Prognostic value of myocardial flow reserve vs corrected myocardial flow reserve in patients without obstructive coronary artery disease.

BACKGROUND: Myocardial flow reserve (MFR) by positron emission tomography (PET) is a validated measure of cardiovascular risk. Elevated resting rate pressure product (RPP = heart rate x systolic blood pressure) can cause high resting myocardial blood flow (MBF), resulting in reduced MFR despite normal/near-normal peak stress MBF. When resting MBF is high, it is not known if RPP-corrected MFR (MFRcorrected) helps reclassify CV risk. We aimed to study this question in patients without obstructive coronary artery disease (CAD). METHODS: We retrospectively studied patients referred for rest/stress cardiac PET at our center from 2006 to 2020. Patients with abnormal perfusion (summed stress score >3) or prior coronary artery bypass grafting (CABG) were excluded. MFRcorrected was defined as stress MBF/corrected rest MBF where corrected rest MBF = rest MBF x 10,000/RPP. The primary outcome was major cardiovascular events (MACE): cardiovascular death or myocardial infarction. Associations of MFR and MFRcorrected with MACE were assessed using unadjusted and adjusted Cox regression. RESULTS: 3276 patients were followed for a median of 7 (IQR 3-12) years. 1685 patients (51%) had MFR <2.0, and of those 366 (22%) had an MFR ≥2.0 after RPP correction. MFR <2.0 was associated with an increased absolute risk of MACE (HR 2.24 [1.79-2.81], P < 0.0001). Among patients with MFR <2.0, the risk of MACE was not statistically different between patients with an MFRcorrected ≥2.0 compared with those with MFRcorrected <2.0 (1.9% vs 2.3% MACE/year, HR 0.84 [0.63-1.13], P = 0.26) even after adjustment for confounders (P = 0.66). CONCLUSIONS: In patients without overt obstructive CAD and MFR< 2.0, there was no significant difference in cardiovascular risk between patients with discordant (≥2.0) and concordant (<2) MFR following RPP correction. This suggests that RPP-corrected MFR may not consistently provide accurate risk stratification in patients with normal perfusion and MFR <2.0. Stress MBF and uncorrected MFR should be reported to more reliably convey cardiovascular risk beyond perfusion results.

Lipoprotein(a) and Major Adverse Cardiovascular Events in Patients With or Without Baseline Atherosclerotic Cardiovascular Disease.

BACKGROUND: Lipoprotein(a) [Lp(a)] is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). However, whether the optimal Lp(a) threshold for risk assessment should differ based on baseline ASCVD status is unknown. OBJECTIVES: The purpose of this study was to assess the association between Lp(a) and major adverse cardiovascular events (MACE) among patients with and without baseline ASCVD. METHODS: We studied a retrospective cohort of patients with Lp(a) measured at 2 medical centers in Boston, Massachusetts, from 2000 to 2019. To assess the association of Lp(a) with incident MACE (nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularization, or cardiovascular mortality), Lp(a) percentile groups were generated with the reference group set at the first to 50th Lp(a) percentiles. Cox proportional hazards modeling was used to assess the association of Lp(a) percentile group with MACE. RESULTS: Overall, 16,419 individuals were analyzed with a median follow-up of 11.9 years. Among the 10,181 (62%) patients with baseline ASCVD, individuals in the 71st to 90th percentile group had a 21% increased hazard of MACE (adjusted HR: 1.21; P < 0.001), which was similar to that of individuals in the 91st to 100th group (adjusted HR: 1.26; P < 0.001). Among the 6,238 individuals without established ASCVD, there was a continuously higher hazard of MACE with increasing Lp(a), and individuals in the 91st to 100th Lp(a) percentile group had the highest relative risk with an adjusted HR of 1.93 (P < 0.001). CONCLUSIONS: In a large, contemporary U.S. cohort, elevated Lp(a) is independently associated with long-term MACE among individuals with and without baseline ASCVD. Our results suggest that the threshold for risk assessment may be different in primary vs secondary prevention cohorts.

Comparative Effectiveness of PET and SPECT MPI for Predicting Cardiovascular Events After Kidney Transplant.

