Quantitative Myocardial Perfusion in Liver Transplantation Candidates: Poorly metabolized caffeine inhibition of vasodilatory stress.

BACKGROUND: Data on cardiac positron emission tomography (PET) in liver transplantation (LT) candidates are limited with no prior study accounting for poorly metabolized caffeine reducing stress perfusion. METHOD: Consecutive LT candidates (n=114) undergoing cardiac rest/stress PET were instructed to abstain from caffeine for 2 days extended to 5 and 7 days. Due to persistently high prevalence of measurable blood caffeine after 5-day caffeine abstinence, dipyridamole (n=41) initially used was changed to dobutamine (n=73). Associations of absolute flow, coronary flow reserve (CFR), detectable blood caffeine, and Modified End-Stage Liver Disease (MELD) score for liver failure severity were evaluated. Coronary flow data of LT candidates were compared to non-LT control group (n=102 for dipyridamole, n=29 for dobutamine) RESULTS: Prevalence of patients with detectable blood caffeine was 63.3%, 36.7% and 33.3% after 2-, 5- and 7-day of caffeine abstinence, respectively. MELD score was associated with detectable caffeine (odd ratio 1.18,p<0.001). CFR was higher during dipyridamole stress without-caffeine vs. with-caffeine (2.22±0.80 vs. 1.55±0.37,p=0.048) but lower than dobutamine stress (2.22±0.80 vs. 2.82±1.02,p=0.026). Mediation analysis suggested that the dominant association between CFR and MELD score in dipyridamole group derived from caffeine-impaired CFR and liver failure/caffeine interaction. CFR in LT candidates was lower than non-LT control population in both dipyridamole and dobutamine group. CONCLUSIONS: We demonstrate exceptionally high prevalence of detectable blood caffeine in LT candidates undergoing stress PET myocardial perfusion imaging resulting in reduced CFR with dipyridamole compared to dobutamine. The delayed caffeine clearance in LT candidates makes dobutamine a preferred stress agent in this population.

Coronary flow capacity and survival prediction after revascularization: physiological basis and clinical implications.

BACKGROUND AND AIMS: Coronary flow capacity (CFC) is associated with an observed 10-year survival probability for individual patients before and after actual revascularization for comparison to virtual hypothetical ideal complete revascularization. METHODS: Stress myocardial perfusion (mL/min/g) and coronary flow reserve (CFR) per pixel were quantified in 6979 coronary artery disease (CAD) subjects using Rb-82 positron emission tomography (PET) for CFC maps of artery-specific size-severity abnormalities expressed as percent left ventricle with prospective follow-up to define survival probability per-decade as fraction of 1.0. RESULTS: Severely reduced CFC in 6979 subjects predicted low survival probability that improved by 42% after revascularization compared with no revascularization for comparable severity (P = .0015). For 283 pre-and-post-procedure PET pairs, severely reduced regional CFC-associated survival probability improved heterogeneously after revascularization (P < .001), more so after bypass surgery than percutaneous coronary interventions (P < .001) but normalized in only 5.7%; non-severe baseline CFC or survival probability did not improve compared with severe CFC (P = .00001). Observed CFC-associated survival probability after actual revascularization was lower than virtual ideal hypothetical complete post-revascularization survival probability due to residual CAD or failed revascularization (P < .001) unrelated to gender or microvascular dysfunction. Severely reduced CFC in 2552 post-revascularization subjects associated with low survival probability also improved after repeat revascularization compared with no repeat procedures (P = .025). CONCLUSIONS: Severely reduced CFC and associated observed survival probability improved after first and repeat revascularization compared with no revascularization for comparable CFC severity. Non-severe CFC showed no benefit. Discordance between observed actual and virtual hypothetical post-revascularization survival probability revealed residual CAD or failed revascularization.

Differences in Myocardial Remodeling and Tissue Characteristics in Chronic Isolated Aortic and Mitral Regurgitation.

