Prevalence and significance of extracardiac uptake on pyrophosphate imaging in the SCAN-MP study: the first 379 cases.

INTRODUCTION: Technetium-labeled bone-avid radiotracers can be used to diagnose transthyretin cardiac amyloidosis (ATTR-CA). Extracardiac uptake of technetium pyrophosphate (Tc-99m PYP) in this context has not been extensively explored and its significance is not well characterized. We assessed extracardiac Tc-99m PYP uptake in individuals undergoing nuclear scintigraphy and the extent of clinically actionable findings. METHODS: The Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations (SCAN-MP) study utilizes Tc-99m PYP imaging to identify ATTR-CA in self-identified Black and Caribbean Hispanic participants ≥ 60 years old with heart failure. We characterized the distribution of extracardiac uptake, including stratification of findings by timing of scan (1 hour vs 3 hours after Tc-99m PYP administration) and noted any additional testing in these subjects. RESULTS: Of 379 participants, 195 (51%) were male, 306 (81%) Black race, and 120 (32%) Hispanic ethnicity; mean age was 73 years. Extracardiac Tc-99m PYP uptake was found in 42 subjects (11.1%): 21 with renal uptake only, 14 with bone uptake only, 4 with both renal and bone uptake, 2 with breast uptake, and 1 with thyroid uptake. Extracardiac uptake was more common in subjects with Tc-99m PYP scans at 1 hour (23.8%) than at 3 hours (6.2%). Overall, four individuals (1.1%) had clinically actionable findings. CONCLUSION: Extracardiac Tc-99m PYP uptake manifested in about 1 in 9 SCAN-MP subjects but was clinically actionable in only 1.1% of cases.

Design and Rationale the SCAN-MP (Screening for Cardiac Amyloidosis With Nuclear Imaging in Minority Populations) Study.

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is an important cause of heart failure in older individuals. Misfolding and deposition of transthyretin or prealbumin protein causes ATTR-CM in the context of a normal (wild-type) or variant TTR sequence. Variant ATTR-CM is most commonly caused by the substitution of valine for isoleucine at position 122 in transthyretin (Val122Ile or pV142I, almost exclusively observed in individuals of West African ancestry), demonstrated in 3.4% of self-identified Black individuals in the United States with an estimated 1.5 million carriers. Despite the large number of known pV142I carriers, the proportion of older Black patients with heart failure attributable to ATTR-CM remains unknown. Methods To address this knowledge gap, the SCAN-MP (Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations) study was funded by the National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL139671) to enroll a targeted population of self-identified, community-dwelling Black or Caribbean Hispanic patients (many of whom are of West African ancestry) >60 years of age with heart failure and identify ATTR-CM by noninvasive nuclear imaging. The principal objective of SCAN-MP is to determine the prevalence of ATTR-CM in this population. Secondary objectives will explore TTR genotype, demographics, progression of variant versus wild-type ATTR-CM, and biochemical mechanisms of transthyretin amyloid fibril formation. Conclusions The SCAN-MP study is the largest, prospective study of cardiac amyloidosis in Black and Hispanic individuals. Both wild-type and variant ATTR-CM are now treatable with the US Food and Drug-approved drug tafamidis. The insights gained from SCAN-MP are likely to improve those at risk for or afflicted with ATTR-CM. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03812172.

Diagnostic performance characteristics of planar quantitative and semi-quantitative parameters of Tc99m pyrophosphate (PYP) imaging for diagnosis of transthyretin (ATTR) cardiac amyloidosis: the SCAN-MP study.

BACKGROUND: The optimal heart-to-contralateral chest (H/CL) ratio threshold for non-invasive diagnosis of transthyretin cardiac amyloidosis (ATTR-CA) using Tc99m pyrophosphate (PYP) imaging in a population with low pretest probability is not known. METHODS: Using myocardial PYP retention by SPECT as the reference standard, we evaluated the diagnostic performance of different semi-quantitative and quantitative (H/CL chest ratio) planar parameters obtained from 3-hour PYP imaging in a prospectively recruited cohort of minority older adults with heart failure and increased LV wall thickness. RESULTS: Of 229 patients, 14 were found to have ATTR-CA (6.1%). No PYP uptake (grade 0) was observed in 77% of scans, all grade 3 scans were ATTR-CA, and only 4 of 11 (36%) grade 2 scans were ATTR-CA. An H/CL threshold of ≥ 1.4 maximized specificity (99%) and positive predictive value (93%) but resulted in decreased sensitivity (93%), compared to the ≥ 1.3 threshold which had 100% sensitivity. CONCLUSION: Among patients with a low pretest likelihood of ATTR-CA, planar interpretation, while useful to exclude disease, must be interpreted with caution. H/CL ratio threshold of ≥ 1.3 resulted in clinically important misclassifications. These data suggest that quantitative planar imaging thresholds may not be appropriate to apply in low pretest likelihood populations being evaluated for ATTR-CA.

Longitudinal systolic strain, cardiac function improvement, and survival following treatment of light-chain (AL) cardiac amyloidosis.