BACKGROUND: Advanced chronic kidney disease is associated with high cardiovascular risk, even after kidney transplant. Pretransplant cardiac testing may identify patients who require additional assessment before transplant or would benefit from risk optimization. The objective of the current study was to determine the relative prognostic utility of pretransplant positron emission tomography (PET) and single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) for posttransplant major adverse cardiovascular events (MACEs). METHODS: We retrospectively followed patients who underwent MPI before kidney transplant for the occurrence of MACE after transplant including myocardial infarction, stroke, heart failure, and cardiac death. An abnormal MPI result was defined as a total perfusion deficit >5% of the myocardium. To determine associations of MPI results with MACE, we utilized Cox hazard regression with propensity weighting for PET versus SPECT with model factors, including demographics and cardiovascular risk factors. RESULTS: A total of 393 patients underwent MPI (208 PET and 185 SPECT) and were followed for a median of 5.9 years post-transplant. Most were male (58%), median age was 58 years, and there was a high burden of hypertension (88%) and diabetes (33%). A minority had abnormal MPI (n=58, 15%). In propensity-weighted hazard regression, abnormal PET result was associated with posttransplant MACE (hazard ratio, 3.02 [95% CI, 1.78-5.11]; P<0.001), while there was insufficient evidence of an association of abnormal SPECT result with MACE (1.39 [95% CI, 0.72-2.66]; P=0.33). The explained relative risk of the PET result was higher than the SPECT result (R2 0.086 versus 0.007). Normal PET was associated with the lowest risk of MACE (2.2%/year versus 3.6%/year for normal SPECT; P<0.001). CONCLUSIONS: Kidney transplant recipients are at high cardiovascular risk, despite a minority having obstructive coronary artery disease on MPI. PET MPI findings predict posttransplant MACE. Normal PET may better discriminate lower risk patients compared with normal SPECT, which should be confirmed in a larger prospective study.

Body Composition, Coronary Microvascular Dysfunction, and Future Risk of Cardiovascular Events Including Heart Failure.

BACKGROUND: Body mass index (BMI) is a controversial marker of cardiovascular prognosis, especially in women. Coronary microvascular dysfunction (CMD) is prevalent in obese patients and a better discriminator of risk than BMI, but its association with body composition is unknown. OBJECTIVES: The authors used a deep learning model for body composition analysis to investigate the relationship between CMD, skeletal muscle (SM), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT), and their contribution to adverse outcomes in patients referred for evaluation of coronary artery disease. METHODS: Consecutive patients (n = 400) with normal perfusion and preserved left ventricular ejection fraction on cardiac stress positron emission tomography were followed (median, 6.0 years) for major adverse events, including death and hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was quantified as stress/rest myocardial blood flow from positron emission tomography. SM, SAT, and VAT cross-sectional areas were extracted from abdominal computed tomography at the third lumbar vertebra using a validated automated algorithm. RESULTS: Median age was 63, 71% were female, 50% non-White, and 50% obese. Compared with the nonobese, patients with obesity (BMI: 30.0-68.4 kg/m2) had higher SAT, VAT, and SM, and lower CFR (all P < 0.001). In adjusted analyses, decreased SM but not increased SAT or VAT was significantly associated with CMD (CFR <2; OR: 1.38; 95% CI: 1.08-1.75 per -10 cm2/m2 SM index; P < 0.01). Both lower CFR and SM, but not higher SAT or VAT, were independently associated with adverse events (HR: 1.83; 95% CI: 1.25-2.68 per -1 U CFR and HR: 1.53; 95% CI: 1.20-1.96 per -10 cm2/m2 SM index, respectively; P < 0.002 for both), especially heart failure hospitalization (HR: 2.36; 95% CI: 1.31-4.24 per -1 U CFR and HR: 1.87; 95% CI: 1.30-2.69 per -10 cm2/m2 SM index; P < 0.004 for both). There was a significant interaction between CFR and SM (adjusted P = 0.026), such that patients with CMD and sarcopenia demonstrated the highest rate of adverse events, especially among young, female, and obese patients (all P < 0.005). CONCLUSIONS: In a predominantly female cohort of patients without flow-limiting coronary artery disease, deficient muscularity, not excess adiposity, was independently associated with CMD and future adverse outcomes, especially heart failure. In patients with suspected ischemia and no obstructive coronary artery disease, characterization of lean body mass and coronary microvascular function may help to distinguish obese phenotypes at risk for cardiovascular events.

