcriteria. Cardiac catheterization. patients underwent right and left heart catheterization for diagnostic purposes. Informed consent wasobtained from all patients, Premeditation consistedof chlordiazepoxide, 10 mg, administered orally 3 h before the psocedure. Vasoactive substanceswere withheld for 24 h before cathererization, Aortic pressurewas measured with an SF pigtail catheter introduced retrogradely from the right femoral artery and pulmonary artery pressure with a 7F Cournand catheter from the right femoral vein. After Ieft ventricular angiography,diagnosticcoronaryarteriography was carried out by the Judkins technique. A nonionic contrast material (iopamidoltrometamol; Lopamiro 370) MS used for quantitative coronary angiography to minimize h-yperemic reactions with transient changesin coronary blood flow (1.5). Cine film was used as a data carrier (filming rate 50 frames/s). Left ventricular voiume and ejection fraction were caiculated according to the area-length method (16). Left ventricu-
lar n~trscfemm wasdetermined with the formula of Kackleyet al. (17). III patients with hypertrophic cardiomyopathy and asymmetrichy~~rtropl~y,cross-sectionalmusciearea at the Ml ventricular equator {LVMA [cm’]) was used as a measure of left ventricular hypertrophy
wflerc h4 = left vcntricutar a~~gi~~~ra~hic short-&& diameter; a& 11= left ventricular angiographicwail thickilessmeasured ifi the right ,tnti&r oblique projection. I+( comparison purposts, this variable wasalso calculatedin all other patients. In patients with hypertrophic cardiomyopathy,~a!1 tl~i~kt~% (!I,.) was calculatedfrom the angiographic thicknessmultiplied by the echocardiographic septal/postcrior wall thickness ratio (s/p) to correct for asymmetricseptal hypertrophy: h, = [lx -i (h * s/p)@
~ua~~t~ta~~~e coronary arteriography. Quantitative evaluation of coronaryarteriograms was p~rfommedwith a scmiautomatic computer system(18). For each vcssc!segment, two to three end-diastolicmeasurementsin different projections we:e carried out and averaged to correct for bio!ogic variations in coronar] artery dimensions (19,20). The computer system is based on a ?&mm film projector (Tagarno AIS, Horserti, Denmark), a slow scan charged coupled device camera (for image digitation) developed at the Institute for Biomedical Engineering in Zurich, and a computer workstation (Apollo DN 3000, Apollo Computer AG, W:‘s&n, Switzeriand) for image storage and processing.Co,*tour detection was carried out by using a geometric-densitometricedge detection algorithm (Z-24). The methodology for computerized analysisof coronary arteriograms has been described elsewhere (18). Briefly, a three-dimensional model of the vessel was constructed by matching center lines of the individual biplane tracings+By digitizing the angiogramswith a resolution of 1,024 by 1,368 pixels, a spatiai resolution of 0.1 mm in the heart can be obtained. The gray scalerange of 12 bits corresponds to the dynamic range of the X-ray film, allowing for a highly reproducible and accuratelumen identification even on low contrast images. Phantom measurements with a Plexiglas model showed excellent correlations between the true and the measured diameter (r = 0.99). The mean difference (= accuracy) amounted to 0.02 mm for both planes and the standard deviation of difference (= precision)was0.09 mm for plane A and 0.12 mm for plane B, respectively.Intraobserver and interobservervariability were small (SEE [biplane data] 0.072 mm” [2.1% of the mean vesselarea] and 0.14 mm’ [4.1% of the mean vesselarea] for intraobserverand interobservervariability) (lb). The proximal cross-sectionalarea of the three major coronary vessels(left anterior descending,left circumflexand right coronary artery) was measured in all patients. The ptoximal cross-sectionalarea of the left anterior descending and left circumflex arterieswas defined as the vesselsegment immcdiateiy beyond the bifurcation of the left main coronary artery
*p -< b.05,i-p < U.Ut~@I< UK>!vxs~~scontrorsubje&: $P < 0.01,lip< 0.001 versuspatients with tiypertrophir cariiorqoyail~y. Data presentedSC mean value i SD.EDV = errd-diastolicvohm~; EF = ejectionfraction; LMM = left ventriculx muscle mass:LVEDP = left ventrictllar end-diastolic pressure: LVMA = cross-sectional muscleareaat the tef vcntricula equator;L.VSP = i& vont&xler systolicpressarc;MPAP = mean pulmonaryartcry pressure.
