RNA-seq profiling reveals different pathways between remodeled vessels and myocardium in hypertrophic cardiomyopathy.

OBJECTIVE: Coronary microvascular dysfunction (CMD) is a key pathophysiological feature of hypertrophic cardiomyopathy (HCM), contributing to myocardial ischemia and representing a critical determinant of patients' adverse outcome. The molecular mechanisms underlying the morphological and functional changes of CMD are still unknown. Aim of this study was to obtain insights on the molecular pathways associated with microvessel remodeling in HCM. METHODS: Interventricular septum myectomies from patients with obstructive HCM (n = 20) and donors' hearts (CTRL, discarded for technical reasons, n = 7) were collected. Remodeled intramyocardial arterioles and cardiomyocytes were microdissected by laser capture and next-generation sequencing was used to delineate the transcriptome profile. RESULTS: We identified 720 exclusive differentially expressed genes (DEGs) in cardiomyocytes and 1315 exclusive DEGs in remodeled arterioles of HCM. Performing gene ontology and pathway enrichment analyses, we identified selectively altered pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls. CONCLUSIONS: We demonstrate the existence of distinctive pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls at the transcriptome level.

Clinical characteristics and prognosis of patients with microvascular angina: an international and prospective cohort study by the Coronary Vasomotor Disorders International Study (COVADIS) Group.

AIMS: To provide multi-national, multi-ethnic data on the clinical characteristics and prognosis of patients with microvascular angina (MVA). METHODS AND RESULTS: The Coronary Vasomotor Disorders International Study Group proposed the diagnostic criteria for MVA. We prospectively evaluated the clinical characteristics of patients according to these criteria and their prognosis. The primary endpoint was the composite of major cardiovascular events (MACE), verified by institutional investigators, which included cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure or unstable angina. During the period from 1 July 2015 to 31 December 2018, 686 patients with MVA were registered from 14 institutes in 7 countries from 4 continents. Among them, 64% were female and the main ethnic groups were Caucasians (61%) and Asians (29%). During follow-up of a median of 398 days (IQR 365-744), 78 MACE occurred (6.4% in men vs. 8.6% in women, P = 0.19). Multivariable Cox proportional hazard analysis disclosed that hypertension and previous history of coronary artery disease (CAD), including acute coronary syndrome and stable angina pectoris, were independent predictors of MACE. There was no sex or ethnic difference in prognosis, although women had lower Seattle Angina Questionnaire scores than men (P < 0.05). CONCLUSIONS: This first international study provides novel evidence that MVA is an important health problem regardless of sex or ethnicity that a diagnosis of MVA portends a substantial risk for MACE associated with hypertension and previous history of CAD, and that women have a lower quality of life than men despite the comparable prognosis.

Microvascular dysfunction in infiltrative cardiomyopathies.

Infiltrative heart diseases are characterized by myocardial tissue alterations leading to mechanical dysfunction which in turn develops into bi-ventricular congestive heart failure. Also the coronary microvasculature undergoes significant remodeling and dysfunction. The effects of the unbalance of the mechanical cross-talk between cardiac muscle and vessels and of the impairment of vasodilatory function can be measured non-invasively by means of positron emission tomography and cardiac magnetic resonance.

Integrated Noninvasive Physiological Assessment of Coronary Circulatory Function and Impact on Cardiovascular Mortality in Patients With Stable Coronary Artery Disease.