AIMS: To determine whether echocardiographic longitudinal systolic strain (LS) parameters identify short-term improvement following chemotherapy for light-chain (AL) cardiac amyloidosis (CA). Among patients with CA, standard echocardiographic measures are commonly unchanged at 1 year following successful chemotherapy, despite observed reductions in cardiac biomarkers. METHODS AND RESULTS: We retrospectively identified 61 patients with AL-CA treated with high-dose melphalan or bortezomib-based regimens. Patients were classified by hematologic response at 1 year into two groups: complete response (CR; n = 18, or 30%) or non-CR (non-CR; n = 43, or 70%), and followed for 20 months. Serum free light chains (FLC), B-type natriuretic peptide (BNP), troponin I (TnI), and echocardiography including LS, were acquired at baseline and 1 year. Seven patients died (11.5%), all in the non-CR group (P < 0.01). At 1 year, while reductions were observed in BNP (44% CR, 18% non-CR) and FLC (94% CR, 73% non-CR), both P < 0.05 from baseline, there were no differences in wall thickness, EF, or diastolic function in either group. LS improved only in the CR group with notable improvement in apical to basal strain ratio (P < 0.05). Strain improvement and BNP reduction were correlated (R = 0.6, P < 0.01). Baseline global LS < -10.2% was associated with survival and proved superior to BNP and TnI. The addition of global LS to biomarkers identified the patients at highest risk of mortality. CONCLUSION: These data suggest that LS is a sensitive measure of pre-treatment cardiac functional impairment in AL-CA, can predict survival over and above that of cardiac biomarkers, and detect early cardiac functional improvement following chemotherapy.

Family history of coronary heart disease and markers of subclinical cardiovascular disease: where do we stand?

OBJECTIVE: The goals of this systematic analysis are to determine the association between family history of coronary heart disease (CHD) and markers of subclinical cardiovascular disease as well as to discuss the inclusion of CHD family history in the frequently used coronary risk prediction algorithms. BACKGROUND: Individuals with a family history of CHD are at high risk for developing atherosclerosis and events related to CHD, regardless of the presence of other coronary risk factors. They form a target population that might benefit from primary prevention strategies; however, family history data is not a part of the frequently used risk prediction algorithms. METHODS: Medline and PubMed databases were searched for all studies evaluating the relationship between measures of subclinical atherosclerosis and family history of CHD, published till June 2010. RESULTS: Thirty-two studies met the above criteria and were included in this review. Coronary artery calcium, carotid intima thickness, vascular function, and inflammatory markers including C reactive protein, fibrinogen, and D-dimer were used as measures of subclinical atherosclerosis. Studies differed in design, demographic data of the population, techniques and validation of family history information. Most studies established a statistically significant relationship between the above markers and family history of CAD; further, the association was noted to be independent of traditional risk factors. CONCLUSION: Family history of CAD is associated with markers of subclinical atherosclerosis, and this relationship remains statistically significant after adjusting for traditional risk factors. The above data suggest these individuals should be considered strongly as candidates for assessment of subclinical CVD to further refine risk and treatment goals.

Dietary factors and incident atrial fibrillation: the Framingham Heart Study.

BACKGROUND: There have been conflicting reported associations between dietary factors and incident atrial fibrillation (AF). OBJECTIVE: We evaluated associations between consumption of alcohol, caffeine, fiber, and polyunsaturated fatty acids (PUFAs) and incident AF in the Framingham Heart Study. DESIGN: Participants without AF (n = 4526; 9640 examinations; mean age: 62 y; 56% women) from the original and offspring cohorts completed food-frequency questionnaires and were followed prospectively for 4 y. We examined the associations between dietary exposures and AF with Cox proportional hazards regression. RESULTS: A total of 296 individuals developed AF (177 men, 119 women). In multivariable analyses, there were no significant associations between examined dietary exposures and AF risk. Hazard ratios (HRs) for increasing quartiles of dietary factors were as follows: for alcohol, 0.73 (95% CI: 0.5, 1.05), 0.85 (95% CI: 0.61, 1.18), and 1.12 (95% CI: 0.83, 1.51) (P for trend = 0.48); for caffeine, 0.84 (95% CI: 0.62, 1.15), 0.87 (95% CI: 0.64, 1.2), and 0.98 (95% CI: 0.7, 1.39) (P for trend = 0.84); for total fiber, 0.86 (95% CI: 0.61, 1.2), 0.64 (95% CI: 0.44, 0.92), and 0.81 (95% CI: 0.54, 1.2) (P for trend = 0.16); and for n-3 (omega-3) PUFAs, 1.11 (95% CI: 0.81, 1.54), 0.92 (95% CI: 0.65, 1.29), and 1.18 (95% CI: 0.85, 1.64) (P for trend = 0.57; quartile 1 was the reference group). In exploratory analyses, consumption of >4 servings of dark fish/wk (5 cases and 21 individuals at risk) was significantly associated with AF risk compared with the consumption of <1 serving of dark fish/wk (HR: 6.53; 95% CI: 2.65, 16.06; P < 0.0001). CONCLUSIONS: Consumption of alcohol, caffeine, fiber, and fish-derived PUFAs was not significantly associated with AF risk. The observed adverse association between the consumption of dark fish and AF merits further investigation. Our findings suggest that the dietary exposures examined convey limited attributable risk of AF in the general population.