BACKGROUND: The left ventricular hemodynamic load differs between aortic regurgitation (AR) and primary mitral regurgitation (MR). We used cardiac magnetic resonance to compare left ventricular remodeling patterns, systemic forward stroke volume, and tissue characteristics between patients with isolated AR and isolated MR. METHODS: We assessed remodeling parameters across the spectrum of regurgitant volume. Left ventricular volumes and mass were compared against normal values for age and sex. We calculated forward stroke volume (planimetered left ventricular stroke volume-regurgitant volume) and derived a cardiac magnetic resonance-based systemic cardiac index. We assessed symptom status according to remodeling patterns. We also evaluated the prevalence of myocardial scarring using late gadolinium enhancement imaging, and the extent of interstitial expansion via extracellular volume fraction. RESULTS: We studied 664 patients (240 AR, 424 primary MR), median age of 60.7 (49.5-69.9) years. AR led to more pronounced increases in ventricular volume and mass compared with MR across the spectrum of regurgitant volume (P<0.001). In ≥moderate regurgitation, AR patients had a higher prevalence of eccentric hypertrophy (58.3% versus 17.5% in MR; P<0.001), whereas MR patients had normal geometry (56.7%) followed by myocardial thinning with low mass/volume ratio (18.4%). The patterns of eccentric hypertrophy and myocardial thinning were more common in symptomatic AR and MR patients (P<0.001). Systemic cardiac index remained unchanged across the spectrum of AR, whereas it progressively declined with increasing MR volume. Patients with MR had a higher prevalence of myocardial scarring and higher extracellular volume with increasing regurgitant volume (P value for trend <0.001), whereas they were unchanged across the spectrum of AR (P=0.24 and 0.42, respectively). CONCLUSIONS: Cardiac magnetic resonance identified significant heterogeneity in remodeling patterns and tissue characteristics at matched degrees of AR and MR. Further research is needed to examine if these differences impact reverse remodeling and clinical outcomes after intervention.

Does financial hardship associate with abnormal quantitative myocardial perfusion and major adverse cardiovascular event?

BACKGROUND: Data on impact of financial hardship on coronary artery disease (CAD) remain incomplete. METHODS: Consecutive subjects referred for clinical rest/stress cardiac positron emission tomography (PET) were enrolled. Financial hardship is defined as patients' inability to pay for their out-of-pocket expense for cardiac PET. Abnormal cardiac PET is defined as at least moderate relative perfusion defects at stress involving > 10% of the left ventricle or global coronary flow reserve ≤ 2.0. Patients were followed for major adverse cardiovascular event (MACE) comprised of all-cause mortality, non-fatal myocardial infarction, and late coronary revascularization. RESULTS: We analyzed a total of 4173 patients with mean age 65.6 ± 11.3 years, 72.2% men, and 93.6% reported as having medical insurance. Of these, 504 (12.1%) patients had financial hardship. On multivariable analysis, financial hardship associated with abnormal cardiac PET (odds ratio 1.377, p = 0.004) and MACE (hazard ratio 1.432, p = 0.010) and its association with MACE was mostly through direct effect with small proportion mediated by abnormal cardiac PET or known CAD. CONCLUSION: Among patients referred for cardiac rest/stress PET, financial hardship independently associates with myocardial perfusion abnormalities and MACE; however, its effect on MACE is largely not mediated by abnormal myocardial perfusion or known CAD suggesting distinct impact of financial hardship beyond traditional risk factors and CAD that deserves attention and intervention to effectively reduced adverse outcomes. Having medical insurance does not consistently protect from financial hardship and a more preventive-oriented restructuring may provide better outcomes at lower cost.

Subendocardial and Transmural Myocardial Ischemia: Clinical Characteristics, Prevalence, and Outcomes With and Without Revascularization.