BACKGROUND: It is suggested that the integration of maximal myocardial blood flow (MBF) and coronary flow reserve (CFR), termed coronary flow capacity, allows for comprehensive evaluation of patients with known or suspected stable coronary artery disease. Because management decisions are predicated on clinical risk, we sought to determine the independent and integrated value of maximal MBF and CFR for predicting cardiovascular death. METHODS: MBF and CFR were quantified in 4029 consecutive patients (median age 66 years, 50.5% women) referred for rest/stress myocardial perfusion positron emission tomography scans from January 2006 to December 2013. The primary outcome was cardiovascular mortality. Maximal MBF <1.8 mL·g-1·min-1 and CFR<2 were considered impaired. Four patient groups were identified based on the concordant or discordant impairment of maximal MBF or CFR. Association of maximal MBF and CFR with cardiovascular death was assessed using Cox and Poisson regression analyses. RESULTS: A total of 392 (9.7%) cardiovascular deaths occurred over a median follow-up of 5.6 years. CFR was a stronger predictor of cardiovascular mortality than maximal MBF beyond traditional cardiovascular risk factors, left ventricular ejection fraction, myocardial scar and ischemia, rate-pressure product, type of radiotracer or stress agent used, and revascularization after scan (adjusted hazard ratio, 1.79; 95% confidence interval [CI], 1.38-2.31; P<0.001 per unit decrease in CFR after adjustment for maximal MBF and clinical covariates; and adjusted hazard ratio, 1.03; 95% CI, 0.84-1.27; P=0.8 per unit decrease in maximal MBF after adjustment for CFR and clinical covariates). In univariable analyses, patients with concordant impairment of CFR and maximal MBF had high cardiovascular mortality of 3.3% (95% CI, 2.9-3.7) per year. Patients with impaired CFR but preserved maximal MBF had an intermediate cardiovascular mortality of 1.7% (95% CI, 1.3-2.1) per year. These patients were predominantly women (70%). Patients with preserved CFR but impaired maximal MBF had low cardiovascular mortality of 0.9% (95% CI, 0.6-1.6) per year. Patients with concordantly preserved CFR and maximal MBF had the lowest cardiovascular mortality of 0.4% (95 CI, 0.3-0.6) per year. In multivariable analysis, the cardiovascular mortality risk gradient across the 4 concordant or discordant categories was independently driven by impaired CFR irrespective of impairment in maximal MBF. CONCLUSIONS: CFR is a stronger predictor of cardiovascular mortality than maximal MBF. Concordant and discordant categories based on integrating CFR and maximal MBF identify unique prognostic phenotypes of patients with known or suspected coronary artery disease.

From Left Ventricular Hypertrophy to Dysfunction and Failure.

Left ventricular hypertrophy (LVH) is growth in left ventricular mass caused by increased cardiomyocyte size. LVH can be a physiological adaptation to strenuous physical exercise, as in athletes, or it can be a pathological condition, which is either genetic or secondary to LV overload. Physiological LVH is usually benign and regresses upon reduction/cessation of physical activity. Pathological LVH is a compensatory phenomenon, which eventually may become maladaptive and evolve towards progressive LV dysfunction and heart failure (HF). Both interstitial and replacement fibrosis play a major role in the progressive decompensation of the hypertrophied LV. Coronary microvascular dysfunction (CMD) and myocardial ischemia, which have been demonstrated in most forms of pathological LVH, have an important pathogenetic role in the formation of replacement fibrosis and both contribute to the evolution towards LV dysfunction and HF. Noninvasive imaging allows detection of myocardial fibrosis and CMD, thus providing unique information for the stratification of patients with LVH. (Circ J 2016; 80: 555-564).

Effects of sex on coronary microvascular dysfunction and cardiac outcomes.

BACKGROUND: Coronary microvascular dysfunction (CMD) is a prevalent and prognostically important finding in patients with symptoms suggestive of coronary artery disease. The relative extent to which CMD affects both sexes is largely unknown. METHODS AND RESULTS: We investigated 405 men and 813 women who were referred for evaluation of suspected coronary artery disease with no previous history of coronary artery disease and no visual evidence of coronary artery disease on rest/stress positron emission tomography myocardial perfusion imaging. Coronary flow reserve was quantified, and coronary flow reserve <2.0 was used to define the presence of CMD. Major adverse cardiac events, including cardiac death, nonfatal myocardial infarction, late revascularization, and hospitalization for heart failure, were assessed in a blinded fashion over a median follow-up of 1.3 years (interquartile range, 0.5-2.3 years). CMD was highly prevalent both in men and women (51% and 54%, respectively; Fisher exact test =0.39; equivalence P=0.0002). Regardless of sex, coronary flow reserve was a powerful incremental predictor of major adverse cardiac events (hazard ratio, 0.80 [95% confidence interval, 0.75-086] per 10% increase in coronary flow reserve; P<0.0001) and resulted in favorable net reclassification improvement (0.280 [95% confidence interval, 0.049-0.512]), after adjustment for clinical risk and ventricular function. In a subgroup (n=404; 307 women/97 men) without evidence of coronary artery calcification on gated computed tomography imaging, CMD was common in both sexes, despite normal stress perfusion imaging and no coronary artery calcification (44% of men versus 48% of women; Fisher exact test P=0.56; equivalence P=0.041). CONCLUSIONS: CMD is highly prevalent among at-risk individuals and is associated with adverse outcomes regardless of sex. The high prevalence of CMD in both sexes suggests that it may be a useful target for future therapeutic interventions.

