There is a preponderance of evidence that, in the setting of an acute coronary syndrome, an invasive approach using coronary revascularization has a morbidity and mortality benefit. However, recent stable ischemic heart disease (SIHD) randomized clinical trials testing whether the addition of coronary revascularization to guideline-directed medical therapy (GDMT) reduces death or major cardiovascular events have been negative. Based on the evidence from these trials, the primary role of GDMT as a front line medical management approach has been clearly defined in the recent SIHD clinical practice guideline; the role of prompt revascularization is less precisely defined. Based on data from observational studies, it has been hypothesized that there is a level of ischemia above which a revascularization strategy might result in benefit regarding cardiovascular events. However, eligibility for recent negative trials in SIHD has mandated at most minimal standards for ischemia. An ongoing randomized trial evaluating the effectiveness of randomization of patients to coronary angiography and revascularization as compared to no coronary angiography and GDMT in patients with moderate-severe ischemia will formally test this hypothesis. The current review will highlight the available evidence including a review of the published and ongoing SIHD trials.
Myocardial perfusion imaging; ischemia; coronary artery disease; clinical trials
The primary objective of this multicenter registry was to study the prognostic value of PET MPI and the improved classification of risk in a large cohort of patients with suspected or known coronary artery disease (CAD).
Limited prognostic data are available for myocardial perfusion imaging (MPI) with positron emission tomography (PET).
7,061 patients from 4 centers underwent a clinically indicated rest/stress rubidium-82 PET MPI with a median follow-up of 2.2 years. The primary outcome of this study was cardiac-death (169 patients) and the secondary outcome was all-cause death (570 patients). Net reclassification improvement (NRI) and integrated discrimination (IDI) analyses were performed.
Risk-adjusted hazard of cardiac-death increased with each 10% abnormal myocardium with mildly, moderately or severely abnormal stress PET [hazard ratio 2.3 (95% CI 1.4–3.8, P=0.001), 4.2 (95% CI 2.3–7.5, P<0.001), and 4.9 (95% CI 2.5–9.6, P <0.0001), respectively, normal MPI: referent]. Addition of %myocardium ischemic and scarred to clinical information (age, female sex, body mass index, history of hypertension, diabetes, dyslipidemia, smoking, angina, betablocker use, prior revascularization and rest heart rate) improved the model performance [C-statistic 0.805 (95% CI, 0.772–0.838) to 0.839 (95% CI, 0.809–0.869)] and risk reclassification for cardiac-death [NRI 0.116 (95% CI 0.021–0.210)] with smaller improvements in risk assessment for all-cause death.
In patients with known or suspected CAD, the extent and severity of ischemia and scar on PET MPI provide powerful and incremental risk estimates of cardiac-death and all-cause death compared to traditional coronary risk factors.
positron emission tomography; registry; prognosis; myocardial perfusion imaging; risk reclassification
The prevalence of heart failure (HF) is rising in industrialized and developing countries. Though invasive coronary angiography (ICA) remains the gold standard for anatomical assessment of coronary artery disease in HF patients, alternatives are being sought. Computed tomographic coronary angiography (CTA) has emerged as an accurate non-invasive diagnostic tool for coronary artery disease (CAD) and has been demonstrated to have prognostic value. Whether or not CTA can be used in HF patients is unknown. Acknowledging the aging population, the growing prevalence of HF and the increasing financial burden of healthcare, we need to identify non-invasive diagnostic tests that are available, safe, accurate and cost-effective.
The proposed study aims to provide insight into the efficacy of CTA in HF patients. A multicenter randomized controlled trial will enroll 250 HF patients requiring coronary anatomical definition. Enrolled patients will be randomized to either CTA or ICA (n = 125 per group) as the first test to define coronary anatomy. The primary outcomes will be collected to determine downstream resource utilization. Secondary outcomes will include the composite clinical events and major adverse cardiac events. In addition, the accuracy of CTA for detecting coronary anatomy and obstruction will be assessed in patients who subsequently undergo both CTA and ICA. It is expected that CTA will be a more cost-effective strategy for diagnosis: yielding similar outcomes with fewer procedural risks and improved resource utilization.
