Cardiac Sarcoidosis Birnie, David H., MD, MBChB; Nery, Pablo B., MD; Ha, Andrew C., MD ...
Journal of the American College of Cardiology,
07/2016, Volume:
68, Issue:
4
Journal Article
Peer reviewed
Open access
Abstract Clinically manifest cardiac involvement occurs in perhaps 5% of patients with sarcoidosis. The 3 principal manifestations of cardiac sarcoidosis (CS) are conduction abnormalities, ...ventricular arrhythmias, and heart failure. An estimated 20% to 25% of patients with pulmonary/systemic sarcoidosis have asymptomatic cardiac involvement (clinically silent disease). In 2014, the first international guideline for the diagnosis and management of CS was published. In patients with clinically manifest CS, the extent of left ventricular dysfunction seems to be the most important predictor of prognosis. There is controversy in published reports as to the outcome of patients with clinically silent CS. Despite a paucity of data, immunosuppression therapy (primarily with corticosteroids) has been advocated for the treatment of clinically manifest CS. Device therapy, primarily with implantable cardioverter-defibrillators, is often recommended for patients with clinically manifest disease.
Objectives We evaluated the prognostic value of myocardial flow reserve (MFR) using rubidium-82 (82 Rb) positron emission tomography (PET) in patients assessed for ischemia. Background The clinical ...value of MFR quantification using82 Rb PET beyond relative myocardial perfusion imaging remains uncertain. Methods We prospectively enrolled 704 consecutive patients; 677 (96%) completed follow-up (median 387 days interquartile range: 375 to 416 days). Patients were divided into 4 groups: I, normal summed stress score (SSS) (<4) and normal myocardial flow reserve (MFR) (>2); II, normal SSS and MFR <2; III, SSS ≥4 and MFR ≥2; IV, SSS ≥4 and MFR <2. Results For patients with a normal SSS and those with an abnormal SSS, there were significant differences in outcomes for hard events (cardiac death and myocardial infarction) between patients with MFR ≥2 and those with MFR <2 (I: 1.3% vs. II: 2% p = 0.029; III: 1.1% vs. IV: 11.4% p = 0.05) and for major adverse cardiac events (MACE) (p = 0.003 and p < 0.001, respectively). In the adjusted Cox model, MFR was an independent predictor of hard events (hazard ratio: 3.3; 95% confidence interval: 1.1 to 9.5; p = 0.029) and MACE (hazard ratio: 2.4, 95% confidence interval: 1.4 to 4.4, p = 0.003). The incremental prognostic value of the MFR over the SSS was demonstrated by comparing the adjusted SSS model with and without the MFR for hard events (p = 0.0197) and MACE (p = 0.002). Conclusions MFR quantified using82 Rb PET predicts hard cardiac events and MACE independent of the SSS and other parameters. Routine assessment of82 Rb PET–quantified MFR could improve risk stratification for patients being investigated for ischemia.
Cardiac allograft vasculopathy (CAV) remains the Achilles' heel of long-term survival after heart transplantation. Almost one-third of patients develop CAV by 5 years post-transplant and 1 in 8 ...deaths beyond a year are due to CAV. Abnormal vascular fibroproliferation in CAV occurs as a result of coronary endothelial inflammation, injury, and dysfunction triggered by immune and nonimmune insults. Surveillance methods for CAV have significant limitations, particularly for detecting early disease. Areas of investigation include myocardial and coronary blood flow quantification, and intracoronary imaging to detect early changes in the vessel wall and high-risk plaques. Treatment approaches continue to evolve, but prevention remains the focus. Newer mammalian target of rapamycin inhibitors can significantly delay the progression of CAV; however, their optimal use remains to be established. Further investigation is needed to understand the complex pathophysiology of CAV, improve surveillance techniques, and develop therapies to prevent and slow disease progression.
Background
Relative myocardial perfusion imaging (MPI) is the standard imaging approach for the diagnosis and prognostic work-up of coronary artery disease (CAD). However, this technique may ...underestimate the extent of disease in patients with 3-vessel CAD. Positron emission tomography (PET) is also able to quantify myocardial blood flow. Rubidium-82 (
82
Rb) is a valid PET tracer alternative in centers that lack a cyclotron. The aim of this study was to assess whether assessment of myocardial flow reserve (MFR) measured with
82
Rb PET is an independent predictor of severe obstructive 3-vessel CAD.
