Relationship of Subendocardial Perfusion to Myocardial Injury, Cardiac Structure, and Clinical Outcomes Among Patients With Hypertension.

BACKGROUND: Coronary microvascular dysfunction has been implicated in the development of hypertensive heart disease and heart failure, with subendocardial ischemia identified as a driver of sustained myocardial injury and fibrosis. We aimed to evaluate the relationships of subendocardial perfusion with cardiac injury, structure, and a composite of major adverse cardiovascular and cerebral events consisting of death, heart failure hospitalization, myocardial infarction, and stroke. METHODS: Layer-specific blood flow and myocardial flow reserve (MFR; stress/rest myocardial blood flow) were assessed by 13N-ammonia perfusion positron emission tomography in consecutive patients with hypertension without flow-limiting coronary artery disease (summed stress score <3) imaged at Brigham and Women's Hospital (Boston, MA) from 2015 to 2021. In this post hoc observational study, biomarkers, echocardiographic parameters, and longitudinal clinical outcomes were compared by tertiles of subendocardial MFR (MFRsubendo). RESULTS: Among 358 patients, the mean age was 70.6±12.0 years, and 53.4% were male. The median MFRsubendo was 2.57 (interquartile range, 2.08-3.10), and lower MFRsubendo was associated with older age, diabetes, lower renal function, greater coronary calcium burden, and higher systolic blood pressure (P<0.05 for all). In cross-sectional multivariable regression analyses, the lowest tertile of MFRsubendo was associated with myocardial injury and with greater left ventricular wall thickness and volumes compared with the highest tertile. Relative to the highest tertile, low MFRsubendo was independently associated with an increased rate of major adverse cardiovascular and cerebral events (adjusted hazard ratio, 2.99 [95% CI, 1.39-6.44]; P=0.005) and heart failure hospitalization (adjusted hazard ratio, 2.76 [95% CI, 1.04-7.32; P=0.042) over 1.1 (interquartile range, 0.6-2.8) years median follow-up. CONCLUSIONS: Among patients with hypertension without flow-limiting coronary artery disease, impaired MFRsubendo was associated with cardiovascular risk factors, elevated cardiac biomarkers, cardiac structure, and clinical events.

Comparative effectiveness of positron emission tomography and single-photon emission computed tomography myocardial perfusion imaging for predicting risk in patients with cardiometabolic disease.

BACKGROUND: The epidemiology of coronary artery disease (CAD) has shifted, with increasing prevalence of cardiometabolic disease and decreasing findings of obstructive CAD on myocardial perfusion imaging (MPI). Coronary microvascular dysfunction (CMD), defined as impaired myocardial flow reserve (MFR) by positron emission tomography (PET), has emerged as a key mediator of risk. We aimed to assess whether PET MFR provides additive value for risk stratification of cardiometabolic disease patients compared with single-photon emission computed tomography (SPECT) MPI. METHODS: We retrospectively followed patients referred for PET, exercise SPECT, or pharmacologic SPECT MPI with cardiometabolic disease (obesity, diabetes, or chronic kidney disease) and without known CAD. We compared rates and hazards of composite major adverse cardiovascular events (MACEs) (annualized cardiac mortality or acute myocardial infarction) among propensity-matched PET and SPECT patients using Poisson and Cox regression. Normal SPECT was defined as a total perfusion deficit (TPD) of <5%, reflecting the absence of obstructive CAD. Normal PET was defined as a TPD of <5% plus an MFR of ≥2.0. RESULTS: Among 21,544 patients referred from 2006 to 2020, cardiometabolic disease was highly prevalent (PET: 2308 [67%], SPECT: 9984 [55%]) and higher among patients referred to PET (P < 0.001). Obstructive CAD findings (TPD > 5%) were uncommon (PET: 21% and SPECT: 11%). Conversely, impaired MFR on PET (<2.0) was common (62%). In a propensity-matched analysis over a median 6.4-year follow-up, normal PET identified low-risk (0.9%/year MACE) patients, and abnormal PET identified high-risk (4.2%/year MACE) patients with cardiometabolic disease; conversely, those with normal pharmacologic SPECT remained moderate-risk (1.6%/year, P < 0.001 compared to normal PET). CONCLUSIONS: Cardiometabolic disease is common among patients referred for MPI and is associated with a heterogenous level of risk. Compared with pharmacologic SPECT, PET with MFR can detect nonobstructive CAD including CMD and can more accurately discriminate low-risk from higher-risk individuals.