Team grant #CIF 99470
Imaging has become a routine part of heart failure (HF) investigation. Echocardiography is a first-line test in HF given its availability and it provides valuable diagnostic and prognostic information. Cardiac magnetic resonance (CMR) is an emerging clinical tool in the management of patients with non-ischemic heart failure. Current ACC/AHA/CCS/ESC guidelines advocate its role in the detection of a variety of cardiomyopathies but there is a paucity of high quality evidence to support these recommendations.
The primary objective of this study is to compare the diagnostic yield of routine cardiac magnetic resonance versus standard care (that is, echocardiography with only selective use of CMR) in patients with non-ischemic heart failure. The primary hypothesisis that the routine use of CMR will lead to a more specific diagnostic characterization of the underlying etiology of non-ischemic heart failure. This will lead to a reduction in the non-specific diagnoses of idiopathic dilated cardiomyopathy and HF with preserved ejection fraction.
Tertiary care sites in Canada and Finland, with dedicated HF and CMR programs, will randomize consecutive patients with new or deteriorating HF to routine CMR or selective CMR. All patients will undergo a standard clinical echocardiogram and the interpreter will assign the most likely HF etiology. Those undergoing CMR will also have a standard examination and will be assigned a HF etiology based upon the findings. The treating physician’s impression about non-ischemic HF etiology will be collected following all baseline testing (including echo ± CMR). Patients will be followed annually for 4 years to ascertain clinical outcomes, quality of life and cost. The expected outcome is that the routine CMR arm will have a significantly higher rate of infiltrative, inflammatory, hypertrophic, ischemic and ‘other’ cardiomyopathy than the selective CMR group.
This study will be the first multicenter randomized, controlled trial evaluating the role of CMR in non-ischemic HF. Non-ischemic HF patients will be randomized to routine CMR in order to determine whether there are any gains over management strategies employing selective CMR utilization. The insight gained from this study should improve appropriate CMR use in HF.
Heart failure; Echocardiography; Cardiac magnetic resonance; Randomized controlled trial
Cellular inhibitor of apoptosis protein 2 (cIAP2) is predicted to participate in atherosclerosis; however, its direct role in atherosclerosis development has not been investigated. We aimed to examine and assess the loss of cIAP2 on atherosclerosis lesion development.
Methods and Results
We used apoE−/− C57BL/6 male mice, either cIAP2−/− or cIAP2+/+. At 8 weeks, mice were fed a high‐fat diet (HFD) for 4 and 12 weeks. Aortic root was serially sectioned and stained with Sudan IV, CD68, α‐actin, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). cIAP2−/− mice displayed a significant decrease in atherosclerotic lesion's macrophage number after 4 weeks of HFD. Similarly, decrease in lesion area at 4 and 12 weeks HFD was detected by use of en face analysis (cIAP2−/− 0.58±0.37% versus cIAP2+/+ 1.51±0.79% [P=0.0056]); (cIAP2−/− 9.34±4.88% versus cIAP2+/+ 17.65±6.24% [P=0.0019]). Aortic root lesion area after 4 and 12 weeks of HFD also decreased (cIAP2−/− 0.0328±0.014 mm2 versus cIAP2+/+ 0.0515±0.021 mm2 [P=0.022]); (cIAP2−/− 0.3614±0.1157 mm2 versus cIAP2+/+ 0.4901±0.125 mm2 [P=0.065]). TUNEL analysis after 4 and 12 weeks of HFD showed a 2.5‐fold increase in TUNEL+ cells (cIAP2−/− 4.47±2.26% versus cIAP2+/+ 1.74±0.98% [P=0.036]); (cIAP2−/− 2.39±0.75% versus cIAP2+/+ 1.29±0.47% [P=0.032]). Smooth muscle cell content in cIAP2−/− mice was 3.075±3.3% compared with cIAP2+/+ with 0.085±0.1% (P=0.0071).
