Background Microvascular dysfunction, reflected by an inadequateincrease in myocardial blood flow in response to dipyridamoleinfusion, is a recognized feature of hypertrophic cardiomyopathy.Its long-term effect on the prognosis is unknown. We prospectivelyevaluated a cohort of patients with hypertrophic cardiomyopathyafter they had undergone quantitative assessment of myocardialblood flow by positron-emission tomography (PET).
Methods Fifty-one patients (New York Heart Association classI or II) were followed for a mean (±SD) of 8.1±2.1years after PET. Twelve subjects with atypical chest pain servedas controls. Measurement of flow was performed at base lineand after the infusion of the coronary vasodilator dipyridamole,with the use of nitrogen-13–labeled ammonia. Patientswere then divided into three equal groups with increasing valuesof myocardial blood flow.
Results The response of myocardial blood flow to dipyridamolewas severely blunted in the patients, as compared with the controls(1.50±0.69 vs. 2.71±0.94 ml per minute per gramof tissue, P<0.001). Sixteen patients (31 percent) had anunfavorable outcome (death from cardiovascular causes, progressionto New York Heart Association class III or IV, or sustainedventricular arrhythmias requiring the implantation of a cardioverter–defibrillator)2.2 to 9.1 years after PET. Reduced blood flow in response todipyridamole was strongly associated with an unfavorable outcome.Multivariate analysis showed that among patients in the lowestof the three flow groups the age-adjusted relative hazard ofdeath from cardiovascular causes was 9.6 (P=0.02) and the relativehazard of an unfavorable outcome (a combined end point) was20.1 (P=0.003), as compared with patients in the two other flowgroups. Specifically, all four patients who died from heartfailure and three of five who died suddenly were in this subgroup.
Conclusions In patients with hypertrophic cardiomyopathy, thedegree of microvascular dysfunction is a strong, independentpredictor of clinical deterioration and death. Severe microvasculardysfunction is often present in patients with mild or no symptomsand may precede clinical deterioration by years.
Hypertrophic cardiomyopathy is a genetically determined diseasewith diverse clinical manifestations and pathophysiologicalsubstrates.1,2,3,4,5,6,7,8,9,10,11,12,13,14 Although severalfactors have been associated with an unfavorable outcome, theidentification of patients at risk for sudden death or progressionto heart failure remains a formidable challenge.8,9,10,11,14,15
An inadequate increase in myocardial blood flow after intravenousadministration of the vasodilator dipyridamole indicates microvasculardysfunction in the absence of coronary stenoses and is detectedon positron-emission tomography (PET) in the majority of patientswith hypertrophic cardiomyopathy.16,17,18,19 Microvascular dysfunction,in turn, represents a predisposing factor for myocardial ischemia,which is also a common feature of hypertrophic cardiomyopathy.3,7,20,21,22,23,24,25,26,27The effect of microvascular dysfunction on the prognosis, however,has not been investigated. The issue is of relevance, sinceboth microvascular dysfunction and myocardial ischemia may beamenable to treatment.28,29 Thus, we prospectively evaluatedthe relation between myocardial blood flow as assessed by PETand the long-term outcome in a cohort of patients with hypertrophiccardiomyopathy.
Methods
Study Population
Patients
The study cohort was part of a regional population of patientsclosely followed by a small number of physicians with expertiseand a long-standing interest in hypertrophic cardiomyopathyat hospitals in Florence and Pescia, Italy. The diagnosis ofhypertrophic cardiomyopathy was based on echocardiographic evidenceof myocardial hypertrophy (as defined by a left ventricularwall thickness of at least 15 mm) in the absence of any othercardiac or systemic cause of left ventricular hypertrophy.1All patients older than 18 years of age who were seen at thesetwo community-based hospitals from January 1989 to May 1990were asked to undergo PET. The only exclusion criterion wassevere congestive heart failure, as defined by a New York HeartAssociation (NYHA) functional class of III or IV.
Of 222 eligible patients, 51 (23 percent) agreed to participateand constituted the study group (Table 1). Their mean (±SD)age was 44±13 years. Of these 51 patients, 14 (27 percent)reported typical angina and were enrolled after the documentationof angiographically normal coronary arteries. The 171 eligiblepatients who did not participate were also followed up and didnot differ significantly with respect to base-line characteristicsand long-term survival free of cardiovascular events (P=0.21).