Coronary Microcirculatory Dysfunction in People With HIV and Its Association With Antiretroviral Therapy.

BACKGROUND: HIV infection and abacavir-containing antiretroviral regimens are associated with vascular endothelial dysfunction and increased cardiovascular risk. Positron emission tomography (PET)-derived myocardial blood flow reserve (MBFR), the ratio of vasodilator stress to rest myocardial blood flow, is a well-validated measure of coronary microvascular health and marker of cardiovascular risk. Our objective was to compare MBFR among people with HIV (PWH) with matched non-HIV controls and to assess whether switching from dolutegravir/lamivudine/abacavir to the non-abacavir regimen bictegravir/emtricitabine/tenofovir alafenamide (TAF) would improve MBFR. METHODS AND RESULTS: Thirty-seven PWH were 1:2 matched on cardiovascular risk factors to 75 people without HIV, and MBFR corrected for differences in resting hemodynamics was compared in a cross-sectional design. PWH were majority men (68%) with a mean age of 56 years. Mean stress myocardial blood flow (1.83 mL/min per g [95% CI, 1.68-1.98] versus 2.40 mL/min per g [95% CI, 2.25-2.54]; P<0.001) and MBFR (2.18 [95% CI, 1.96-2.40] versus 2.68 [95% CI, 2.47-2.89]; P=0.002) was significantly lower in PWH than in people without HIV. In a single-arm, multicenter trial, a subset of 25 PWH who were virologically suppressed on dolutegravir/lamivudine/abacavir underwent positron emission tomography myocardial perfusion imaging at baseline and after switching to bictegravir/emtricitabine/TAF. MBFR was unchanged after switching to bictegravir/emtricitabine/TAF for a mean of 27 weeks (MBFR, 2.34 to 2.29; P=0.61), except in PWH with impaired MBFR at baseline (<2.00; N=6) in whom MBFR increased from 1.58 to 2.02 (P=0.02). CONCLUSIONS: PWH had reduced coronary microvascular function compared with controls without HIV. Coronary microvascular function did not improve after switching from dolutegravir/lamivudine/abacavir to bictegravir/emtricitabine/TAF. REGISTRATION: URL: https://www.clinicaltrials.gov; unique identifier: NCT03656783.

Feasibility of Simultaneous Quantification of Myocardial and Renal Perfusion With Cardiac Positron Emission Tomography.

BACKGROUND: Given the central importance of cardiorenal interactions, mechanistic tools for evaluating cardiorenal physiology are needed. In the heart and kidneys, shared pathways of neurohormonal activation, hypertension, and vascular and interstitial fibrosis implicate the relevance of systemic vascular health. The availability of a long axial field of view positron emission tomography (PET)/computed tomography (CT) system enables simultaneous evaluation of cardiac and renal blood flow. METHODS: This study evaluated the feasibility of quantification of renal blood flow using data acquired during routine, clinically indicated 13N-ammonia myocardial perfusion PET/CT. Dynamic PET image data were used to calculate renal blood flow. Reproducibility was assessed by the intraclass correlation coefficient among 3 independent readers. PET-derived renal blood flow was correlated with imaging and clinical parameters in the overall cohort and with histopathology in a small companion study of patients with a native kidney biopsy. RESULTS: Among 386 consecutive patients with myocardial perfusion PET/CT, 296 (76.7%) had evaluable images to quantify renal perfusion. PET quantification of renal blood flow was highly reproducible (intraclass correlation coefficient 0.98 [95% CI, 0.93-0.99]) and was correlated with the estimated glomerular filtration rate (r=0.64; P<0.001). Compared across vascular beds, resting renal blood flow was correlated with maximal stress myocardial blood flow and myocardial flow reserve (stress/rest myocardial blood flow), an integrated marker of endothelial health. In patients with kidney biopsy (n=12), resting PET renal blood flow was strongly negatively correlated with histological interstitial fibrosis (r=-0.85; P<0.001). CONCLUSIONS: Renal blood flow can be reliably measured from cardiac 13N-ammonia PET/CT and allows for simultaneous assessment of myocardial and renal perfusion, opening a potential novel avenue to interrogate the mechanisms of emerging therapies with overlapping cardiac and renal benefits.