BACKGROUND: Subendocardial ischemia is commonly diagnosed but not quantified by imaging. OBJECTIVES: This study sought to define size and severity of subendocardial and transmural stress perfusion deficits, clinical associations, and outcomes. METHODS: Regional rest-stress perfusion in mL/min/g, coronary flow reserve, coronary flow capacity (CFC), relative stress flow, subendocardial stress-to-rest ratio and stress subendocardial-to-subepicardial ratio as percentage of left ventricle were measured by positron emission tomography (PET) with rubidium Rb 82 and dipyridamole stress in serial 6,331 diagnostic PETs with prospective 10-year follow-up for major adverse cardiac events with and without revascularization. RESULTS: Of 6,331 diagnostic PETs, 1,316 (20.7%) had severely reduced CFC with 41.4% having angina or ST-segment depression (STΔ) >1 mm during hyperemic stress, increasing with size. For 5,015 PETs with no severe CFC abnormality, 402 (8%) had angina or STΔ during stress, and 82% had abnormal subendocardial perfusion with 8.7% having angina or STΔ >1 mm during dipyridamole stress. Of 947 cases with stress-induced angina or STΔ >1 mm, 945 (99.8%) had reduced transmural or subendocardial perfusion reflecting sufficient microvascular function to increase coronary blood flow and reduce intracoronary pressure, causing reduced subendocardial perfusion; only 2 (0.2%) had normal subendocardial perfusion, suggesting microvascular disease as the cause of the angina. Over 10-year follow-up (mean 5 years), severely reduced CFC associated with major adverse cardiac events of 44.4% compared to 8.8% for no severe CFC (unadjusted P < 0.00001) and mortality of 15.2% without and 6.9% with revascularization (P < 0.00002) confirmed by multivariable Cox regression modeling. For no severe CFC, mortality was 3% with and without revascularization (P = 0.90). CONCLUSIONS: Reduced subendocardial perfusion on dipyridamole PET without regional stress perfusion defects is common without angina, has low risk of major adverse cardiac events, reflecting asymptomatic nonobstructive diffuse coronary artery disease, or angina without stenosis. Severely reduced CFC causes angina in fewer than one-half of cases but incurs high mortality risk that is significantly reduced after revascularization.

Double Delayed Enhancement: Concomitant Cardiac Amyloidosis and Acute Coronary Embolism.

Hereditary cardiac amyloidosis (CA) is a relatively rare cause of nonischemic cardiomyopathy. The risk of intracardiac thrombi increases significantly in patients with CA. We report a case of a patient presenting with chest pain and acute myocardial infarction who was subsequently diagnosed with concomitant CA and acute coronary embolism.

Design and rationale of the randomized trial of comprehensive lifestyle modification, optimal pharmacological treatment and utilizing PET imaging for quantifying and managing stable coronary artery disease (the CENTURY study).

BACKGROUND: The literature reports no randomized trial in chronic coronary artery disease (CAD) of a comprehensive management strategy integrating intense lifestyle management, maximal medical treatment to specific goals and high precision quantitative cardiac positron emission tomography (PET) for identifying high mortality risk patients needing essential invasive procedures. We hypothesize that this comprehensive strategy achieves greater risk factor reduction, lower major adverse cardiovascular events and fewer invasive procedures than standard practice. METHODS: The CENTURY Study (NCT00756379) is a randomized-controlled-trial study in patients with stable or at high risk for CAD. Patients are randomized to standard of care (Standard group) or intense comprehensive lifestyle-medical treatment to targets and PET guided interventions (Comprehensive group). Comprehensive Group patients are regularly consulted by the CENTURY team implementing diet/lifestyle/exercise program and medical treatment to target risk modification. Cardiac PET at baseline, 24-, and 60-months quantify the physiologic severity of CAD and guide interventions in the Comprehensive group while patients and referring physicians of the Standard group are blinded to PET results. The primary end-point is the CENTURY risk score reduction during 5 years follow-up. The secondary endpoint is a composite of death, non-fatal myocardial infarction, stroke, and coronary revascularization. CONCLUSIONS: The CENTURY Study is the first study in stable CAD to test the incremental benefit of a comprehensive strategy integrating intense lifestyle modification, medical treatment to specific goals, and high-precision quantitative myocardial perfusion imaging to guide revascularization. A total of 1028 patients have been randomized, and the 5 years follow-up will conclude in 2022.

Reliability and Reproducibility of Absolute Myocardial Blood Flow: Does It Depend on the PET/CT Technology, the Vasodilator, and/or the Software?