Lipoprotein(a) as a cardiovascular risk factor among patients with and without diabetes Mellitus: the Mass General Brigham Lp(a) Registry.

BACKGROUND: Diabetes mellitus (DM) and Lp(a) are well-established predictors of coronary artery disease (CAD) outcomes. However, their combined association remains poorly understood. OBJECTIVE: To investigate the relationship between elevated Lp(a) and DM with CAD outcomes. METHODS: Retrospective analysis of the MGB Lp(a) Registry involving patients ≥ 18 years who underwent Lp(a) measurements between 2000 and 2019. Exclusion criteria were severe kidney dysfunction, malignant neoplasms, and prior atherosclerotic cardiovascular disease (ASCVD). The primary outcome was a combination of cardiovascular death or myocardial infarction (MI). Elevated Lp(a) was defined as > 90th percentile (≥ 216 nmol/L). RESULTS: Among 6,238 patients who met the eligibility criteria, the median age was 54, 45% were women, and 12% had DM. Patients with DM were older, more frequently male, and had a higher prevalence of additional cardiovascular risk factors. Over a median follow-up of 12.9 years, patients with either DM or elevated Lp(a) experienced higher rates of the primary outcome. Notably, those with elevated Lp(a) had a higher incidence of the primary outcome regardless of their DM status. The annual event rates were as follows: No-DM and Lp(a) < 90th% - 0.6%; No-DM and Lp(a) > 90th% - 1.3%; DM and Lp(a) < 90th% - 1.9%; DM and Lp(a) > 90th% - 4.7% (p < 0.001). After adjusting for confounders, elevated Lp(a) remained independently associated with the primary outcome among both patients with DM (HR = 2.66 [95%CI: 1.55-4.58], p < 0.001) and those without DM (HR = 2.01 [95%CI: 1.48-2.74], p < 0.001). CONCLUSIONS: Elevated Lp(a) constitutes an independent and incremental risk factor for CAD outcomes in patients with and without DM.

Prognostic Value of Left Ventricular 18F-Florbetapir Uptake in Systemic Light-Chain Amyloidosis.

BACKGROUND: Positron emission tomography/computed tomography (PET/CT) with 18F-florbetapir, a novel amyloid-targeting radiotracer, can quantify left ventricular (LV) amyloid burden in systemic light-chain (AL) amyloidosis. However, its prognostic value is not known. OBJECTIVES: The authors' aim was to evaluate the prognostic value of LV amyloid burden quantified by 18F-florbetapir PET/CT, and to identify mechanistic pathways mediating its association with outcomes. METHODS: A total of 81 participants with newly diagnosed AL amyloidosis underwent 18F-florbetapir PET/CT imaging. Amyloid burden was quantified using 18F-florbetapir LV uptake as percent injected dose. The Mayo stage for AL amyloidosis was determined using troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and free light chain levels. Major adverse cardiac events (MACE) were defined as all-cause death, heart failure hospitalization, or cardiac transplantation within 12 months. RESULTS: Among participants (median age, 61 years; 57% males), 36% experienced MACE, increasing from 7% to 63% across tertiles of LV amyloid burden (P < 0.001). LV amyloid burden was associated with MACE (HR: 1.46; 95% CI: 1.16-1.83; P = 0.001). However, this association became nonsignificant when adjusted for Mayo stage. In mediation analysis, the association between LV amyloid burden and MACE was mediated by NT-proBNP (P < 0.001), a marker of cardiomyocyte stretch and heart failure, and a component of Mayo stage. CONCLUSIONS: In this first study to link cardiac 18F-florbetapir uptake to subsequent outcomes, LV amyloid burden estimated by percent injected dose predicted MACE in AL amyloidosis. This effect was not independent of Mayo stage and was mediated primarily through NT-proBNP. These findings provide novel insights into the mechanism linking myocardial amyloid deposits to MACE.

Myocardial Characteristics, Cardiac Structure, and Cardiac Function in Systemic Light-Chain Amyloidosis.