Markers of inflammation and coronary artery calcification: a systematic review.

OBJECTIVES: The goal of this systematic review is to assess the cross-sectional relationship of inflammatory markers with the presence and extent of coronary artery calcium (CAC) to identify asymptomatic individuals with a higher risk of coronary heart disease (CHD). BACKGROUND: Markers of subclinical inflammation and subclinical atherosclerosis have both been used to improve detection of individuals at high risk of developing cardiovascular disease. CAC has emerged as a surrogate maker for underlying coronary atherosclerosis, and has been shown to predict future CHD events. Although inflammation is intimately associated with atherosclerosis, and levels of inflammatory markers predict cardiovascular risk, the relationship of subclinical inflammatory markers with the burden of coronary atherosclerosis is not clear. METHODS: Medline and Pub Med databases were searched for all studies assessing the relationship of inflammatory markers with CAC published till July 2007. RESULTS: We found 12 studies that met our criteria. CRP, fibrinogen, metallic metalloproteinase-9 (MMP-9), monocyte chemotactic protein 1 (MCP-1), resistin, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), IL-6, tumor necrosis factor alpha (TNF-alpha) and beta-fibroblast growth factor (bFGF) were used as inflammatory markers. There was a wide variation among studies with regards to population size, inclusion criterias, age range and techniques. It was observed that in almost all studies the relationship between inflammatory markers and CAC was weak, and was mostly found upon univariate analysis in women. However, this association was lost after correction for obesity and BMI. The data on the relationship of inflammation and CAC with progression of atherosclerosis is scarce and did not show any predictive benefits for future CHD. CONCLUSION: Variable associations between CAC and inflammatory markers were identified. In most studies where a positive relationship was found, this relationship disappeared after appropriate correction for the presence of traditional risk factors. Our data suggests that an approach in which inflammatory markers are used to further characterize risk in individuals with an established coronary artery disease burden is more warranted than using biomarkers as sole risk predictors of future CHD events. Large, well-planned comprehensive studies are required to identify the combined role of measuring inflammatory markers in assessment of atherosclerotic disease.

A synergistic relationship of elevated low-density lipoprotein cholesterol levels and systolic blood pressure with coronary artery calcification.

We sought to evaluate this "response-to-injury" hypothesis of atherosclerosis by studying the interaction between systolic blood pressure (SBP) and LDL- cholesterol (LDL-C) in predicting the presence of coronary artery calcification (CAC) in asymptomatic men. We studied 526 men (46+/-7 years of age) referred for electron-beam tomography (EBT) exam. The prevalence of CAC was determined across LDL-C tertiles (low: <115 mg/dl; middle: 115-139 mg/dl; high: >or=140 mg/dl) within tertiles of SBP (low: <121 mmHg; middle: 121-130 mmHg; high: >or=131 mmHg). CAC was found in 220 (42%) men. There was no linear trend in the presence of CAC across LDL-C tertiles in the low (p=0.6 for trend) and middle (p=0.3 for trend) SBP tertile groups, respectively. In contrast, there was a significant trend for increasing CAC with increasing LDL-C (1st: 44%; 2nd: 49%; 3rd: 83%; p<0.0001 for trend) in the high SBP tertile group. In multivariate logistic analyses (adjusting for age, smoking, triglyceride levels, HDL-cholesterol levels, body mass index, and fasting glucose levels), the odds ratio for any CAC associated with increasing LDL-C was significantly higher in those with highest SBP levels, whereas no such relationship was observed among men with SBP in the lower two tertiles. An interaction term (LDL-C x SBP) incorporated in the multivariate analyses was statistically significant (p=0.038). The finding of an interaction between SBP and LDL-C relation to CAC in asymptomatic men support the response-to-injury model of atherogenesis.

Favorable cardiovascular risk factor profile is associated with reduced prevalence of coronary artery calcification and inflammation in asymptomatic nondiabetic white men.

Middle-aged individuals with favorable levels of all major cardiovascular risk factors (CVRFs) have much lower age-specific risks for incident cardiovascular disease (CVD). However, the relationship of the absence of CVRFs with subclinical CVD and inflammation is not well described. We classified 440 asymptomatic Brazilian men (aged 46+/-7 years) based on the number of CVRFs (smoking, systolic blood pressure > or =130 mm Hg, low-density lipoprotein cholesterol > or =130 mg/dL, high-density lipoprotein cholesterol <40 mg/dL, triglycerides > or =150 mg/dL, fasting glucose > or =100 mg/dL, and waist circumference >102 cm). Only 7% had no CVRFs, whereas 1, 2, 3, and > or =4 CVRFs were observed in 18%, 24%, 21%, and 29%, respectively. In age-adjusted analysis, each lower CVRF profile was associated with lower odds of prevalent coronary artery calcium (odds ratio, 0.75; P=.002) and elevated white blood cell count (odds ratio, 0.70; P<.001). Our study supports the notion that a favorable CVD profile is associated with less underlying atherosclerosis and inflammation and further highlights the importance of primary prevention of CVRFs.