Table 1. Base-Line Characteristics of the Patients at the Time of Positron-Emission Tomography (PET), According to the Level of Myocardial Blood Flow (MBF) after Dipyridamole Infusion.
Control Subjects
The control group comprised 12 subjects who had a syndrome ofatypical chest pain (4 were men); their mean age was 51±8years (P=0.1 for the comparison with the patients). All hadnormal findings on physical examination, electrocardiography,echocardiography, treadmill exercise testing, and coronary andleft ventricular angiography.
Measurement of Myocardial Blood Flow
All PET scans were performed at the Institute of Clinical Physiologyin Pisa, Italy, between June 1990 and May 1993. To eliminateany effects of drug treatment on the assessment of microvascularfunction, all studies were performed after an appropriate periodof pharmacologic washout.16
Regional myocardial blood flow was measured with the use ofPET with nitrogen-13–labeled ammonia under basal conditionsand during near-maximal hyperemia induced by dipyridamole (0.56mg per kilogram of body weight administered intravenously overa period of four minutes), as described previously.16,28 Briefly,patients were positioned on the couch of a three-slice PET tomograph(ECAT3, CTI), and a five-minute rectilinear transmission scanwas recorded to facilitate positioning of the left ventriclewithin the field of view of the camera. Then, a 20-minute transmissionscan was obtained to correct the subsequent emission scans fortissue attenuation.
For each measurement of myocardial blood flow, a bolus of nitrogen-13–labeledammonia (0.25 mCi per kilogram) was injected intravenously overa period of 15 to 20 seconds and dynamic acquisition was startedsimultaneously.16 Myocardial blood flow was remeasured 50 minutesafter the basal scan had been obtained, according to the sameacquisition protocol, four minutes after the end of the dipyridamoleinfusion.
Absolute regional myocardial blood flow was calculated in millilitersper minute per gram of tissue as described previously.16 Theaverage flow value for the entire left ventricle was obtainedby drawing a region of interest that encompassed the entireleft ventricle on a transaxial PET slice. Coronary vasodilatorreserve was calculated as the ratio of myocardial blood flowafter dipyridamole infusion to basal myocardial blood flow.
The study protocol was approved by the research ethics committeeat each institution, and written informed consent was obtainedfrom each patient and control subject. The scans were obtainedand analyzed in a blinded manner by physicians with expertisein nuclear cardiology. The results of the scans were eventuallymade available to the patients' physicians, although no decisionregarding treatment was based on these results.
Follow-up Strategy
Patients were prospectively followed for an average of 8.1±2.1years (range, 2.2 to 11.1) after PET to assess the long-termprognostic value of studies of myocardial blood flow. Therewas no prespecified cutoff value for myocardial blood flow.The follow-up protocol and chosen end points were the same onesthat are used for the entire cohort of patients with hypertrophiccardiomyopathy who are followed at our institutions, as previouslydescribed.11,12,13,14,30 Patients were followed at yearly intervalsor more often if required, with clinical and echocardiographicexaminations, 12-lead electrocardiography, and 24- to 48-hourambulatory electrocardiography.12 In the case of an acute cardiacevent, the patient was admitted to one of the two institutions.Patients who had not been seen for one year were contacted bytelephone by a research nurse. Causes of death were determinedby autopsy whenever possible or by interviewing the patients'relatives and physicians.
At the time of the PET study and during follow-up, standardmedical treatment was used to control symptoms, left ventricularoutflow obstruction, supraventricular arrhythmias, or recurrentnonsustained ventricular tachycardia.12 Implantable cardioverter–defibrillatorshave been used at our facilities since 1992 for the preventionof sudden death in patients with hypertrophic cardiomyopathy.15
Echocardiographic Studies
All patients underwent base-line echocardiography at the timeof PET. Standard M-mode measurements were obtained in the parasternallong- and short-axis views.31 The peak instantaneous left ventricularoutflow tract gradient was estimated under basal conditionswith the use of continuous-wave Doppler echocardiography.32
Assessment of Outcome
Two end points were assessed. One was death from cardiovascularcauses, defined as death due to hypertrophic cardiomyopathy–relatedheart failure (occurring in the context of cardiac decompensationand a progressive course of disease, particularly one complicatedby pulmonary edema or progression to end-stage disease), suddenand unexpected death (including cardiac arrest with resuscitationafter cardiac arrest), and ischemic stroke.13 The second endpoint, defined as an unfavorable outcome, was a combined endpoint that included death from cardiovascular causes, progressionto severe functional limitation (NYHA class III or IV), andsustained, life-threatening ventricular arrhythmias requiringthe implantation of a cardioverter–defibrillator. Eventswere adjudicated by the two senior cardiologists who were directlyresponsible for the care of all study patients.