Determinants of outcome in patients with chronic ischemic left ventricular dysfunction undergone percutaneous coronary interventions.

BACKGROUND: Percutaneous coronary interventions (PCI) in patients with ischemic systolic left ventricular dysfunction (SLVD) are routinely performed although their impact on prognosis remains unclear. METHODS: We retrospectively evaluated 385 consecutive patients (76 % male, 66 ± 9 years) with SLVD (left ventricular ejection fraction [LVEF] ≤40 %) due to chronic coronary artery disease, who underwent PCI between 1999 and 2009, and explored clinical factors associated with higher risk of death or of a composite of death and hospitalization for acute decompensated heart failure (ADHF). RESULTS: The median follow-up was 28 months (inter-quartile range 14-46 months). Death and the composite outcome of death and hospitalization for ADHF occurred in 80 (21 %) and 109 (28 %) patients respectively (8.4 and 11.5 per 100 patient-years of follow-up). Insulin-dependent diabetes mellitus (IDDM), multivessel disease, LVEF < 35 %, symptoms of heart failure (HF) emerged both as independent predictors of death (adjusted hazard ratios [HR] 2.64; 1.92, 1.88 and 1.67 respectively) and composite outcome of death and hospitalization for ADHF (adjusted HR 2.22, 1.92, 1.79 and 1.94 respectively). Furthermore advanced age (HR = 1.03) emerged as independent predictors of death and having performed a stress test before PCI correlated with reduced number of deaths and ADHF hospitalizations (HR = 0.60). Of note, PCI significantly reduced the symptom of angina from 63.2 % at baseline to 16.3 % at the last follow up (p < 0.0001). CONCLUSIONS: IDDM, symptoms of HF, multivessel disease and LVEF < 35 % appear to be associated with worse outcome patients with ischemic SLVD undergoing PCI, and may be taken into account for optimal risk stratification. On the other hand, performing a stress testing before PCI seems to be associated with a more favorable outcome.

Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy.

BACKGROUND: Relevant preclinical models are necessary for further mechanistic and translational studies of c-kit+ cardiac stem cells (CSCs). The present study was undertaken to determine whether intracoronary CSCs are beneficial in a porcine model of chronic ischemic cardiomyopathy. METHODS AND RESULTS: Pigs underwent a 90-minute coronary occlusion followed by reperfusion. Three months later, autologous CSCs (n=11) or vehicle (n=10) were infused into the infarct-related artery. At this time, all indices of left ventricular (LV) function were similar in control and CSC-treated pigs, indicating that the damage inflicted by the infarct in the 2 groups was similar; 1 month later, however, CSC-treated pigs exhibited significantly greater LV ejection fraction (echocardiography) (51.7±2.0% versus 42.9±2.3%, P<0.01), systolic thickening fraction in the infarcted LV wall, and maximum LV dP/dt, as well as lower LV end-diastolic pressure. Confocal microscopy showed clusters of small α-sarcomeric actin-positive cells expressing Ki67 in the scar of treated pigs, consistent with cardiac regeneration. The origin of these cycling myocytes from the injected cells was confirmed in 4 pigs that received enhanced green fluorescent protein -labeled CSCs, which were positive for the cardiac markers troponin I, troponin T, myosin heavy chain, and connexin-43. Some engrafted CSCs also formed vascular structures and expressed α-smooth muscle actin. CONCLUSIONS: Intracoronary infusion of autologous CSCs improves regional and global LV function and promotes cardiac and vascular regeneration in pigs with old myocardial infarction (scar). The results mimic those recently reported in humans (Stem Cell Infusion in Patients with Ischemic CardiOmyopathy [SCIPIO] trial) and establish this porcine model of ischemic cardiomyopathy as a useful and clinically relevant model for studying CSCs.

Non-invasive anatomic and functional imaging of vascular inflammation and unstable plaque.