PURPOSE OF REVIEW: The COURAGE and ISCHEMIA trials showed no reduced mortality after revascularization compared to medical treatment. Is this lack of benefit due to revascularization having no benefit regardless of CAD severity or to suboptimal patient selection due to non-quantitative cardiac imaging? RECENT FINDINGS: Comprehensive, integrated, myocardial perfusion quantified by regional pixel distribution of coronary flow capacity (CFC) is the final common expression of objective CAD severity for which revascularization reduces mortality. Current lack of revascularization benefit derives from narrow thinking focused on measuring one isolated aspect of coronary characteristics, such as angiogram stenosis, its fractional flow reserve (FFR), anatomic FFR simulations, relative stress imaging, absolute stress ml/min/g or coronary flow reserve (CFR) alone, or even more narrowly on global CFR or fixed regions of interest in assumed coronary artery distributions, or in arbitrary 17 segments on bull's-eye displays, rather than regional pixel distribution of perfusion metrics as they actually are in an individual. Comprehensive integration of all quantitative perfusion metrics per regional pixel into coronary flow capacity guides artery-specific interventions for reduced mortality in non-acute CAD but requires addressing the methodologic questions in the title.

Resolving the Disproportionate Left Ventricular Enlargement in Mitral Valve Prolapse Due to Barlow Disease: Insights From Cardiovascular Magnetic Resonance.

OBJECTIVES: This study hypothesized that left ventricular (LV) enlargement in Barlow disease can be explained by accounting for the total volume load that consists of transvalvular mitral regurgitation (MR) and the prolapse volume. BACKGROUND: Barlow disease is characterized by long prolapsing mitral leaflets that can harbor a significant amount of blood-the prolapse volume-at end-systole. The LV in Barlow disease can be disproportionately enlarged relative to MR severity, leading to speculation of Barlow cardiomyopathy. METHODS: Cardiac magnetic resonance (CMR) was used to compare MR, prolapse volume, and heart chambers remodeling in patients with Barlow disease (bileaflet prolapse [BLP]) and in single leaflet prolapse (SLP). RESULTS: A total of 157 patients (81 with BLP, 76 with SLP) were included. Patients with SLP were older and more had hypertension. Patients with BLP had more heart failure. Indexed LV end-diastolic volume was larger in BLP despite similar transvalvular MR. However, the prolapse volume was larger in BLP, which led to larger total volume load compared with SLP. Increasing tertiles of prolapse volume and MR both led to an incremental increase in LV end-diastolic volume in BLP. Using the total volume load improved the correlation with indexed LV end-diastolic volume in the BLP group, which closely matched that of SLP. A multivariable model that incorporated the prolapse volume explained left heart chamber enlargement better than a MR-based model, independent of prolapse category. CONCLUSIONS: The prolapse volume is part of the total volume load exerted on the LV during the cardiac cycle and could help explain the disproportionate LV enlargement relative to MR severity noted in Barlow disease.

Extracellular Volume in Primary Mitral Regurgitation.

OBJECTIVES: This study used cardiovascular magnetic resonance (CMR) to evaluate whether elevated extracellular volume (ECV) was associated with mitral valve prolapse (MVP) or if elevated ECV was a consequence of remodeling independent of primary mitral regurgitation (MR) etiology. BACKGROUND: Replacement fibrosis in primary MR is more prevalent in MVP; however, data on ECV as a surrogate for diffuse interstitial fibrosis in primary MR are limited. METHODS: Patients with chronic primary MR underwent comprehensive CMR phenotyping and were stratified into an MVP cohort (>2 mm leaflet displacement on a 3-chamber cine CMR) and a non-MVP cohort. Factors associated with ECV and replacement fibrosis were assessed. The association of ECV and symptoms related to MR and clinical events (mitral surgery and cardiovascular death) was ascertained. RESULTS: A total of 424 patients with primary MR (229 with MVP and 195 non-MVP) were enrolled. Replacement fibrosis was more prevalent in the MVP cohort (34.1% vs. 6.7%; p < 0.001), with bi-leaflet MVP having the strongest association with replacement fibrosis (odds ratio: 10.5; p < 0.001). ECV increased with MR severity in a similar fashion for both MVP and non-MVP cohorts and was associated with MR severity but not MVP on multivariable analysis. Elevated ECV was independently associated with symptoms related to MR and clinical events. CONCLUSIONS: Although replacement fibrosis was more prevalent in MVP, diffuse interstitial fibrosis as inferred by ECV was associated with MR severity, regardless of primary MR etiology. ECV was independently associated with symptoms related to MR and clinical events. (DeBakey Cardiovascular Magnetic Resonance Study [DEBAKEY-CMR]; NCT04281823).