Results uncover a key role for cIAP2 in atherosclerotic lesion development, and targeting it may represent a novel therapeutic strategy.
apoptosis; atherosclerosis; C57BL/6 mice; cIAP2
Ischemic heart disease (IHD) is the most common cause of heart failure (HF); however, the role of revascularization in these patients is still unclear. Consensus on proper use of cardiac imaging to help determine which candidates should be considered for revascularization has been hindered by the absence of clinical studies that objectively and prospectively compare the prognostic information of each test obtained using both standard and advanced imaging.
This paper describes the design and methods to be used in the Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) multi-center trial. The primary objective is to compare the effect of HF imaging strategies on the composite clinical endpoint of cardiac death, myocardial infarction (MI), cardiac arrest and re-hospitalization for cardiac causes.
In AIMI-HF, patients with HF of ischemic etiology (n = 1,261) will follow HF imaging strategy algorithms according to the question(s) asked by the physicians (for example, Is there ischemia and/or viability?), in agreement with local practices. Patients will be randomized to either standard (SPECT, Single photon emission computed tomography) imaging modalities for ischemia and/or viability or advanced imaging modalities: cardiac magnetic resonance imaging (CMR) or positron emission tomography (PET). In addition, eligible and consenting patients who could not be randomized, but were allocated to standard or advanced imaging based on clinical decisions, will be included in a registry.
AIMI-HF will be the largest randomized trial evaluating the role of standard and advanced imaging modalities in the management of ischemic cardiomyopathy and heart failure. This trial will complement the results of the Surgical Treatment for Ischemic Heart Failure (STICH) viability substudy and the PET and Recovery Following Revascularization (PARR-2) trial. The results will provide policy makers with data to support (or not) further investment in and wider dissemination of alternative ‘advanced’ imaging technologies.
The cardiac PRKAG2 mutation in the γ2-subunit of adenosine monophosphate activated kinase (AMPK) is characterized by excessive glycogen deposition, hypertrophy, frequent arrhythmias, and progressive conduction system disease. We investigated whether myocardial glucose uptake (MGU) was augmented following insulin stimulation in a mouse model of the PRKAG2 cardiac syndrome.
Myocardial and skeletal muscle glucose uptake was assessed with 2-[18F]fluoro-2-deoxyglucose positron emission tomography imaging in n = 3 transgenic wildtype (TGwt) vs n = 7 PRKAG2 mutant (TGmut) mice at baseline and 1 week later, 30 min following acute insulin. Systolic function, cardiac glycogen stores, phospho-AMPK α, and insulin-receptor expression levels were analyzed to corroborate to the in vivo findings.
TGmut Patlak Ki was reduced 56% at baseline compared to TGwt (0.3 ± 0.2 vs 0.7 ± 0.1, t test p = 0.01). MGU was augmented 71% in TGwt mice following acute insulin from baseline (0.7 ± 0.1 to 1.2 ± 0.2, t test p < 0.05). No change was observed in TGmut mice. As expected for this cardiac specific transgene, skeletal muscle was unaffected at baseline with a 33% to 38% increase (standard uptake values) for both genotypes following insulin stimulation. TGmut mice had a 47% reduction in systolic function with a fourfold increase in cardiac glycogen stores correlated with a 29% reduction in phospho-AMPK α levels. There was no difference in cardiac insulin receptor expression between mouse genotypes.
These results demonstrate a correlation between insulin resistance and AMPK activity and provide the basis for the use of this animal model for assessing metabolic therapy in the treatment of affected PRKAG2 patients.
Positron emission tomography; FDG; Patlak; Echocardiography; Glucose
Prodigious efforts and landmark discoveries have led toward significant advances in our understanding of atherosclerosis. Despite significant efforts, atherosclerosis continues globally to be a leading cause of mortality and reduced quality of life. With surges in the prevalence of obesity and diabetes, atherosclerosis is expected to have an even more pronounced impact upon the global burden of disease. It is imperative to develop strategies for the early detection of disease. Positron emission tomography (PET) imaging utilizing [18F]fluorodeoxyglucose (FDG) may provide a non-invasive means of characterizing inflammatory activity within atherosclerotic plaque, thus serving as a surrogate biomarker for detecting vulnerable plaque. The aim of this review is to explore the rationale for performing FDG imaging, provide an overview into the mechanism of action, and summarize findings from the early application of FDG PET imaging in the clinical setting to evaluate vascular disease. Alternative imaging biomarkers and approaches are briefly discussed.