Over the last several decades, basic cardiovascular research has significantly enhanced our understanding of pathobiological processes leading to formation, progression, and complications of atherosclerotic plaques. By harnessing these advances in cardiovascular biology, imaging has advanced beyond its traditional anatomical domains to a tool that permits probing of particular molecular structures to image cellular behaviour and metabolic pathways involved in atherosclerosis. From the nascent atherosclerotic plaque to the death of inflammatory cells, several potential molecular and micro-anatomical targets for imaging with particular selective imaging probes and with a variety of imaging modalities have emerged from preclinical and animal investigations. Yet, substantive barriers stand between experimental use and wide clinical application of these novel imaging strategies. Each of the imaging modalities described herein faces hurdles-for example, sensitivity, resolution, radiation exposure, reproducibility, availability, standardization, or costs. This review summarizes the published literature reporting on functional imaging of vascular inflammation in atherosclerotic plaques emphasizing those techniques that have the greatest and/or most immediate potential for broad application in clinical practice. The prospective evaluation of these techniques and standardization of protocols by multinational networks could serve to determine their added value in clinical practice and guide their development and deployment.

Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/computed tomography.

AIMS: We sought to determine whether intraplaque inflammation could be measured with positron emission tomography/computed tomography angiography (PET/CTA) using (11)C-PK11195, a selective ligand of the translocator protein (18 kDa) (TSPO) which is highly expressed by activated macrophages. METHODS AND RESULTS: Patients (n = 32; mean age 70 ± 9 years) with carotid stenoses (n = 36; 9 symptomatic and 27 asymptomatic) underwent (11)C-PK11195 PET/CTA imaging. (11)C-PK11195 uptake into carotid plaques was measured using target-to-background ratios (TBR). On CTA images, plaque composition was assessed by measuring CT attenuation of the carotid plaque. Eight patients underwent carotid endarterectomy and ultrathin contiguous sections were processed for TSPO and CD68 (using immunohistochemical staining, (3)H-PK11195 autoradiography, and confocal fluorescence microscopy). Carotid plaques associated with ipsilateral symptoms (stroke or transient ischaemic attack) had higher TBR (1.06 ± 0.20 vs. 0.86 ± 0.11, P = 0.001) and lower CT attenuation [(median, inter-quartile range) 37, 24-40 vs. 71, 56-125 HU, P = 0.01] than those without. On immunohistochemistry and confocal fluorescence microscopy, CD68 and PBR co-localized with (3)H-PK11195 uptake at autoradiography. There was a significant correlation between (11)C-PK11195 TBR and autoradiographic percentage-specific binding (r = 0.77, P = 0.025). Both TBR and CT plaque attenuation had high negative predictive values (91 and 92%, respectively) for detecting symptomatic patients. However, the best positive predictive value (100%) was achieved when TBR and CT attenuation were combined. CONCLUSION: Imaging intraplaque inflammation in vivo with (11)C-PK11195 PET/CTA is feasible and can distinguish between recently symptomatic and asymptomatic plaques. Patients with a recent ischaemic event had ipsilateral plaques with lower CT attenuation and increased (11)C-PK11195 uptake.

The coronary circulation and blood flow in left ventricular hypertrophy.

Two distinct types of left ventricular hypertrophy (LVH) have been described: the so called "physiologic" hypertrophy, which is normally found in professional athletes, and "pathologic" LVH which is found in patients with inherited heart muscle disease such as hypertrophic cardiomyopathy (HCM) or patients with cardiac and systemic diseases characterized by pressure or volume overload. Patients with pathologic LVH have often symptoms and signs suggestive of myocardial ischemia despite normal coronary angiograms. Under these circumstances ischemia is due to coronary microvascular dysfunction (CMD). The abnormalities of the coronary microcirculation may be unrelated to the degree of LVH and cause a reduction in maximum myocardial blood flow which, in the absence of epicardial stenoses, is suggestive of CMD. There is no technique that enables direct visualization of coronary microcirculation in vivo in humans. Therefore, its assessment relies on the measurement of parameters which reflect its functional status, such as myocardial blood flow and coronary flow reserve which is an integrated measure of flow through both the large epicardial coronary arteries and the microcirculation. In this review article we discuss the pathophysiological mechanisms responsible for CMD in patients with primary and secondary LVH and how the recognition of this phenomenon is providing new important information on patient stratification and prognosis. Finally, we discuss how assessment of CMD may be used as a valuable surrogate marker to test the efficacy of old and new drugs. This article is part of a Special Issue entitled "Coronary Blood Flow".

Prognostic association of plasma NT-proBNP levels in patients with microvascular angina -A report from the international cohort study by COVADIS.