Mortality Prediction by Quantitative PET Perfusion Expressed as Coronary Flow Capacity With and Without Revascularization.

OBJECTIVES: This study sought to determine the relationship between the severity of reduced quantitative perfusion parameters and mortality with and without revascularization. BACKGROUND: The physiological mechanisms for differential mortality risk of coronary flow reserve (CFR) and coronary flow capacity (CFC) before and after revascularization are unknown. METHODS: Global and regional rest-stress (ml/min/g), CFR, their regional per-pixel combination as CFC, and relative stress in ml/min/g were measured as percent of LV in all serial routine 5,274 diagnostic PET scans with systematic follow-up over 10 years (mean 4.2 ± 2.5 years) for all-cause mortality with and without revascularization. RESULTS: Severely reduced CFR of 1.0 to 1.5 and stress perfusion ≤1.0 cc/min/g incurred increasing size-dependent risks that were additive because regional severely reduced CFC (CFCsevere) was associated with the highest major adverse cardiac event rate of 80% (p < 0.0001 vs. either alone) and a mortality risk of 14% (vs. 2.3% for no CFCsevere; p = 0.001). Small regions of CFCsevere ≤0.5% predicted high risk (p < 0.0001 vs. no CFCsevere) related to a wave front of border zones at risk around the small most severe center. By receiver-operating characteristic analysis, relative stress topogram maps of stress (ml/min/g) as a fraction of LV defined these border zones at risk or for mildly reduced CFC (area under the curve [AUC]: 0.69) with a reduced relative tomographic subendocardial-to-subepicardial ratio. CFCsevere incurred the highest mortality risk that was reduced by revascularization (p = 0.005 vs. no revascularization) for artery-specific stenosis not defined by global CFR or stress perfusion alone. CONCLUSIONS: CFC is associated with the size-dependent highest mortality risk resulting from the additive risk of CFR and stress (ml/min/g) that is significantly reduced after revascularization, a finding not seen for global CFR. Small regions of CFCsevere ≤0.5% of LV also carry a high risk because of the surrounding border zones at risk defined by relative stress perfusion and a reduced relative subendocardial-to-subepicardial ratio.

Pitfalls in quantitative myocardial PET perfusion II: Arterial input function.

RATIONALE: We aimed to define the impact of variable arterial input function on myocardial perfusion severity that may misguide interventional decisions and relates to limited capacity of 3D PET for high-count arterial input function of standard bolus R-82. METHODS: We used GE Discovery-ST 16 slice PET-CT, serial 2D and 3D acquisitions of variable Rb-82 dose in a dynamic circulating arterial function model, static resolution and uniformity phantoms, and in patients with dipyridamole stress to quantify per-pixel rest and stress cc·min-1·g-1, CFR and CFC with (+) and (-) 10% simulated change in arterial input. RESULTS: For intermediate, border zone severity of stress perfusion, CFR and CFC comprising 7% of 3987 cases, simulated arterial input variability of ± 10% may cause over or underestimation of perfusion severity altering interventional decisions. In phantom tests, current 3D PET has capacity for quantifying high activity of arterial input and high-count per-pixel values of perfusion metrics per artery or branches. CONCLUSIONS: Accurate, reproducible arterial input function is essential for at least 7% of patients at thresholds of perfusion severity for optimally guiding interventions and providing high-activity regional per-pixel perfusion metrics by 3D PET for displaying complex quantitative perfusion readily understood ("owned") by interventionalists to guide procedures.

Pitfalls in quantitative myocardial PET perfusion I: Myocardial partial volume correction.