over a length of -1 cm. The computer traced this segment automatically and calculated the mean area over this segment. The proximal cross-sectionalarea of the right coronary artery was defined as the vessel segment 1 to 2 cm distal to the coronary ostimn. A vesselsegment was analyzedover 2 length of 1 cm, and the mean cross-sectionalarea was calculated as for the left coronay artery. Calibration wa.sperformed automatically by usingthe proximal part of the SFJudkinscatheter as a scalingdevice (2&Z). As index of the enisrgement of the coronary arieries with respect to muscle mass, the crosssectionalarea of the left coronary artery (Ir.it anterior descending artery plus left circumflexartery) per 100 g of angiogtaphic masswas calculated. In patients with hypertrophic catdiomyapathy (and in all others) coronary artery dimensions were normalized to cross-sectionalmuscle area at the left ventricular equator. Statistical analysis. Hemodynamic and angiographic data were compared by a one-way analysisof variamze.When the analysiswas significant, the Tukey zest was applied. Linear regressionanalysiswas performed by using the least squares technique. Data are reported as mean value +- 1 SD. Resultits Hemadynemic, ciirical arnd angiographic data. Of the I3 patients with hypertrophic cardiomyopathy, 10 were classified preoperativelyin tinctional classII and 3 in classIII. Six of the 12 patients with dilated cardiomyopathy were in functional class11,4 in ciassIII and 2 in class IV. Hemodynamic and angiographic data in control subjectsand patients with primary hypertrophy are reported in Table I. Data from patients with secondary hypertrophy are not included because they have been reported previously (4). In patients with hypertrophic cardiomyopathy,the peak systolicpressuregradient was 33 I 25 mm Hg at rest, 107 ? 381mm Hg during postextrasystolic beats and 78 t 28 during the Valsalva mane.uver. Mitral regurgitation fraction as assessedby the angio-Fick method was 19 t 9%. Left ventricular ejection fraction was 75% and
29%, respectivc!y, in patients with hypertrophio or dilated cardiomyopathy (p < 0.001). Left ventricular end-diastolic pressurewassignificantlyhigher than con&o1valcesin paGents with hypertrophic cardiomyopathy, but not in those with dilated cardiomyopathy. Left ventricular muscle mass was increasedto 318 2 189 g in patients with dilated cardiom;yopathy and to 307 ? 72 g in those with aortic valve disease.Left ventricular mass was 125 t 29 g in control subjects(p < 0.01 vs. patients with dilated cardiomyopathy and those with aortic valve disease).Cross-sectionamusclearea was33.0 -C6.6 cm’ in patients with hypertrophic cardiomyopathy, 28.4 I 8.2 cm* in those with dilated cardiomyopathy, 29.8 rt 6.5 in those with aortic valvediseaseand 17.7 t- 6.3 cm2 in control wbju%s fall p < 0.001 vs. control subjects) Coronary artery dimensions. Coronary an&graphic data are summarized in Table 2. In patients with dilated and hypertrophic cardiomyopnthy~ the left and right coronary arteries w*:re larger than those in control subjects (Fig. 1). However, noimalized coronary cross-sectionaldrea per 100 g muscle mass (left anterior descending plus left circumflex coronary artery) was significantlylower (Fig 2) in patients with Figure 1. Cross-sectional areaof the left cnronav arteryin patients with @nary and secondaryhypertrophy. AI = pat&& v&h a&c insuticiency;AS = patientswith aorticstenosis;C = controlsubjects; DCM and HCM = patients with dilated and hy~ertro~hi~ cardiomyopathy, respectively; LCA = sm of the I& anterior descending and circumRes coronary arteries. Data for patients with aortk stenosis aud aortic insutkiency ax kern Villari et al. (4). *p c tI.05 versus controi subjects. secondary
c
UCM
HCM
AS
hypertrophy
Al
Figure 2. Plot of the left coronaryarteq dimensions(LCA, mm”) versus(top panel)left ventricularmusclemass(LMM) and (buttom panef) ieft ventricularequatorialmusclearea (LVMrt). There is en inappropriateincreasein icft coronaryarterydimensionsin patienfs with severeieft ventricukrhypWrophy;that is,a relativedccteilsein coronaryartery size wit37 an increase in mass. Abbreviations as in Figure 1. Data for patienls with aortic stenosis and aortic inadliciency are from Vi& et A
dilated cardiomyopathy (7.1 I 1.5 mm2/100g) and aortic valve diseaset7.9 f 2.1 mm*!100 g) than in control subjects(II.5 t 5.8 mm*/100 g, p < 0.05). Similarly, normalized coronary cross-sectiona!area/l cm’ cross-sectionalmuscle area was smaller in patients with hypertrophic cardiomyopathy (0.83 4 0.13 mm*/cm’, p < 0.05) than in control subjects (0.92 + 0.63 mm%m2). Correfations. A significant correlation was found bchveen left coronary artery size and left ventricular end-diastolic volume, kf ventricular muscle massand cross-seectitwai muscle area (Table 3, Fig. 3). However, left coronav afiev size was not correlated with ejection fraction. A correlation was aiso found between right coronary artery size and mean pnlmonaty artery pressure (Fig. 4) or left ventricular enddiastoiic volume but not vvithcross-sectiona:musk area.