BackgroudThe aim of this study was to assess the prognostic association of plasma levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) with clinical outcomes of patients with microvascular angina (MVA). Methods: In this international prospective cohort study of MVA by the Coronary Vasomotor Disorders International Study (COVADIS) group, we examined the association between plasma NT-proBNP levels and the incidence of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure or unstable angina. Results: We examined a total of 226 MVA patients (M/F 66/160, 61.9 ± 10.2 [SD] yrs.) with both plasma NT-proBNP levels and echocardiography data available at the time of enrolment. The median level of NT-proBNP level was 94 pg/ml, while mean left ventricular ejection fraction was 69.2 ± 10.9 % and E/e' 10.7 ± 5.2. During follow-up period of a median of 365 days (IQR 365-482), 29 MACEs occurred. Receiver-operating characteristics curve analysis identified plasma NT-proBNP level of 78 pg/ml as the optimal cut-off value. Multivariable logistic regression analysis revealed that plasma NT-proBNP level ≥ 78 pg/ml significantly correlated with the incidence of MACE (odds ratio (OR) [95 % confidence interval (CI)] 3.11[1.14-8.49], P = 0.001). Accordingly, Kaplan-Meier survival analysis showed a significantly worse prognosis in the group with NT-proBNP ≥ 78 (log-rank test, P < 0.03). Finally, a significant positive correlation was observed between plasma NT-proBNP levels and E/e' (R = 0.445, P < 0.0001). Conclusions: These results indicate that plasma NT-proBNP levels may represent a novel prognostic biomarker for MVA patients.

Myosins and MyomiR Network in Patients with Obstructive Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. The molecular mechanisms determining HCM phenotypes are incompletely understood. Myocardial biopsies were obtained from a group of patients with obstructive HCM (n = 23) selected for surgical myectomy and from 9 unused donor hearts (controls). A subset of tissue-abundant myectomy samples from HCM (n = 10) and controls (n = 6) was submitted to laser-capture microdissection to isolate cardiomyocytes. We investigated the relationship among clinical phenotype, cardiac myosin proteins (MyHC6, MyHC7, and MyHC7b) measured by optimized label-free mass spectrometry, the relative genes (MYH7, MYH7B and MYLC2), and the MyomiR network (myosin-encoded microRNA (miRs) and long-noncoding RNAs (Mhrt)) measured using RNA sequencing and RT-qPCR. MyHC6 was lower in HCM vs. controls, whilst MyHC7, MyHC7b, and MyLC2 were comparable. MYH7, MYH7B, and MYLC2 were higher in HCM whilst MYH6, miR-208a, miR-208b, miR-499 were comparable in HCM and controls. These results are compatible with defective transcription by active genes in HCM. Mhrt and two miR-499-target genes, SOX6 and PTBP3, were upregulated in HCM. The presence of HCM-associated mutations correlated with PTBP3 in myectomies and with SOX6 in cardiomyocytes. Additionally, iPSC-derived cardiomyocytes, transiently transfected with either miR-208a or miR-499, demonstrated a time-dependent relationship between MyomiRs and myosin genes. The transfection end-stage pattern was at least in part similar to findings in HCM myectomies. These data support uncoupling between myosin protein/genes and a modulatory role for the myosin/MyomiR network in the HCM myocardium, possibly contributing to phenotypic diversity and providing putative therapeutic targets.

Progenitor cells from the explanted heart generate immunocompatible myocardium within the transplanted donor heart.

RATIONALE: Chronic rejection, accelerated coronary atherosclerosis, myocardial infarction, and ischemic heart failure determine the unfavorable evolution of the transplanted heart in humans. OBJECTIVE: Here we tested whether the pathological manifestations of the transplanted heart can be corrected partly by a strategy that implements the use of cardiac progenitor cells from the recipient to repopulate the donor heart with immunocompatible cardiomyocytes and coronary vessels. METHODS AND RESULTS: A large number of cardiomyocytes and coronary vessels were created in a rather short period of time from the delivery, engraftment, and differentiation of cardiac progenitor cells from the recipient. A proportion of newly formed cardiomyocytes acquired adult characteristics and was integrated structurally and functionally within the transplant. Similarly, the regenerated arteries, arterioles, and capillaries were operative and contributed to the oxygenation of the chimeric myocardium. Attenuation in the extent of acute damage by repopulating cardiomyocytes and vessels decreased significantly the magnitude of myocardial scarring preserving partly the integrity of the donor heart. CONCLUSIONS: Our data suggest that tissue regeneration by differentiation of recipient cardiac progenitor cells restored a significant portion of the rejected donor myocardium. Ultimately, immunosuppressive therapy may be only partially required improving quality of life and lifespan of patients with cardiac transplantation.