Positron emission tomography; Computed tomography; [18F]fluorodeoxyglucose; Inflammation; Calcification; Vulnerable plaque
Diabetes is commonly associated with increased risk of cardiovascular morbidity and mortality. Perturbations in sympathetic nervous system (SNS) signaling have been linked to the progression of diabetic heart disease. Glucose, insulin, and free fatty acids contribute to elevated sympathetic nervous activity and norepinephrine release. Reduced left ventricular compliance and impaired cardiac function lead to further SNS activation. Chronic elevation of cardiac norepinephrine culminates in altered expression of pre- and post-synaptic sympathetic signaling elements, changes in calcium regulatory proteins, and abnormal contraction-excitation coupling. Clinically, these factors manifest as altered resting heart rate, depressed heart rate variability, and impaired cardiac autonomic reflex, which may contribute to elevated cardiovascular risk. Development of molecular imaging probes enable a comprehensive evaluation of cardiac SNS signaling at the neuron, postsynaptic receptor, and intracellular second messenger sites of signal transduction, providing mechanistic insights into cardiac pathology. This review will examine the evidence for abnormal SNS signaling in the diabetic heart and establish the physiological consequences of these changes, drawing from basic biological research in isolated heart and rodent models of diabetes, as well as from clinical reports. Particular attention will be paid to the use of molecular imaging approaches to non-invasively characterize and evaluate sympathetic signal transduction in diabetes, including pre-synaptic norepinephrine reuptake assessment using 11C-meta-hydroxyephedrine (11C-HED) with PET or 123I-metaiodobenzylguanidine (123I-MIBG) with SPECT, and postsynaptic β-adrenoceptor density measurements using CGP12177 derivatives. Finally, the review will attempt to define the future role of these non-invasive nuclear imaging techniques in diabetes research and clinical care.
Sympathetic neuronal imaging; SNS signaling; norepinephrine; β-adrenoceptor; norepinephrine reuptake transporter
Diabetes mellitus is strongly associated with cardiovascular dysfunction, derived in part from impairment of sympathetic nervous system signaling. Glucose, insulin, and non-esterified fatty acids are potent stimulants of sympathetic activity and norepinephrine (NE) release. We hypothesized that sustained hyperglycemia in the high fat diet-fed streptozotocin (STZ) rat model of sustained hyperglycemia with insulin resistance would exhibit progressive sympathetic nervous dysfunction in parallel with deteriorating myocardial systolic and/or diastolic function.
Cardiac sympathetic nervous integrity was investigated in vivo via biodistribution of the positron emission tomography radiotracer and NE analogue [11C]meta-hydroxyephedrine ([11C]HED). Cardiac systolic and diastolic function was evaluated by echocardiography. Plasma and cardiac NE levels and NE reuptake transporter (NET) expression were evaluated as correlative measurements.
The animal model displays insulin resistance, sustained hyperglycemia, and progressive hypoinsulinemia. After 8 weeks of persistent hyperglycemia, there was a significant 13-25% reduction in [11C]HED retention in myocardium of STZ-treated hyperglycemic but not euglycemic rats as compared to controls. There was a parallel 17% reduction in immunoblot density for NE reuptake transporter, a 1.2 fold and 2.5 fold elevation of cardiac and plasma NE respectively, and no change in sympathetic nerve density. No change in ejection fraction or fractional area change was detected by echocardiography. Reduced heart rate, prolonged mitral valve deceleration time, and elevated transmitral early to atrial flow velocity ratio measured by pulse-wave Doppler in hyperglycemic rats suggest diastolic impairment of the left ventricle.