Methods
We enrolled a cohort of 120 consecutive patients referred to a dipyridamole
82
Rb PET MPI for evaluation of ischemia neither with prior coronary artery bypass graft nor with recent percutaneous coronary intervention that also underwent coronary angiogram within 6 months of the PET study. Patients with and without 3-vessel CAD were compared.
Results
Among patients with severe 3-vessel CAD, MFR was globally reduced (<2) in 88% (22/25). On the adjusted logistic Cox model, MFR was an independent predictor of 3-vessel CAD .5 unit decrease, HR: 2.1, 95% CI (1.2-3.8);
P
= .015. The incremental value of
82
Rb MFR over the SSS was also shown by comparing the adjusted SSS models with and without
82
Rb MFR (
P
= .005).
Conclusion
82
Rb MFR is an independent predictor of 3-vessel CAD and provided added value to relative MPI. Clinical integration of this approach should be considered to enhance detection and risk assessment of patients with known or suspected CAD.
Cardiac allograft vasculopathy (CAV) is a leading cause of graft failure and death after heart transplantation. Absolute myocardial blood flow (MBF) quantification using rubidium 82 (Rb-82) positron ...emission tomography (PET) could enable evaluation of diagnostically challenging diffuse epicardial and microvascular disease in CAV.
The authors aimed to evaluate Rb-82 PET detection of CAV.
Consecutive transplant recipients undergoing coronary angiography were prospectively evaluated with PET, multivessel intravascular ultrasound (IVUS), and intracoronary hemodynamics. CAV was defined as International Society of Heart and Lung Transplantation CAV1–3 on angiography and maximal intimal thickness ≥0.5 mm on IVUS.
Forty patients (mean age 56 years, 4.8 years post-transplant) completed evaluation. CAV was detected in 32 patients (80%) by IVUS and 14 (35%) by angiography. PET correlated significantly with invasive coronary flow indices: r = 0.29, rate-pressure product–adjusted myocardial flow reserve (cMFR) versus coronary flow reserve; r = 0.28, relative flow reserve versus fractional flow reserve; and r = 0.37, coronary vascular resistance (CVR) versus index of microcirculatory resistance. Patients with CAV or microvascular dysfunction had reduced cMFR and stress MBF and increased CVR. Receiver operator characteristic curves demonstrated good accuracy of PET for CAV on IVUS (area under the curve 0.77 to 0.81) and optimal diagnostic cutoffs of cMFR <2.9, stress MBF <2.3, and CVR >55. Combined PET assessment for CAV yielded excellent >93% sensitivity (>65% specificity) for 1 abnormal parameter and >96% specificity (>55% sensitivity) for 2 abnormal parameters.
Rb-82 PET flow quantification has high diagnostic accuracy for CAV, with potential for noninvasive evaluation after heart transplantation.
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Fluorine-18 flurpiridaz is a novel positron emission tomography (PET) myocardial perfusion imaging tracer.
This study sought to assess the diagnostic efficacy of flurpiridaz PET versus ...technetium-99m–labeled single photon emission computed tomography SPECT for the detection and evaluation of coronary artery disease (CAD), defined as ≥50% stenosis by quantitative invasive coronary angiography (ICA). Flurpiridaz safety was also evaluated.
In this phase III prospective multicenter clinical study, 795 patients with known or suspected CAD from 72 clinical sites in the United States, Canada, and Finland were enrolled. A total of 755 patients were evaluable, and the mean age was 62.3 ± 9.5 years, 31% were women, 55% had body mass index ≥30 kg/m2, and 71% had pharmacological stress. Patients underwent 1-day rest-stress (pharmacological or exercise) flurpiridaz PET and 1- or 2-day rest-stress Tc-99m–labeled SPECT and ICA. Images were read by 3 experts blinded to clinical and ICA data.