BACKGROUND: In systemic light-chain (AL) amyloidosis, cardiac involvement portends poor outcomes. OBJECTIVES: The authors' objectives were to detect early myocardial alterations, to analyze longitudinal changes with therapy, and to predict major adverse cardiac events (MACE) in participants with AL amyloidosis using cardiac magnetic resonance imaging (MRI). METHODS: Recently diagnosed participants were prospectively enrolled. AL amyloidosis with and without cardiomyopathy (AL-CMP, AL-non-CMP) were defined based on abnormal cardiac biomarkers and wall thickness. MRI was performed at baseline, 6 months in all participants, and 12 months in participants with AL-CMP. MACE were defined as all-cause death, heart failure hospitalization, and cardiac transplantation. Mayo stage was based on troponin T, N-terminal pro-B-type natriuretic peptide, and difference in free light chains. RESULTS: This study included 80 participants (median age 62 years, 58% men). Extracellular volume (ECV) was abnormal (>32%) in all participants with AL-CMP and in 47% of those with AL-non-CMP. ECV tended to increase at 6 months (median +2%; AL-CMP P = 0.120; AL-non-CMP P = 0.018) and returned to baseline values at 12 months in participants with AL-CMP. Global longitudinal strain (GLS) improved at 6 months (median -0.6%; P = 0.048) and 12 months (median -1.2%; P < 0.001) in participants with AL-CMP. ECV and GLS were strongly associated with MACE (P < 0.001) and improved the prognostic value when added to Mayo stage (P ≤ 0.002). No participant with ECV ≤32% had MACE, while 74% of those with ECV >48% had MACE. CONCLUSIONS: In patients with systemic AL amyloidosis, ECV detects subclinical myocardial alterations. With therapy, ECV tends to increase at 6 months and returns to values unchanged from baseline at 12 months, whereas GLS improves at 6 and 12 months in participants with AL-CMP. ECV and GLS offer additional prognostic performance over Mayo stage. (Molecular Imaging of Primary Amyloid Cardiomyopathy [MICA]; NCT02641145).

Mechanisms of left ventricular systolic dysfunction in light chain amyloidosis: a multiparametric cardiac MRI study.

Background: Cardiac systolic dysfunction is a poor prognostic marker in light-chain (AL) cardiomyopathy, a primary interstitial disorder; however, its pathogenesis is poorly understood. Purpose: This study aims to analyze the effects of extracellular volume (ECV) expansion, a surrogate marker of amyloid burden on myocardial blood flow (MBF), myocardial work efficiency (MWE), and left ventricular (LV) systolic dysfunction in AL amyloidosis. Methods: Subjects with biopsy-proven AL amyloidosis were prospectively enrolled (April 2016-June 2021; Clinicaltrials.gov ID NCT02641145) and underwent cardiac magnetic resonance imaging (MRI) to quantify rest MBF by perfusion imaging, LV ejection fraction (LVEF) by cine MRI, and ECV by pre- and post-contrast T1 mapping. The MWE was estimated as external cardiac work from the stroke volume and mean arterial pressure normalized to the LV myocardial mass. Results: Rest MBF in 92 subjects (62 ± 8 years, 52 men) with AL amyloidosis averaged 0.87 ± 0.21 ml/min/g and correlated with MWE (r = 0.42; p < 0.001). Rest MBF was similarly low in subjects with sustained hematologic remission after successful AL amyloidosis therapy (n = 21), as in those with recently diagnosed AL amyloidosis. Both MBF and MWE decreased by ECV tertile (p < 0.01 for linear trends). The association of ECV with MWE comprised a direct effect (84% of the total effect; p < 0.001) on MWE from adverse interstitial remodeling assessed by ECV and an indirect effect (16% of the total effect; p < 0.001) mediated by MBF. There was a significant base-to-apex gradient of rest MBF in subjects with higher amyloid burden. Conclusions: In AL amyloidosis, both MBF and MWE decrease as cardiac amyloid burden and ECV expansion increase. Both structural and vascular changes from ECV expansion and myocardial amyloid burden appear to contribute to lower MWE.

Association of Lipoprotein (a) and Standard Modifiable Cardiovascular Risk Factors With Incident Myocardial Infarction: The Mass General Brigham Lp(a) Registry.