Taken together, these data suggest that sustained hyperglycemia is associated with elevated myocardial NE content and dysregulation of sympathetic nervous system signaling in the absence of systolic impairment.
norepinephrine; [11C]meta-hydroxyephedrine (HED); small animal echocardiography; positron emission tomography; diabetes mellitus; cardiovascular disease
Coronary artery disease is the major cause of heart failure in North America. Viability assessment is important as it aims to identify patients who stand to benefit from coronary revascularization. Radionuclide modalities currently used in the assessment of viability include 201Tl SPECT, 99mTc-based SPECT imaging, and 18F-fluorodexoyglucose (18F-FDG)-PET imaging. Different advances have been made in the last year to improve the sensitivity and specificity of these modalities. In addition, the optimum amount of viable (yet dysfunctional) myocardium is important to identify in patients, as a risk–benefit ratio must be considered. Patients with predominantly viable/hibernating myocardium can benefit from revascularization from a mortality and morbidity standpoint. However, in patients with minimal viability (predominantly scarred myocardium), revascularization risk may certainly be too high to justify revascularization without expected benefit. Understanding different radionuclide modalities and new developments in the assessment of viability in ischemic heart failure patients is the focus of this discussion.
Viability; Heart failure; SPECT; PET
Although positron emission tomography (PET) is routinely performed using vasodilator stress, exercise and dobutamine stress are available alternatives. Evidence suggests that vasodilator PET myocardial perfusion imaging (MPI) has prognostic value, but the prognostic value of treadmill exercise and dobutamine PET MPI is unknown.
To determine the potential prognostic value of nonvasodilator stress PET MPI.
Patients underwent treadmill exercise or dobutamine PET MPI. Images were assessed qualitatively and semiquantitatively. PET results were categorized as normal (summed stress score [SSS] of less than 4), abnormal (SSS of 4 or greater) or inconclusive (SSS of less than 4 and submaximal peak stress heart rate). Patient follow-up (cardiac death, nonfatal myocardial infarction [MI] and/or late revascularization) was performed.
Of the 124 patients (mean follow-up period of 2.3±1.6 years), 46 patients (37%) had a normal study, 15 patients (12%) had an inconclusive study and 63 (51%) had an abnormal PET. Patients with a normal PET had no deaths or nonfatal MI. One patient with a normal PET underwent late revascularization (annual event rate of 1.7%). Patients with an abnormal PET had 15 cardiac events (one cardiac death, four nonfatal MIs and 10 late revascularizations), with an annual event rate of 13.0% (P=0.002).
Although small, the present study suggests that defects seen on PET myocardial perfusion, resulting from stressors (treadmill exercise and dobutamine) that increase myocardial oxygen demand, may have prognostic value.
Coronary artery disease; Dobutamine; Positron emission tomography; Prognosis; Treadmill exercise
Obstructive sleep apnea (OSA) may contribute to the pathogenesis of congestive heart failure (CHF). Nocturnal continuous positive airway pressure (CPAP) therapy can alleviate OSA and may have a role in the treatment of CHF patients.
To investigate the acute and chronic effects of CPAP therapy on left ventricular systolic function, diastolic function and filling pressures in CHF patients with OSA.
Twelve patients with stable CHF (New York Heart Association II or III, radionuclide ejection fraction lower than 40%) underwent overnight polysomnography to detect OSA. In patients with OSA (n=7), echocardiography was performed at baseline (awake, before and during acute CPAP administration) and after 6.9±3.3 weeks of nocturnal CPAP therapy. Patients without OSA (n=5) did not receive CPAP therapy, but underwent a baseline and follow-up echocardiogram.