Statistical Analysis
Data are expressed as means ±SD. An unpaired Student'st-test or one-way analysis of variance was used for the comparisonof normally distributed data. Fisher's exact test was used tocompare noncontinuous variables expressed as proportions. Relativehazards and 95 percent confidence intervals were calculatedwith the use of univariate and multivariate Cox proportional-hazardsregression models.
For multivariate analyses of survival, patients were dividedinto three equal groups with increasing values of myocardialblood flow after dipyridamole infusion (cutoff values for thesegroups were 0.59 to 1.11, 1.13 to 1.57, and 1.62 to 3.77 mlper minute per gram). The relation of this ordinal variableto the outcome was assessed in an age-adjusted manner. Multivariateanalyses were performed with the use of a stepwise forward regressionmodel, with an entry probability for each variable set at 0.05.
Survival curves were constructed according to the Kaplan–Meiermethod. In the analysis of death from cardiovascular causes,other causes of death were censored. A receiver-operating-characteristiccurve was used to identify the optimal threshold value for myocardialblood flow after dipyridamole infusion.
All reported P values are two-sided; a P value of less than0.05 was considered to indicate statistical significance. Nointerim analyses were performed during follow-up.
Results
Myocardial Blood Flow
Under basal conditions, myocardial blood flow did not differsignificantly between patients and control subjects (0.84±0.31and 1.00±0.23 ml per minute per gram, respectively; P=0.10).By contrast, the response of myocardial blood flow to dipyridamoleinfusion was severely blunted in patients with hypertrophiccardiomyopathy, as compared with the control subjects (1.50±0.69and 2.71±0.94 ml per minute per gram, respectively; P<0.001)(Figure 1); among the patients, the extent of impairment wassimilar in the interventricular septum and the left ventricularfree wall (Table 1). The coronary vasodilator reserve was alsosmaller in the patients (1.8±0.7, as compared with 2.7±0.9in the controls; P<0.001). There was no significant differencein myocardial blood flow after dipyridamole infusion betweenpatients with angina and those without angina or between thosewith left ventricular outflow obstruction (peak outflow gradient,30 mm Hg or greater) and those without obstruction. No relationwas found between the maximal left ventricular thickness andmyocardial blood flow after dipyridamole infusion (R2=0.03,P=0.23).
Figure 1. Myocardial Blood Flow under Resting (Basal) Conditions and after Dipyridamole Infusion in the 12 Control Subjects, the 35 Patients with a Favorable Clinical Outcome, and the 16 Patients with an Unfavorable Outcome.
Values are the average of the entire left ventricle. Vertical bars indicate mean (±SD) values for each group.
Patients in the lowest of the three categories of myocardialblood flow after dipyridamole infusion (0.59 to 1.11 ml perminute per gram) were significantly more likely to be male,to have atrial fibrillation, and to have received medical treatment,and on average, they had larger end-systolic and end-diastolicdimensions and less fractional shortening than the patientsin the other two categories of blood flow, but the three groupshad otherwise similar base-line characteristics (Table 1). Specifically,the proportion of patients who were receiving pharmacologicagents with potential anti-ischemic properties — thatis, beta-blockers and calcium-channel blockers — was similarin each category of flow after dipyridamole infusion, both atthe time of PET and during follow-up (overall P value >0.1for all comparisons) (Table 1).
Clinical Course and Outcome
No patient was lost to follow-up, and the condition of 35 patients(69 percent) remained stable, in NYHA class I or II with a benignclinical course. By contrast, 16 patients (31 percent) had anunfavorable outcome: 9 died from cardiovascular causes (suddendeath in 5 and heart failure or stroke in 4), recurrent sustainedventricular tachycardia developed in 1 and required the implantationof a cardioverter–defibrillator, and 6 had progressionto NYHA functional class III or IV (including 1 patient in whomtypical restrictive end-stage features of hypertrophic cardiomyopathydeveloped) (Table 2). These end points occurred 2.2 to 9.1 yearsafter PET (average, 5.5±2.3).