Coronary Flow Reserve, Inflammation, and Myocardial Strain: The CIRT-CFR Trial.

Inflammation is a key determinant of cardiovascular outcomes, but its role in heart failure is uncertain. In patients with cardiometabolic disease enrolled in the prospective, multicenter ancillary study of CIRT (Cardiovascular Inflammation Reduction Trial), CIRT-CFR (Coronary Flow Reserve to Assess Cardiovascular Inflammation), impaired coronary flow reserve was independently associated with increased inflammation and myocardial strain despite well-controlled lipid, glycemic, and hemodynamic profiles. Inflammation modified the relationship between CFR and myocardial strain, disrupting the association between cardiac blood flow and function. Future studies are needed to investigate whether an early inflammation-mediated reduction in CFR capturing microvascular ischemia may lead to heart failure in patients with cardiometabolic disease. (Cardiovascular Inflammation Reduction Trial [CIRT]; NCT01594333; Coronary Flow Reserve to Assess Cardiovascular Inflammation [CIRT-CFR]; NCT02786134).

Functional testing, coronary artery calcifications, and outcomes in Hodgkin lymphoma survivors treated with chest radiation.

BACKGROUND: Consensus guidelines recommend periodic screening for coronary artery disease (CAD) in Hodgkin lymphoma (HL) survivors treated with radiation therapy (RT) to the chest. However, the prognostic utility of screening strategies in this population remains unclear. We evaluated the association between functional testing, coronary artery calcifications (CAC), and guideline-based risk assessment and major adverse cardiovascular events (MACE) in HL survivors treated with RT. METHODS: We retrospectively studied HL survivors treated with RT who underwent functional testing between 2003 and 2020 and chest computed tomography (CT) within 12 months of each other at our center. CAC was assessed semi-quantitatively from CT images. Cardiovascular risk was estimated using the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. Diagnostic test characteristics were calculated using major adverse cardiac events (MACE) during follow-up as the gold standard. RESULTS: The study included 159 patients (median age at functional testing 48 years, median age at HL diagnosis 27 years, 62.9% female). Abnormal functional testing had the highest specificity (94.2% (95% CI 88.4%-97.6%)) and positive likelihood ratio (4.55 (95% CI 1.86-11.13)) while CAC had the highest sensitivity (63.2% (95% CI 46.0%-78.2%)) and lowest negative likelihood ratio (0.52 (95% CI 0.34-0.80)). Specificity for ACC/AHA risk assessment was also high (88.5% (95% CI 81.1%-93.7%)). Over 3.3 years of follow-up, abnormal functional testing (adjusted subdistribution hazard ratio (SHR) 5.10, 95% CI 2.41 - 10.78, p < 0.001) and CAC (adjusted SHR 3.58, 95% CI 1.35 - 9.47, p = 0.010) were both significantly associated with MACE. CONCLUSIONS: In HL survivors treated with RT, both abnormal functional testing and ACC/AHA risk assessment had high specificity for subsequent MACE, but CAC had higher sensitivity. Further research is needed to inform CAD screening and primary prevention strategies in this population.

Prior SARS-CoV-2 Infection Is Associated With Coronary Vasomotor Dysfunction as Assessed by Coronary Flow Reserve From Cardiac Positron Emission Tomography.