In CHF patients with OSA, acute CPAP administration resulted in a decrease in stroke volume (44±15 mL versus 50±14 mL, P=0.002) and left ventricular ejection fraction ([LVEF] 34.8±5.0% versus 38.4±3.3%, P=0.006) compared with baseline, but no change in diastolic function or filling pressures (peak early diastolic mitral annular velocity [Ea]: 6.0±1.6 cm/s versus 6.3±1.6 cm/s, P not significant; peak early filling velocity to peak late filling velocity [E/A] ratio: 1.05±0.74 versus 1.00±0.67, P not significant; E/Ea ratio: 10.9±4.1 versus 11.3±4.1, P not significant). In contrast, chronic CPAP therapy resulted in a trend to an increase in stroke volume (59±19 mL versus 50±14 mL, P=0.07) and a significant increase in LVEF (43.4±4.8% versus 38.4±3.3%, P=0.01) compared with baseline, but no change in diastolic function or filling pressures (Ea: 6.2±1.2 cm/s versus 6.3±1.6 cm/s, P not significant; E/A ratio: 1.13±0.61 versus 1.00±0.67, P not significant; E/Ea ratio: 12.1±2.7 versus 11.3±4.1, P not significant). There was no change in left ventricular systolic function, diastolic function or filling pressures at follow-up in CHF patients without OSA.
Acute CPAP administration decreased stroke volume and LVEF in stable CHF patients with OSA. In contrast, chronic CPAP therapy for seven weeks improved left ventricular systolic function, but did not affect diastolic function or filling pressures. The potential clinical implications of the discrepant effects of CPAP therapy on left ventricular systolic and diastolic function in CHF patients with OSA warrant further study.
Congestive heart failure; Continuous positive airway pressure therapy; Echocardiography; Left ventricular function; Obstructive sleep apnea
The present study compared computed tomo-graphic coronary angiography (CTA) and positron emission tomography (PET) for the detection of significant anatomical coronary artery stenosis as defined by conventional invasive coronary angiography (CICA).
The study protocol was approved by the local ethics board, and informed consent was obtained from all patients. Of the 26 patients (mean age 57±9 years, 18 men) who prospectively underwent CTA and rubidium-82 PET before CICA, 24 patients had a history of chest pain. Images were interpreted by expert readers and assessed for the presence of anatomically significant coronary stenosis (50% luminal diameter stenosis or greater) or myocardial perfusion defects. Diagnostic test characteristics were analyzed using patient-based, territory-based, vessel-based and segment-based analyses.
In the 24 patients referred for chest pain, CTA had similar sensitivity to PET, but was more specific (sensitivity 95% [95% CI 72% to 100%] versus 95% [95% CI 72% to 100%], respectively; specificity 100% [95% CI 46% to 100%] versus 60% [95% CI 17% to 93%], respectively) in the detection of patients with anatomical coronary artery stenosis of 50% or greater. On a per-segment basis of all 26 patients, CTA had a sensitivity, specificity, positive predictive value and negative predictive value of 72%, 99%, 91% and 95%, respectively, in all coronary segments.
Coronary CTA has a similar sensitivity and specificity to rubidium-82 PET for the identification of patients with significant anatomical coronary artery disease.
Computed tomographic coronary angiography; Coronary artery disease; Diagnosis; Positron emission tomography
The Council of the Canadian Cardiovascular Society commissioned working groups to examine issues of access to, and wait times for, various aspects of cardiovascular care. The present article summarizes the deliberations on targets for medically acceptable wait times for access to cardiovascular specialist evaluation and on the performance of non-invasive testing needed to complete this evaluation. Three categories of referral indications were identified: those requiring hospitalization due to substantial ongoing risk of mortality and morbidity; those requiring an expedited early review in an ambulatory setting; and, finally, a larger category in which delays of two to six weeks can be justified. The proposed wait time targets will provide guidance on the timeliness of care to busy clinicians charged with the care of patients with cardiovascular disease, help policy makers appreciate the clinical challenges in providing access to high quality care, and highlight the critical need for a thoughtful review of cardiology human resource requirements. Wait time implementation suggestions are also included, such as the innovative use of disease management and special need clinics. The times proposed assume that available clinical practice guidelines are followed for clinical coronary syndrome management and for treatment of associated conditions such as hypertension, diabetes, renal disease, smoking cessation and lipid disorders. Although media attention tends to focus on wait times for higher profile surgical procedures and high technology imaging, it is likely that patients face the greatest wait-related risk at the earlier phases of care, before the disease has been adequately characterized.
Access; Canadian Cardiovascular Society; Consultation; Noninvasive testing; Wait times