Table 2. Outcome among the 51 Patients Overall and According to Myocardial Blood Flow (MBF) after Dipyridamole Infusion.
Relevance of Myocardial Blood Flow to Clinical Outcome
As compared with patients who had a benign clinical course,those with an unfavorable outcome had a more severely bluntedresponse of myocardial blood flow to dipyridamole infusion (Figure 1).An age-adjusted univariate survival analysis showed thatmyocardial blood flow values under basal conditions and afterdipyridamole infusion were inversely related to the risk ofdeath from any cause, death from cardiovascular causes, andan unfavorable outcome (Table 3); myocardial blood flow afterdipyridamole infusion showed the strongest association witheach end point.
Table 3. Results of Univariate Cox Regression Analyses of the Relation between Myocardial Blood Flow (MBF) Values and Clinical Outcome, Adjusted for Age.
Multivariate analysis showed that the myocardial blood flowafter dipyridamole infusion was the only independent predictorof death and the most potent predictor of an unfavorable outcome(Table 4). Specifically, patients in the group with the lowestmyocardial blood flow after dipyridamole infusion had a markedlyincreased likelihood of both death from cardiovascular causesand an unfavorable outcome (Figure 2). The relative risk associatedwith the lowest myocardial blood flow, as compared with thetwo higher categories, on age-adjusted multivariate analysiswas 9.6 with respect to death from cardiovascular causes (95percent confidence interval, 1.1 to 88.4; P=0.02) and 20.1 withrespect to an unfavorable outcome (95 percent confidence interval,2.4 to 167.8; P=0.003). All four patients who subsequently diedfrom heart failure or stroke and three of five who died suddenlywere in the lowest category (Table 2). Analysis of the receiver-operating-characteristiccurve identified a myocardial blood flow value of 1.1 ml perminute per gram or less after dipyridamole infusion as the bestthreshold for the identification of patients at risk for anunfavorable outcome.
Table 4. Results of the Multivariate Cox Regression Analyses Assessing the Relation between Base-Line Clinical Variables and Outcome, Adjusted for Age.
Figure 2. Myocardial Blood Flow (MBF) Values after Dipyridamole Infusion and Long-Term Prognosis.
Patients were divided into three equal groups according to MBF after dipyridamole infusion. Panel A shows overall cumulative suvival, and Panel B cumulative survival free from an unfavorable outcome.
Discussion
Our principal finding is that the severity of coronary microvasculardysfunction, assessed by PET, is an independent predictor oflong-term clinical deterioration and death from cardiovascularcauses in patients with hypertrophic cardiomyopathy. Microvasculardysfunction is a common feature of hypertrophic cardiomyopathy16,17,18,19,27,28,29and reflects the interplay of a variety of mechanisms, includingreduced arteriolar density, fibrosis, myocyte disarray, andelevated left ventricular end-diastolic pressure.3,4,5,24,25Moreover, structural abnormalities of small vessels have beendescribed in patients with hypertrophic cardiomyopathy and arethought to represent a primary abnormality.3 The failure ofmyocardial blood flow to increase adequately on demand in patientswith hypertrophic cardiomyopathy is clinically relevant in thatit predisposes them to myocardial ischemia, which in turn, hasbeen implicated in the pathogenesis of syncope, an abnormalblood-pressure response to exercise, left ventricular systolicdysfunction, and sudden death.1,7,20,21,22
In agreement with prior investigations,16,17,18,19,27,33 ourstudy showed that most patients with hypertrophic cardiomyopathyhad various degrees of impairment in myocardial blood flow inresponse to dipyridamole infusion. During an average follow-upof more than eight years, 31 percent of the patients died orhad a severe deterioration in their condition: both end pointswere significantly associated with a low value for myocardialblood flow after dipyridamole infusion. Age-adjusted multivariateanalysis showed that the myocardial blood flow after dipyridamoleinfusion was the most powerful independent predictor of theoutcome in our cohort. Patients in the group with the lowestmyocardial blood flow appeared to be at particularly high risk,with an independent increase in the risk of death from cardiovascularcauses that was almost 10 times as high as that in the othertwo groups. It was noteworthy that all four deaths from heartfailure and three of the five sudden deaths were in this subgroup.Such an adverse outcome could hardly have been predicted onthe basis of the base-line clinical characteristics of our patients,since none had severe symptoms at the time of PET and only afew would have been considered at high risk on the basis ofthe established indicators of outcome.1,2,8,9,10,11,14 Nevertheless,substantial microvascular dysfunction could already be demonstratedseveral years before clinical progression in most of the patientswho subsequently had a deterioration in their condition or died.It is worth emphasizing that no event occurred during the firsttwo years of follow-up and that the average time to an end pointexceeded five years.