BACKGROUND: Lipoprotein (a) [Lp(a)] is a robust predictor of coronary heart disease outcomes, with targeted therapies currently under investigation. We aimed to evaluate the association of high Lp(a) with standard modifiable risk factors (SMuRFs) for incident first acute myocardial infarction (AMI). METHODS AND RESULTS: This retrospective study used the Mass General Brigham Lp(a) Registry, which included patients aged ≥18 years with an Lp(a) measurement between 2000 and 2019. Exclusion criteria were severe kidney dysfunction, malignant neoplasm, and prior known atherosclerotic cardiovascular disease. Diabetes, dyslipidemia, hypertension, and smoking were considered SMuRFs. High Lp(a) was defined as >90th percentile, and low Lp(a) was defined as <50th percentile. The primary outcome was fatal or nonfatal AMI. A combination of natural language processing algorithms, International Classification of Diseases (ICD) codes, and laboratory data was used to identify the outcome and covariates. A total of 6238 patients met the eligibility criteria. The median age was 54 (interquartile range, 43-65) years, and 45% were women. Overall, 23.7% had no SMuRFs, and 17.8% had ≥3 SMuRFs. Over a median follow-up of 8.8 (interquartile range, 4.2-12.8) years, the incidence of AMI increased gradually, with higher number of SMuRFs among patients with high (log-rank P=0.031) and low Lp(a) (log-rank P<0.001). Across all SMuRF subgroups, the incidence of AMI was significantly higher for patients with high Lp(a) versus low Lp(a). The risk of high Lp(a) was similar to having 2 SMuRFs. Following adjustment for confounders and number of SMuRFs, high Lp(a) remained significantly associated with the primary outcome (hazard ratio, 2.9 [95% CI, 2.0-4.3]; P<0.001). CONCLUSIONS: Among patients with no prior atherosclerotic cardiovascular disease, high Lp(a) is associated with significantly higher risk for first AMI regardless of the number of SMuRFs.

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.

Coronary Microvascular Function Following Severe Preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating proangiogenic and antiangiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk. METHODS: Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography within 4 weeks of delivery. A control group of premenopausal, nonpostpartum women was also included. Myocardial flow reserve, myocardial blood flow, and coronary vascular resistance were compared across groups. sFlt-1 (soluble fms-like tyrosine kinase receptor-1) and PlGF (placental growth factor) were measured at imaging. RESULTS: The primary cohort included 19 women with severe preeclampsia (imaged at a mean of 15.3 days postpartum), 5 with normotensive pregnancy (mean, 14.4 days postpartum), and 13 nonpostpartum female controls. Preeclampsia was associated with lower myocardial flow reserve (ß, -0.67 [95% CI, -1.21 to -0.13]; P=0.016), lower stress myocardial blood flow (ß, -0.68 [95% CI, -1.07 to -0.29] mL/min per g; P=0.001), and higher stress coronary vascular resistance (ß, +12.4 [95% CI, 6.0 to 18.7] mm Hg/mL per min/g; P=0.001) versus nonpostpartum controls. Myocardial flow reserve and coronary vascular resistance after normotensive pregnancy were intermediate between preeclamptic and nonpostpartum groups. Following preeclampsia, myocardial flow reserve was positively associated with time following delivery (P=0.008). The sFlt-1/PlGF ratio strongly correlated with rest myocardial blood flow (r=0.71; P<0.001), independent of hemodynamics. CONCLUSIONS: In this exploratory cross-sectional study, we observed reduced coronary microvascular function in the early postpartum period following preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves coronary microcirculation. Further research is needed to establish interventions to mitigate the risk of preeclampsia-associated cardiovascular disease.

Interplay Between Systemic Inflammation, Myocardial Injury, and Coronary Microvascular Dysfunction in Rheumatoid Arthritis: Results From the LiiRA Study.

BACKGROUND: Coronary microvascular dysfunction as measured by myocardial flow reserve (MFR) is associated with increased cardiovascular risk in rheumatoid arthritis (RA). The objective of this study was to determine the association between reducing inflammation with MFR and other measures of cardiovascular risk. METHODS AND RESULTS: Patients with RA with active disease about to initiate a tumor necrosis factor inhibitor were enrolled (NCT02714881). All subjects underwent a cardiac perfusion positron emission tomography scan to quantify MFR at baseline before tumor necrosis factor inhibitor initiation, and after tumor necrosis factor inhibitor initiation at 24 weeks. MFR <2.5 in the absence of obstructive coronary artery disease was defined as coronary microvascular dysfunction. Blood samples at baseline and 24 weeks were measured for inflammatory markers (eg, high-sensitivity C-reactive protein [hsCRP], interleukin-1b, and high-sensitivity cardiac troponin T [hs-cTnT]). The primary outcome was mean MFR before and after tumor necrosis factor inhibitor initiation, with Δhs-cTnT as the secondary outcome. Secondary and exploratory analyses included the correlation between ΔhsCRP and other inflammatory markers with MFR and hs-cTnT. We studied 66 subjects, 82% of which were women, mean RA duration 7.4 years. The median atherosclerotic cardiovascular disease risk was 2.5%; 47% had coronary microvascular dysfunction and 23% had detectable hs-cTnT. We observed no change in mean MFR before (2.65) and after treatment (2.64, P=0.6) or hs-cTnT. A correlation was observed between a reduction in hsCRP and interleukin-1b with a reduction in hs-cTnT. CONCLUSIONS: In this RA cohort with low prevalence of cardiovascular risk factors, nearly 50% of subjects had coronary microvascular dysfunction at baseline. A reduction in inflammation was not associated with improved MFR. However, a modest reduction in interleukin-1b and no other inflammatory pathways was correlated with a reduction in subclinical myocardial injury. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02714881.