BACKGROUND: PET quantitative myocardial perfusion requires correction for partial volume loss due to one-dimensional LV wall thickness smaller than scanner resolution. METHODS: We aimed to assess accuracy of risk stratification for death, MI, or revascularization after PET using partial volume corrections derived from two-dimensional ACR and three-dimensional NEMA phantoms for 3987 diagnostic rest-stress perfusion PETs and 187 MACE events. NEMA, ACR, and Tree phantoms were imaged with Rb-82 or F-18 for size-dependent partial volume loss. Perfusion and Coronary Flow Capacity were recalculated using different ACR- and NEMA-derived partial volume corrections compared by Kolmogorov-Smirnov statistics to standard perfusion metrics with established correlations with MACE. RESULTS: Partial volume corrections based on two-dimensional ACR rods (two equal radii) and three-dimensional NEMA spheres (three equal radii) over estimate partial volume corrections, quantitative perfusion, and Coronary Flow Capacity by 50% to 150% over perfusion metrics with one-dimensional partial volume correction, thereby substantially impairing correct risk stratification. CONCLUSIONS: ACR (2-dimensional) and NEMA (3-dimensional) phantoms overestimate partial volume corrections for 1-dimensional LV wall thickness and myocardial perfusion that are corrected with a simple equation that correlates with MACE for optimal risk stratification applicable to most PET-CT scanners for quantifying myocardial perfusion.

Safety of Transesophageal Echocardiography in Patients with Thrombocytopenia.

BACKGROUND: According to current literature and guidelines, thrombocytopenia is considered a relative contraindication for performing transesophageal echocardiogram (TEE). In cancer patients, thrombocytopenia is frequently present. No prior studies have assessed the safety and complications of TEE in a thrombocytopenic population. METHODS: From January 2002 to December 2017, all patients who underwent TEE at MD Anderson Cancer Center in the nonoperative setting were included in the study. Patient characteristics, laboratory data, indications, and complications of TEE were obtained from medical records. Thrombocytopenia was defined as platelet count <100,000/µL prior to procedure. In this retrospective study, medical records were reviewed up to 30 days after procedure to search for possible complications related to TEE. RESULTS: During the study period, 2,345 TEE studies were performed. The mean age was 58.2 ± 15.3 years and 58.8% of patients were male. Thrombocytopenia was found in 814 patients (34.7%). More thrombocytopenic patients had hematologic malignancy, when compared with patients with normal platelet level (79.7% vs 30.2%; P < .001). The most common indication for TEE study was to evaluate for suspected endocarditis (48.0%) and was found more frequently in thrombocytopenic patients compared with those with normal platelet count (69.5% vs 36.5%; P < .001). Overall, 10 patients (0.4%) had complications related to TEE: eight minor oropharyngeal bleeding that did not require transfusion, one transient atrial fibrillation, and one esophageal perforation. There was no major bleeding, respiratory failure, or death related to TEE examination during the study period. Minor oropharyngeal bleeding was the only complication seen in thrombocytopenic patients (seven patients, 0.3%). CONCLUSIONS: Thrombocytopenia is common in cancer patients undergoing TEE. TEE-related complications are minimal in patients with both normal or low platelet count. With appropriate patient preparation and careful probe manipulation, TEE can be safely performed in thrombocytopenic patients.

Outcomes of Acute Myocardial Infarction in Patients with Influenza and Other Viral Respiratory Infections.

BACKGROUND: Acute influenza infection can trigger acute myocardial infarction, however, outcome of patients with acute myocardial infarction during influenza infection is largely unknown. METHODS: Patients ≥18 years old with ST-elevation and non-ST-elevation myocardial infarction during January 2013-December 2014 were identified using the National Inpatient Sample. The clinical outcomes were compared among patients who had no respiratory infection to the ones with influenza and other viral respiratory infections using propensity score-matched analysis. RESULTS: Of 1,884,985 admissions for acute myocardial infarction, acute influenza and other viral infections were diagnosed in 9,885 and 11,485 patients, respectively, accounting for 1.1% of patients. Acute myocardial infarction patients with concomitant influenza infection had a worse outcome than those with acute myocardial infarction alone, in terms of in-hospital case fatality rate, development of shock, acute respiratory failure, acute kidney injury, and higher rate of blood transfusion after propensity scores. The length of stay is also significantly longer in influenza patients with acute myocardial infarction, compared with patients with acute myocardial infarction alone. However, patients who developed acute myocardial infarction during other viral respiratory infection have a higher rate of acute respiratory failure but overall lower mortality rate, and are less likely to develop shock or require blood transfusion after propensity match. Despite presenting with acute myocardial infarction, less than one-fourth of patients with concomitant influenza infection underwent coronary angiography, but more than half (51.4%) required revascularization. CONCLUSION: Influenza infection is associated with worse outcomes in acute myocardial infarction patients, and patients were less likely to receive further evaluation with invasive coronary angiography.