Is there evidence supporting coronary revascularization in patients with left ventricular systolic dysfunction?

The mid- and long-term outcomes of revascularization procedures in patients with chronic left ventricular (LV) systolic dysfunction due to coronary artery disease (CAD) in the presence or absence of heart failure (HF) symptoms are still uncertain. The identification of dysfunctional myocardial segments with residual viability that can improve after revascularization is pivotal for further patient management. Hibernating myocardium (ie, chronically dysfunctional but still viable tissue) can be identified by positron emission tomography (PET) and cardiac magnetic resonance (CMR) and its presence and extent can predict functional recovery after revascularization. Before ß-blockers were introduced as routine care for HF, surgical revascularization appeared to improve survival in these patients. Nowadays, novel medical treatments and devices, such as cardiac-resynchronization therapy and implantable cardioverter-defibrillators, have improved the prognosis of HF patients and their use is supported by a number of clinical trials. To adequately address the unresolved issue of the prognostic benefits of coronary revascularization in CAD patients with chronic LV dysfunction on optimal medical therapy with/without devices a randomized trial is warranted. In such a trial the presence of viability will be assessed by either PET or CMR. This is an overview of the pathophysiological mechanisms, as well as of the main clinical studies and meta-analyses that have addressed this issue in the past 4 decades.

Assessment of myocardial ischaemia and viability: role of positron emission tomography.

In developed countries, coronary artery disease (CAD) continues to be a major cause of death and disability. Over the past two decades, positron emission tomography (PET) imaging has become more widely accessible for the management of ischemic heart disease. Positron emission tomography has also emerged as an important alternative perfusion imaging modality in the context of recent shortages of molybdenum-99/technetium-99m ((99m)Tc). The clinical application of PET in ischaemic heart disease falls into two main categories: first, it is a well-established modality for evaluation of myocardial blood flow (MBF); second, it enables assessment of myocardial metabolism and viability in patients with ischaemic left ventricular dysfunction. The combined study of MBF and metabolism by PET has led to a better understanding of the pathophysiology of ischaemic heart disease. While there are potential future applications of PET for plaque and molecular imaging, as well as some clinical use in inflammatory conditions, this article provides an overview of the physical and biological principles behind PET imaging and its main clinical applications in cardiology, namely the assessment of MBF and metabolism.

Myocardial beta-adrenoceptor down-regulation early after infarction is associated with long-term incidence of congestive heart failure.

AIMS: Adverse left ventricular (LV) remodelling after myocardial infarction (MI) frequently leads to congestive heart failure (CHF). We have previously shown that myocardial beta-adrenoceptor density (beta-ARD) is reduced soon after acute MI and correlates with LV dilatation in the short term. The aim of the present study was to determine whether myocardial beta-ARD measured early after MI was associated with progression to CHF in the long term. METHODS AND RESULTS: We prospectively included 61 consecutive patients (mean age, 52 +/- 11 years, 10 female) in whom MI was the first manifestation of coronary artery disease. Two to 4 weeks after MI, patients underwent positron emission tomography with S-[(11)C]CGP 12177 to measure beta-ARD and (15)O-labelled water to measure myocardial blood flow and coronary flow reserve. Patients were followed-up for a median of 12.7 years (interquartile range, 6.5-13.7 years) and incidence of CHF was recorded. Eleven patients (18%) developed CHF during follow-up. They had lower beta-ARD compared with those who did not (5.35 vs. 6.49 pmol/g, P < 0.001). In patients with myocardial beta-ARD < or =5.57 pmol/g, 10-year CHF incidence rates were higher than in patients with beta-ARD >5.57 pmol/g (57% vs. 9%, P < 0.001). In a Cox regression model, only whole-heart beta-ARD [hazard ratio (HR) 0.29; 95% confidence interval (CI), 0.15-0.58, P < 0.001] and beta-ARD in remote myocardium (HR 0.32; 95% CI, 0.16-0.61, P = 0.001) were significantly associated with the incidence of CHF at follow-up. CONCLUSION: Reduced myocardial beta-ARD early after MI is associated with the incidence of CHF on long-term follow-up.