Impact of cardiac size on diagnostic performance of single-photon emission computed tomography myocardial perfusion imaging: insights from the REgistry of Fast Myocardial Perfusion Imaging with NExt generation single-photon emission computed tomography.

AIMS: Variation in diagnostic performance of single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) has been observed, yet the impact of cardiac size has not been well characterized. We assessed whether low left ventricular volume influences SPECT MPI's ability to detect obstructive coronary artery disease (CAD) and its interaction with age and sex. METHODS AND RESULTS: A total of 2066 patients without known CAD (67% male, 64.7 ± 11.2 years) across nine institutions underwent SPECT MPI with solid-state scanners followed by coronary angiography as part of the REgistry of Fast Myocardial Perfusion Imaging with NExt Generation SPECT. Area under receiver-operating characteristic curve (AUC) analyses evaluated the performance of quantitative and visual assessments according to cardiac size [end-diastolic volume (EDV); <20th vs. ≥20th population or sex-specific percentiles], age (<75 vs. ≥75 years), and sex. Significantly decreased performance was observed in patients with low EDV compared with those without (AUC: population 0.72 vs. 0.78, P = 0.03; sex-specific 0.72 vs. 0.79, P = 0.01) and elderly patients compared with younger patients (AUC 0.72 vs. 0.78, P = 0.03), whereas males and females demonstrated similar AUC (0.77 vs. 0.76, P = 0.67). The reduction in accuracy attributed to lower volumes was primarily observed in males (sex-specific threshold: EDV 0.69 vs. 0.79, P = 0.01). Accordingly, a significant decrease in AUC, sensitivity, specificity, and negative predictive value for quantitative and visual assessments was noted in patients with at least two characteristics of low EDV, elderly age, or male sex. CONCLUSION: Detection of CAD with SPECT MPI is negatively impacted by small cardiac size, most notably in elderly and male patients.

Impact of vutrisiran on exploratory cardiac parameters in hereditary transthyretin-mediated amyloidosis with polyneuropathy.

AIMS: HELIOS-A was a Phase 3, open-label study of vutrisiran, an RNA interference therapeutic, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy. This analysis evaluated vutrisiran's impact on exploratory cardiac endpoints in HELIOS-A patients. METHODS AND RESULTS: Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months or intravenous patisiran 0.3 mg/kg every 3 weeks (reference group) for 18 months. Exploratory cardiac endpoints included change from baseline in N-terminal prohormone of brain-type natriuretic peptide (NT-proBNP) and echocardiographic parameters versus external placebo (APOLLO study). The modified intent-to-treat (mITT) population comprised randomized patients receiving any study drug (n = 122). A cardiac subpopulation with evidence of cardiac amyloid involvement (n = 40) was prespecified. 99mTc scintigraphy exploratory assessments in a planned vutrisiran-treated cohort at select sites were compared with baseline. At Month 18, vutrisiran demonstrated beneficial effects on NT-proBNP versus external placebo in the mITT and cardiac subpopulations (adjusted geometric mean fold change ratio [95% confidence interval] 0.480 [0.383-0.600], p = 9.606 × 10-10 and 0.491 [0.337-0.716], p = 0.0004, respectively). Benefits or trends towards benefit in echocardiographic parameters versus external placebo were observed for both populations. In 99mTc scintigraphy assessments, 32/47 (68.1%) and 31/48 (64.6%) patients exhibited reduced normalized left ventricular total uptake and heart-to-contralateral lung ratio, respectively. Perugini grade was reduced or unchanged versus baseline in 55/57 (96.5%) evaluable patients. No increase in cardiac adverse events was observed with vutrisiran versus external placebo. CONCLUSIONS: Vutrisiran demonstrated evidence of potential benefit on cardiac manifestations in patients with ATTRv amyloidosis with polyneuropathy, with an acceptable safety profile.