Background Cardiovascular complications from COVID-19 contribute to its high morbidity and mortality. The effect of COVID-19 infection on the coronary vasculature is not known. The objective of this study was to investigate the prevalence of coronary vasomotor dysfunction identified by coronary flow reserve from cardiac positron emission tomography in patients with previous COVID-19 infection. Methods and Results All patients who had polymerase chain reaction-confirmed SARS-CoV-2 infection referred for myocardial stress perfusion positron emission tomography imaging at Brigham and Women's Hospital from April 2020 to July 2021 were compared with a matched control group without prior SARS-CoV-2 infection imaged in the same period. The main outcome was the prevalence of coronary vasomotor dysfunction. Myocardial perfusion and myocardial blood flow reserve were quantified using N13-ammonia positron emission tomography imaging. Thirty-four patients with prior COVID-19 were identified and compared with 103 matched controls. The median time from polymerase chain reaction-confirmed SARS-CoV-2 to cardiac positron emission tomography was 4.6 months (interquartile range,1.2-5.6 months). There were 16 out of 34 (47%) patients previously hospitalized for COVID-19 infection. Baseline cardiac risk factors were common, and 18 (53%) patients in the COVID-19 group had abnormal myocardial perfusion. Myocardial blood flow reserve was abnormal (<2) in 44.0% of the patients with COVID-19 compared with 11.7% of matched controls (P<0.001). The mean myocardial blood flow reserve was 19.4% lower in patients with COVID-19 compared with control patients (2.00±0.45 versus 2.48±0.47, P<0.001). Conclusions Myocardial blood flow reserve was impaired in patients with prior COVID-19 infection compared with cardiovascular risk factor-matched controls, suggesting a relationship between SARS-CoV-2 infection and coronary vascular health. These data highlight the need to assess long-term consequences of COVID-19 on vascular health in future prospective studies.

Accuracy and Reproducibility of Myocardial Blood Flow Quantification by Single Photon Emission Computed Tomography Imaging in Patients With Known or Suspected Coronary Artery Disease.

BACKGROUND: Single photon emission computed tomography (SPECT) has limited ability to identify multivessel and microvascular coronary artery disease. Gamma cameras with cadmium zinc telluride detectors allow the quantification of absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR). However, evidence of its accuracy is limited, and of its reproducibility is lacking. We aimed to validate 99mTc-sestamibi SPECT MBF and MFR using standard and spline-fitted reconstruction algorithms compared with 13N-ammonia positron emission tomography in a cohort of patients with known or suspected coronary artery disease and to evaluate the reproducibility of this technique. METHODS: Accuracy was assessed in 34 participants who underwent dynamic 99mTc-sestamibi SPECT and 13N-ammonia positron emission tomography and reproducibility in 14 participants who underwent 2 99mTc-sestamibi SPECT studies, all within 2 weeks. A rest/pharmacological stress single-day SPECT protocol was performed. SPECT images were reconstructed using a standard ordered subset expectation maximization (OSEM) algorithm with (N=21) and without (N=30) application of spline fitting. SPECT MBF was quantified using a net retention kinetic model' and MFR was derived as the stress/rest MBF ratio. RESULTS: SPECT global MBF with splines showed good correlation with 13N-ammonia positron emission tomography (r=0.81, P<0.001) and MFR estimates (r=0.74, P<0.001). Correlations were substantially weaker for standard reconstruction without splines (r=0.61, P<0.001 and r=0.34, P=0.07, for MBF and MFR, respectively). Reproducibility of global MBF estimates with splines in paired SPECT scans was good (r=0.77, P<0.001), while ordered subset expectation maximization without splines led to decreased MBF (r=0.68, P<0.001) and MFR correlations (r=0.33, P=0.3). There were no significant differences in MBF or MFR between the 2 reproducibility scans independently of the reconstruction algorithm (P>0.05 for all). CONCLUSIONS: MBF and MFR quantification using 99mTc-sestamibi cadmium zinc telluride SPECT with spatiotemporal spline fitting improved the correlation with 13N-ammonia positron emission tomography flow estimates and test/retest reproducibility. The use of splines may represent an important step toward the standardization of SPECT flow estimation.

Usefulness of ventilatory inefficiency in predicting prognosis across the heart failure spectrum.