In e~peri~en~i and clinical studies a direct rehtion between left ventricuiar muscle mass and coronary dimensions has been reported (6-&l&26-29), Blood ftow ,eiocity has been postulated as a regulatory mechanism. An increase in
Fable 3. Correlation Between Corcmq Acteq~ Dirrrensions and
Ilemnci,yt?anric Variables _I~^_I___ ._-. -
--.---~--
Lcfr Coronary Arteiy (0 =---35)
r CoeB --__ ii.075
Varia1blc l_l^ll___llWSP (mm 142) LVEDP jmn1Hgj MPM (mn, Hg) EF (%) LVEDV (in!) LMM (g) L?MA (d)
P Vaitrc ..-.- -111111 omi
(i.O:!
O.O!t7 0.07 5.42 0.012 0.0002 (n = 21)
ii.45
0.31 -0.14 5.42 0.72
c.75
_-1-_11--__-
Right Cor?mn!y Amy (11= 37) __-.____l_-r P vain: ’ Cock o.G-
0.i’) ci.?B -0.291
0.35 0.019 0.0s 0.524 5.037 5.117
0.371 0.44
0.0001(n = 26)
0.30
--
“Linear regressionanalysis.Coeff = coellicieni; other abbreviationsas in Table 1.
mean flow velocityhas hcen associatedwith a change in shear stress,which hasbeen shown to be a mediator for the release of the endothelium-derived relaxing factor, the putative nitric oxide. Endothelium-derived relaxing factor is a potent vasodi-
Figure
3.
Correlation between left coroilaq arteq cross-sectional area
(LCA) slndleft ventricularmusclemass(LMM) (ton panel)and left ventricularcross-sectional musclearea(LVMA) (bottompanel).The curvilinearrelation was better than the linear relation. Data for patientswithaorticstenosis arefromVillariet al. (4).Abbreviations as in Figure1. 40
linear
curvilinear
0.686
0.758
P eO.001
r
0 0
100
200
300
400
500
LMM (99
linear
0
10
20
30
40
so
LVMA (cm2) BC
0
A5
V DCM
A HCM
curvilinear
0.724
0.748
P
<0.001
r
--..1
T-----l-----I_TI_--?0 20
4
30
40
MPAP (mm tig)
5 AS V DCM b HCM mc Figure 4. Correlationbetweenright coronaryarterycress-sectional area (RCA) and mean pulmonaryartery pressure(MPAP).The curvilinearrelation was better than the linear relation. Data for patientswith aorticstencGsare from Villariet al.(4).Abbreviationsas in Figure1.