Sensitivity of flurpiridaz PET (for detection of ≥50% stenosis by ICA) was 71.9% (95% confidence interval CI: 67.0% to 76.3%), significantly (p < 0.001) higher than SPECT (53.7% 95% CI: 48.5% to 58.8%), while specificity did not meet the prespecified noninferiority criterion (76.2% 95% CI: 71.8% to 80.1% vs. 86.6% 95% CI: 83.2% to 89.8%; p = NS). Receiver-operating characteristic curve analysis demonstrated superior discrimination of CAD by flurpiridaz PET versus SPECT in the overall population, in women, obese patients, and patients undergoing pharmacological stress testing (p < 0.001 for all). Flurpiridaz PET was superior to SPECT for defect size (p < 0.001), image quality (p < 0.001), diagnostic certainty (p < 0.001), and radiation exposure (6.1 ± 0.4 mSv vs. 13.4 ± 3.2 mSv; p < 0.001). Flurpiridaz PET was safe and well tolerated.
Flurpiridaz PET myocardial perfusion imaging shows promise as a new tracer for CAD detection and assessment of women, obese patients, and patients undergoing pharmacological stress testing. A second phase III Food and Drug Administration trial is ongoing. (A Phase 3 Multi-center Study to Assess PET Imaging of Flurpiridaz F 18 Injection in Patients with CAD; NCT01347710)
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What is the Prognostic Value of Myocardial Perfusion Imaging Using Rubidium-82 Positron Emission Tomography?
Keiichiro Yoshinaga, Benjamin J. W. Chow, Kathryn Williams, Li Chen, Robert A. deKemp, ...Linda Garrard, Alexander Lok-Tin Szeto, May Aung, Ross A. Davies, Terrence D. Ruddy, Rob S. B. Beanlands
The prognostic value of dipyridamole stress rubidium-82 positron emission tomography (PET) was determined in 367 patients followed up for 3.1 ± 0.9 years. Rubidium-82 PET showed a significant prognostic value for predicting cardiac events, including death and nonfatal myocardial infarction. Normal PET myocardial perfusion imaging (MPI) indicated a low risk. Among patients referred for PET MPI after an equivocal single-photon-emission computed tomography study, patients with an abnormal PET MPI had higher event rates compared with patients with a normal PET MPI. In a subset of patients with obesity, rubidium-82 PET also seemed to have prognostic value. The prognostic value of PET MPI supports its use in the risk stratification of cardiac patients.
The objective was to determine the prognostic value of rubidium-82 (82Rb) positron emission tomography (PET) myocardial perfusion imaging (MPI).
82Rb PET MPI accurately diagnoses coronary artery disease (CAD). However, there are limited data evaluating its prognostic value.
Follow-up (3.1 ± 0.9 years) was obtained in 367 patients who underwent dipyridamole 82Rb PET MPI. Patients were divided into groups based on their summed stress score (SSS): group I, normal (<4); group II, mild (4 to 7); and group III, moderate (8 to 11) to severe (≥12).
There were significant differences among patients in the 3 SSS groups for hard events (cardiac death and myocardial infarction MI) (p < 0.001) and total cardiac events (hard events, revascularization and hospitalization) (p < 0.001). The annual hard events rates were 0.4%, 2.3%, and 7.0% in the normal, mild, and moderate-severe groups, respectively. In adjusted survival models, 82Rb PET SSS was the strongest predictor of total cardiac events and a significant predictor of hard events. Among patients referred for PET after 99mTc single-photon emission computed tomography, the annual total event rate was higher with abnormal versus normal SSS on PET (15.2% vs. 1.3%, p < 0.001). In patients with obesity, the annual total event rate was 11.1% with an abnormal scan and 1.5% with a normal scan (p < 0.001).
This study shows that 82Rb PET MPI has significant prognostic value for predicting cardiac events, including death and MI. It also seems to have prognostic value in patients whose diagnosis remains uncertain after single-photon emission computed tomography MPI and in obese patients. The prognostic value of PET MPI may improve the management of cardiac patients.
Approximately 5% of patients with sarcoidosis have clinically manifest cardiac involvement. Clinical features of Cardiac Sarcoidosis are dependent on the location, extent, and activity of the ...disease. First line therapy is usually with prednisone and this is recommended based on clinician experience, expert opinion and small observational cohorts. There are no published clinical trials in cardiac sarcoidosis and multiple experts in the field have called for randomized clinical trials to answer important patient care questions. Corticosteroid are associated with multiple adverse effects including hypertension, diabetes, weight gain, osteoporosis, and increased risk of infections. In contrast Methotrexate is generally well tolerated and is increasingly used in other forms of sarcoidosis.