AIMS: The minute ventilation-carbon dioxide production relationship (VE/VCO2 slope) is widely used for prognostication in heart failure (HF) with reduced left ventricular ejection fraction (LVEF). This study explored the prognostic value of VE/VCO2 slope across the spectrum of HF defined by ranges of LVEF. METHODS AND RESULTS: In this single-centre retrospective observational study of 1347 patients with HF referred for cardiopulmonary exercise testing, patients with HF were categorized into HF with reduced (HFrEF, LVEF < 40%, n = 598), mid-range (HFmrEF, 40% ≤ LVEF < 50%, n = 164), and preserved (HFpEF, LVEF ≥ 50%, n = 585) LVEF. Four ventilatory efficiency categories (VC) were defined: VC-I, VE/VCO2 slope ≤ 29; VC-II, 29 < VE/VCO2 slope < 36; VC-III, 36 ≤ VE/VCO2 slope < 45; and VC-IV, VE/VCO2 slope ≥ 45. The associations of these VE/VCO2 slope categories with a composite outcome of all-cause mortality or HF hospitalization were evaluated for each category of LVEF. Over a median follow-up of 2.0 (interquartile range: 1.9, 2.0) years, 201 patients experienced the composite outcome. Compared with patients in VC-I, those in VC-II, III, and IV demonstrated three-fold, five-fold, and eight-fold increased risk for the composite outcome. This incremental risk was observed across HFrEF, HFmrEF, and HFpEF cohorts. CONCLUSIONS: Higher VE/VCO2 slope is associated with incremental risk of 2 year all-cause mortality and HF hospitalization across the spectrum of HF defined by LVEF. A multilevel categorical approach to the interpretation of VE/VCO2 slope may offer more refined risk stratification than the current binary approach employed in clinical practice.

Coronary vasomotor dysfunction portends worse outcomes in patients with breast cancer.

BACKGROUND: Impaired MFR in the absence of flow-limiting CAD is associated with adverse events. Cardiovascular disease is an important cause of morbidity and mortality in patients with breast cancer. We sought to test the utility of MFR to predict outcomes in a cohort of patients with breast cancer. METHODS: We retrospectively studied consecutive patients with breast cancer or breast cancer survivors who underwent cardiac stress PET imaging from 2006 to 2017 at Brigham and Women's Hospital. Patients with a history of clinically overt CAD, LVEF < 45%, or abnormal myocardial perfusion were excluded. Subjects were followed from time of PET to the occurrence of a first major adverse cardiovascular event (MACE) and all-cause death. RESULTS: The final cohort included 87 patients (median age 69.0 years, 98.9% female, mean MFR 2.05). Over a median follow-up of 7.6 years after PET, the lowest MFR tertile was associated with higher cumulative incidence of MACE (adjusted subdistribution hazard ratio 4.91; 95% CI 1.68-14.38; p = 0.004) when compared with the highest MFR tertile. CONCLUSIONS: In patients with breast cancer, coronary vasomotor dysfunction was associated with incident cardiovascular events. MFR may have potential as a risk stratification biomarker among patients with/survivors of breast cancer.

Association of inflammatory disease and long-term outcomes among young adults with myocardial infarction: the Mass General Brigham YOUNG-MI Registry.

AIMS: Autoimmune systemic inflammatory diseases (SIDs) are associated with an increased risk of cardiovascular (CV) disease, particularly myocardial infarction (MI). However, there are limited data on the prevalence and effects of SID among adults who experience an MI at a young age. We sought to determine the prevalence and prognostic implications of SID among adults who experienced an MI at a young age. METHODS AND RESULTS: The YOUNG-MI registry is a retrospective cohort study from two large academic centres, which includes patients who experienced a first MI at 50 years of age or younger. SID was ascertained through physician review of the electronic medical record (EMR). Incidence of death was ascertained through the EMR and national databases. The cohort consisted of 2097 individuals, with 53 (2.5%) possessing a diagnosis of SID. Patients with SID were more likely to be female (36% vs. 19%, P = 0.004) and have hypertension (62% vs. 46%, P = 0.025). Over a median follow-up of 11.2 years, patients with SID experienced an higher risk of all-cause mortality compared with either the full cohort of non-SID patients [hazard ratio (HR) = 1.95, 95% confidence interval (CI) (1.07-3.57), P = 0.030], or a matched cohort based on age, gender, and CV risk factors [HR = 2.68, 95% CI (1.18-6.07), P = 0.018]. CONCLUSIONS: Among patients who experienced a first MI at a young age, 2.5% had evidence of SID, and these individuals had higher rates of long-term all-cause mortality. Our findings suggest that the presence of SID is associated with worse long-term survival after premature MI.