lator and is responsiblefor the regulatir?t of coronary artery size,during exercise,for example. In low and moderate grades of left ventricular hypertrophy an appropriate increase in coronary artery size has beer reported, whereas in severe left ventricular hypertrophy an inappropriate growth of the coronary arteries with a reduction in cross-sectional vessel area/l00 g muscie masshas been noted (4). Coronary artery dimensions in primary and secondary bypertrophy. In the present study, coronary artery dimensions in patients with primary hypertrophy were analyzed and compared with those in patients with secondaryhypertrophy due to aortic valve disease(Fig. 1). In both hypertrophic and dilated cardiomyopathy, we observed a large increase in coronary artery size that was independent of the cause and insufficient for the degree of left ventricular hypertrophy. There was a curvilinear relation between left coronary artery size and left ventricular hypertrophy (muscle mass and area, respectively) (Fig. 3); that is, the slope of this relation becomes asymptomatic with large masses and, thus, the ratio behveen crosssectional area and muscle mass decreases(Table 2). Thus, patients with primary and secondaryhypertrophy demonstrate an inadequate growth of the coronary artery with regard to the increasein left ventricular mass;that is, in severehypertrophy the coronary arteries are too small for the increase in left ventricular muscle mass. Pathophysiologicconsiderations. Although the sizeof the coronary arteries is not a limiting factor for myocatdial perfusion, functional adaptation by way of the release of endothelium-derived relaxing factor seemsto be inadequate in severe hypertrophy. An insufficient growth of the coronary arteries has been observed in severe left ventricular hypertrophy (5) and may explain the occurrenceof myocardial ischemia in high demand situations such as exercise. The exact mechanism of controlling the growth of the coronary arteries is co! understood but may involve several
factor” wh
as structural (vascular ren1odcljng)
md fi~nct~ollal
(e~dothe~al dys~~i~~tio~~) changes. For example, vasodilator response of the left ccwoaary artery co&i
be abnormal
in
patients wri1.hleft ventricular hypertrophy becausethe state of the artery at rest is ?nore dilated” than usual its a result oi increasedshear sl-ressdue to higher blood How; such changes would iead to enhanced releaseof endotllejium~derivedreiaxing factor, and, thus, to vascularsmooth made relaxation with increased medial circumference. Therefore, the release of endothelium-derived relaxing factor is chronically stimulated by the increase in left ventricular mass (30); thus, signal transduction mechanismsrelating left ventricular massto left coronary artery dimension are intact but perhaps maximally stimulated. In this regard, a reduced coronary vasodilator capacity has been reported after administration of sublingual nitroglycerin in patients with left ventricular pressureoverload hypertrophy due to aortic stenosis (31). In contrast, the increase in left ventricular mass may cause or be associated with a defect in the signal transduction mechanisms that relate blood flow to vesselcaliber. In this case: the defect in signal transduction mechanismswould inhibit the left coronary artery from responding appropriately to an increasein left ventricular mass. Although increased coronary blood flow has been postulated to be the major growth stimulus, enlargement of the coronary arteries may be related to other factors such as perfusion pressure, endothelium-derived relaxing factor (32.34), circulating neurohormones and local growth factors (34,35). As Lmg as coronary artery enlargement is “adequately” matched to left ventricular muscle mass, it allows mean flow velocityand shear stressto be kept normal despite the increase in absolute coronary blood 3ow (13,35,X). This mechanism depends largely on the capacity of the endothelium to sense shear stress and, thus, to release the endothelium-derived relaxing factor (38,39). However, an impaired coronary vasodilator response to intracoronary nitroglycerin has been reported in patients with dilated cardiomyopathy (40) and aortic valve disease(31). In agreement with previous reports from our group (4), different patterns of changes in coronary artery sizehave been observed for the right and left coronary artery. Whereas the left coronary artery seemsto follow changesin left ventricular mass, the right coronary artery does not. For instance, crosssectional area of the proximal right coronary artery was directly correlated with mean pulmonary artery pressure(Fig. 4), suggestingthat right coronary artery dimensions are it&renced by the extent of right ventricular pressureoverload and, hence, right ventricular muscle mass. Limitations of tIte study. Other determinants of coronary artery sizemust also be addressed,such as age, gender, body surfacearea and coronary basalvasomotor tone (I&41). In the present study, age, gender and body surface area were similar in patients with hypertrophic or dilated cardiomyopathy and control subjects. Heart rate was similar in all three groups, suggestingthat ‘“overall” autonomic nervous activity was sim-
Canchtsions, Coronay artery size is increased in patients with hypertrophic or dilater! ~~~rdicr~yo~~th~ to an extent skdar to that in pat&% with seconda? left ventricular ~~F3ertroFhy. The ~~nlarge~n~nt of the proximal left cSXra1y artery correlates directly with the increasein left v~~tr~~~~l~ musc!e mass, but coronary artery size remains in~~~ro~r~~t~e with reggardto the degreeof left ventricular hypertrophy. ‘Ihns: coronary arteries in patients with severeleft ventricular hypertrophy are relatively too small for the degree of hypertrophy and may contribute :o subendocardtalhypoperfusion in situations of high demand, causing angina pectoris, increased ventricular ectopic activity and sudden card& death. The main determinant of size seemsto be left ventricular hypertrophy for the left coronary artery and mean pulmonary artery pressure for the right coronary artery. Thus, the stimulus for growth of the coronary arteries seemsto be similar in primary and secondary left ventricular hypertrophy and probably is directly related to muscle massand flow.
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