Myocardial ischemia is difficult to evaluate in patients withhypertrophic cardiomyopathy, and its effect on the prognosishas often been surmised.1,24,25,26 Our demonstration of bluntedmyocardial blood flow after dipyridamole infusion is not itselfa proof of myocardial ischemia, unlike the documentation oflactate production in the coronary sinus or of typical electrocardiographicchanges.21,24 Nevertheless, dipyridamole infusion elicits electrocardiographicsigns of myocardial ischemia in patients with hypertrophic cardiomyopathy,which can be used to identify patients at increased risk forcardiac events.21 This finding suggests that the failure ofmyocardial blood flow to increase predisposes patients withhypertrophic cardiomyopathy to myocardial ischemia in the presenceof triggers that abruptly increase oxygen consumption22,29 andmay explain the ominous effects of atrial fibrillation withrapid ventricular response,30,31 as well as the frequent occurrenceof an abnormal response of blood pressure to exercise in thesepatients.22
Although drug treatment may have some beneficial effect on microvasculardysfunction28 and silent ischemia29 in patients with hypertrophiccardiomyopathy, we believe our results are largely independentof therapy. The proportion of patients who received pharmacologicagents with potential anti-ischemic properties — thatis, beta-blockers and calcium-channel blockers — did notdiffer significantly among the three groups with different levelsof myocardial blood flow after dipyridamole infusion. Furthermore,none of these pharmacologic agents are known to alter the progressionor outcome of hypertrophic cardiomyopathy.
The small size of our cohort is one reason to exercise cautionin extrapolating these results to the broad spectrum of hypertrophiccardiomyopathy. PET is a highly sophisticated technique withlimited availability, and its use in cardiology is virtuallyconfined to research purposes. Therefore, sample size has beena constant limitation of PET studies. Nevertheless, we wereable to obtain meaningful data through the use of a very extendedfollow-up and to provide a rationale for the clinical use ofPET in large populations of patients with hypertrophic cardiomyopathy.
Finally, our findings may have implications for patients withcardiomyopathy from other causes. Indeed, a smaller degree ofmicrovascular dysfunction has been documented in patients withleft ventricular hypertrophy due to pressure overload.33,34Furthermore, an impaired response of myocardial blood flow todipyridamole has been shown to be associated with a poor prognosisin patients with idiopathic dilated cardiomyopathy.35 Thus,our findings support the hypothesis that microvascular dysfunctionmay represent a common pathway leading to disease progressionin different cardiomyopathies,36 including conditions as prevalentas aortic stenosis and hypertensive heart disease.
Supported by a grant from the Italian Ministry for Scientificand Technologic Research (COFIN 2002).
We are indebted to Dr. Perry M. Elliot for his critical reviewof the manuscript and helpful suggestions and to Ms. DanielaVargiu, R.N., for valuable assistance.
Source Information
From the Regional Referral Center for Myocardial Diseases, Azienda Ospedaliera Careggi, Florence (F.C., I.O., R.G.); the Cardiology Unit, Ospedale di Lucca, Lucca (R.L.); the Cardiology Unit, Ospedale di Pescia, Pescia (G.C.); the Consiglio Nazionale delle Ricerche Institute of Clinical Physiology, Pisa (P.G.C.) — all in Italy; and the Medical Research Centre, Hammersmith Hospital, Imperial College, London (P.G.C.).
Address reprint requests to Dr. Cecchi at Via Jacopo Nardi 30, 50132 Florence, Italy, or at franco.cecchi{at}asf.toscana.it.
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