Quantitative myocardial perfusion positron emission tomography and caffeine revisited with new insights on major adverse cardiovascular events and coronary flow capacity.

AIMS: To evaluate effects of caffeine on quantitative myocardial perfusion by positron emission tomography (PET) and associated major adverse cardiovascular events (MACE). METHODS AND RESULTS: Serum caffeine was measured for all 6087 PETs with 328 positive results (5.4%). Paired caffeine positive/negative PETs (84 patients for dipyridamole with median caffeine 1.6 mg/L, and additional 25 volunteers for regadenoson with median caffeine 7.4 mg/L) were compared for quantitative perfusion. Multivariate regression analysis for associations among caffeine, clinical/imaging variables, predicted caffeine probability was performed. MACEs were followed up to 9 years after PETs. For caffeine vs. no caffeine, respectively, stress flow was 1.74 ± 0.55 vs. 2.14 ± 0.53 for dipyridamole and 1.82 ± 0.61 vs. 2.33 ± 0.49 mL/min/g for regadenoson, and coronary flow reserve (CFR) was 2.26 ± 0.67 vs. 2.67 ± 0.72 for dipyridamole and 1.84 ± 0.33 vs. 2.31 ± 0.41 for regadenoson (all P < 0.001). Subjects were reclassified from high-risk CFR ≤2.0 with caffeine to low-risk CFR >2.0 without caffeine in 66.7% and 80% of dipyridamole and regadenoson caffeine-no-caffeine pairs, respectively. While relative images showed no differences, caffeine significantly altered coronary flow capacity (CFC) to false negative and false positive severity in 2.1% and 5.5% of the 328 caffeine positives, respectively (0.1% and 0.3% of 6087 PETs) but without change in severity guided management in most patients (92.4% of 328 caffeine or 99.6% of total 6087 PETs). CONCLUSION: Even low serum caffeine levels reduce quantitative perfusion during vasodilatory stress with false positive or false negative results minimized by empathic instruction, CFC analysis or repeat PET after strict caffeine abstention for definitive individualized risk stratification and management.

Myocardial Fibrosis in Patients With Primary Mitral Regurgitation With and Without Prolapse.

BACKGROUND: Recent studies reported left ventricular (LV) fibrosis in patients with primary mitral regurgitation (MR) thought to be principally due to mitral valve prolapse (MVP). OBJECTIVES: This study sought to evaluate the prevalence, characteristics, and prognostic implications of LV fibrosis in a large cohort of primary MR patients with and without MVP using cardiovascular magnetic resonance (CMR). METHODS: Patients referred for contrast CMR assessment of chronic primary MR were enrolled and underwent comprehensive assessment of cardiac remodeling, severity of MR, and LV replacement fibrosis. Primary MR patients were stratified into: an MVP group if there was >2 mm mitral leaflet displacement on cine-CMR, or a non-MVP group. Patients were followed for arrhythmic events (sudden cardiac death, aborted sudden cardiac arrest, and sustained or inducible ventricular arrhythmia). RESULTS: A total of 356 primary MR patients (177 MVP and 179 non-MVP) were enrolled. LV fibrosis was more prevalent in the MVP group than the non-MVP group (36.7% vs. 6.7%; p < 0.001). The presence of MVP had the strongest association (odds ratio: 6.82; p < 0.001) with LV fibrosis even after adjustment for clinical variables, measures of cardiac remodeling, and MR severity. During follow-up (median 1,354 days), MVP patients with LV fibrosis had the highest event rate for arrhythmic events. CONCLUSIONS: In primary MR patients, LV fibrosis is more prevalent in MVP than non-MVP, suggesting a unique pathophysiology beyond volume overload in MVP. LV fibrosis in primary MR may represent a risk marker of arrhythmic events.