The Cardiac Sarcoidosis Multi-Center Randomized Controlled Trial (CHASM CS-RCT; NCT03593759) is a multicenter randomized controlled trial designed to evaluate the optimal initial treatment strategy for patients with active cardiac sarcoidosis. We hypothesize that (1) a low dose prednisone/methotrexate combination will have non-inferior efficacy to standard dose prednisone and that (2) the low dose prednisone/ methotrexate combination will result in significantly better quality of life than standard dose prednisone, as a result of reduced burden of side effects.
Eligible study subjects will have active clinically manifest cardiac sarcoidosis presenting with one or more of the following clinical findings: advanced conduction system disease, significant sinus node dysfunction, non-sustained or sustained ventricular arrhythmia, left ventricular dysfunction or right ventricular dysfunction. Subjects will be randomized in a 1:1 ratio to prednisone 0.5 mg/kg/day for 6 months (maximum dose 30 mg daily) OR to prednisone 20 mg daily for 1 month, then 10 mg daily for 1 month, then 5 mg daily for one month then stop AND methotrexate 15–20 mg once weekly for 6 months. The primary endpoint is summed perfusion rest score on 6-month PET (blinded core-lab review). The summed perfusion rest score is measure of myocardial fibrosis/scar. The design is non-inferiority with a sample size of 97 per group.
Given the multiorgan system potential adverse side effects of prednisone, proving noninferiority of an alternate regimen would be sufficient to make the alternative compare favorably to standard dose steroids. This is the first ever clinical trial in cardiac sarcoidosis and thus in addition to the listed goals of the trial, we will also establish a multi-center, multinational cardiac sarcoidosis clinical trials network. Such a collaborative infrastructure will enable a new era of high quality data to guide physicians when treating cardiac sarcoidosis patients.
Cardiac sarcoidosis is a potentially fatal complication of sarcoidosis. The 1993 guidelines of the Ministry of Health, Labour, and Welfare (MHLW) of Japan have been used as the diagnostic gold ...standard and for comparison with imaging modalities. (18)F-FDG PET is not currently included in the guidelines. However, studies have shown promising data using (18)F-FDG PET. We conducted a systematic review of studies that evaluated the accuracy of (18)F-FDG PET for the diagnosis of cardiac sarcoidosis compared with MHLW guidelines. Data from a prospective Ontario provincial registry are also reported and included in the metaanalysis.
PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies that satisfied predetermined criteria. Quality evaluation using the Quality Assessment for Diagnostic Accuracy Studies was performed by 2 independent masked observers. Data were extracted and analyzed to measure study-specific and pooled accuracy for (18)F-FDG PET compared with the MHLW as the reference.
A total of 519 titles was identified; 7 studies, including the Ontario registry, were selected for inclusion. Metaanalysis of these 7 studies was conducted, with a total of 164 patients, most of whom had been diagnosed with systemic sarcoidosis. The prevalence of cardiac sarcoidosis was 50% in the whole population. Pooled estimates for (18)F-FDG PET yielded 89% sensitivity (95% confidence interval CI, 79%-96%), 78% specificity (95% CI, 68%-86%), a 4.1 positive likelihood ratio (95% CI, 1.7-10), and a 0.19 negative likelihood ratio (95% CI, 0.1-0.4). The overall diagnostic odds ratio was 25.6 (95% CI, 7.3-89.5), and the area under the summary receiver operator characteristic curve was 93% ± 3.5. The Ontario study yielded sensitivity and specificity of 79% and 70%, respectively.
The high diagnostic accuracy determined for (18)F-FDG PET in this metaanalysis suggests potential value for diagnosis of cardiac sarcoidosis compared with the MHLW guidelines. These results may affect patient care by providing supportive evidence for more effective use of (18)F-FDG PET in the diagnosis of cardiac sarcoidosis. Large-scale multicenter studies are required to further evaluate this role.
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 (99mTc). 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.
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