Role of Exercise Treadmill Testing in the Assessment of Coronary Microvascular Disease.

OBJECTIVES: The authors aimed to study the sensitivity and specificity of exercise treadmill testing (ETT) in the diagnosis of coronary microvascular disease (CMD), as well as the prognostic implications of ETT results in patients with CMD. BACKGROUND: ETT is validated to evaluate for flow-limiting coronary artery disease (CAD), however, little is known about its use for evaluating CMD. METHODS: We retrospectively studied 249 consecutive patients between 2006 and 2016 who underwent ETT and positron emission tomography within 12 months. Patients with obstructive CAD or left ventricular systolic dysfunction were excluded. CMD was defined as a coronary flow reserve <2. Patients were followed for the occurrence of a first major adverse event (composite of death or hospitalization for myocardial infarction or heart failure). RESULTS: The sensitivity and specificity of a positive ETT to detect CMD were 34.7% (95% CI: 25.4%-45.0%) and 64.9% (95% CI: 56.7%-72.5%), respectively. The specificity of a positive ETT to detect CMD increased to 86.8% (95% CI: 80.3%-91.7%) when only classifying studies with ischemic electrocardiogram changes that lasted at least 1 minute into recovery as positive, although at a cost of lower sensitivity (15.3%; 95% CI: 8.8%-24.0%). Over a median follow-up of 6.9 years (IQR: 5.1-8.2 years), 30 (12.1%) patients met the composite endpoint, including 13 (13.3%) with CMD (n = 98). In patients with CMD, ETT result was not associated with the composite endpoint (P = 0.076). CONCLUSIONS: Our data suggest limited sensitivity of ETT to detect CMD. However, a positive ETT with ischemic changes that persist at least 1 minute into recovery in the absence of obstructive CAD should raise suspicion for the presence of CMD given a high specificity. Further study is needed with larger patient sample sizes to assess the association between ETT results and outcomes in patients with CMD.

Low coronary flow relative to myocardial mass predicts heart failure in symptomatic hypertensive patients with no obstructive coronary artery disease.

AIMS: The transition from hypertension to heart failure (HF) remains poorly understood. We hypothesized that insufficient perfusion to match global metabolic demand, reflected by a low ratio of myocardial blood flow to global myocardial mass, may be a HF risk marker. METHODS AND RESULTS: A retrospective cohort (n = 346) of patients with hypertension who underwent clinical positron emission tomography (PET) myocardial perfusion imaging for chest pain and/or dyspnoea at Brigham and Women's Hospital (Boston, MA, USA) were studied. Patients without obstructive coronary artery disease by history or PET perfusion (summed stress score <3), HF, cardiomyopathy, or ejection fraction (EF) <40% were followed for HF hospitalization (primary outcome), all-cause death, and their composite. Myocardial blood flow, left ventricular (LV) mass, volumes, and EF were obtained from PET, and a 'flow/mass ratio' was determined as hyperaemic myocardial blood flow over LV mass indexed to body surface area. A lower flow/mass ratio was independently associated with larger end-diastolic (ß = -0.44, P < 0.001) and end-systolic volume (ß = -0.48, P < 0.001) and lower EF (ß = 0.33, P < 0.001). A flow/mass ratio below the median was associated with an adjusted hazard ratio of 2.47 [95% confidence interval (CI) 1.24-4.93; P = 0.01] for HF hospitalization, 1.95 (95% CI 1.12-3.41; P = 0.02) for death, and 2.20 (95% CI 1.39-3.49; P < 0.001) for the composite. CONCLUSION: An integrated physiological measure of insufficient myocardial perfusion to match global metabolic demand identifies subclinical hypertensive heart disease and elevated risk of HF and death in symptomatic patients with hypertension but without flow-limiting coronary artery disease.

Association of Myocardial Blood Flow Reserve With Adverse Left Ventricular Remodeling in Patients With Aortic Stenosis: The Microvascular Disease in Aortic Stenosis (MIDAS) Study.

Importance: Impaired myocardial flow reserve (MFR) and stress myocardial blood flow (MBF) on positron emission tomography (PET) myocardial perfusion imaging may identify adverse myocardial characteristics, including myocardial stress and injury in aortic stenosis (AS). Objective: To investigate whether MFR and stress MBF are associated with LV structure and function derangements, and whether these parameters improve after aortic valve replacement (AVR). Design, Setting, and Participants: In this single-center prospective observational study in Boston, Massachusetts, from 2018 to 2020, patients with predominantly moderate to severe AS underwent ammonia N13 PET myocardial perfusion imaging for myocardial blood flow (MBF) quantification, resting transthoracic echocardiography (TTE) for assessment of myocardial structure and function, and measurement of circulating biomarkers for myocardial injury and wall stress. Evaluation of health status and functional capacity was also performed. A subset of patients underwent repeated assessment 6 months after AVR. A control group included patients without AS matched for age, sex, and summed stress score who underwent symptom-prompted ammonia N13 PET and TTE within 90 days. Exposures: MBF and MFR quantified on ammonia N13 PET myocardial perfusion imaging. Main Outcomes and Measures: LV structure and function parameters, including echocardiographic global longitudinal strain (GLS), circulating high-sensitivity troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-pro BNP), health status, and functional capacity. Results: There were 34 patients with AS (1 mild, 9 moderate, and 24 severe) and 34 matched control individuals. MFR was independently associated with GLS and LV ejection fraction, (ß,-0.31; P = .03; ß, 0.41; P = .002, respectively). Stress MBF was associated with hs-cTnT (unadjusted ß, -0.48; P = .005) and log NT-pro BNP (unadjusted ß, -0.37; P = .045). The combination of low stress MBF and high hs-cTnT was associated with higher interventricular septal thickness in diastole, relative wall thickness, and worse GLS compared with high stress MBF and low hs-cTnT (12.4 mm vs 10.0 mm; P = .008; 0.62 vs 0.46; P = .02; and -13.47 vs -17.11; P = .006, respectively). In 9 patients studied 6 months after AVR, mean (SD) MFR improved from 1.73 (0.57) to 2.11 (0.50) (P = .008). Conclusions and Relevance: In this study, in AS, MFR and stress MBF were associated with adverse myocardial characteristics, including markers of myocardial injury and wall stress, suggesting that MFR may be an early sensitive marker for myocardial decompensation.

Natural language processing for the assessment of cardiovascular disease comorbidities: The cardio-Canary comorbidity project.

OBJECTIVE: Accurate ascertainment of comorbidities is paramount in clinical research. While manual adjudication is labor-intensive and expensive, the adoption of electronic health records enables computational analysis of free-text documentation using natural language processing (NLP) tools. HYPOTHESIS: We sought to develop highly accurate NLP modules to assess for the presence of five key cardiovascular comorbidities in a large electronic health record system. METHODS: One-thousand clinical notes were randomly selected from a cardiovascular registry at Mass General Brigham. Trained physicians manually adjudicated these notes for the following five diagnostic comorbidities: hypertension, dyslipidemia, diabetes, coronary artery disease, and stroke/transient ischemic attack. Using the open-source Canary NLP system, five separate NLP modules were designed based on 800 "training-set" notes and validated on 200 "test-set" notes. RESULTS: Across the five NLP modules, the sentence-level and note-level sensitivity, specificity, and positive predictive value was always greater than 85% and was most often greater than 90%. Accuracy tended to be highest for conditions with greater diagnostic clarity (e.g. diabetes and hypertension) and slightly lower for conditions whose greater diagnostic challenges (e.g. myocardial infarction and embolic stroke) may lead to less definitive documentation. CONCLUSION: We designed five open-source and highly accurate NLP modules that can be used to assess for the presence of important cardiovascular comorbidities in free-text health records. These modules have been placed in the public domain and can be used for clinical research, trial recruitment and population management at any institution as well as serve as the basis for further development of cardiovascular NLP tools.