Coronary artery calcium score and pre-test probabilities as gatekeepers to predict and rule out perfusion defects in positron emission tomography.

BACKGROUND: Little is known about the gatekeeper performance of coronary artery calcium score (CACS) before myocardial perfusion positron emission tomography (PET), compared with updated pre-test probabilities from American and European guidelines (pre-test-AHA/ACC, pre-test-ESC). METHODS: We enrolled participants without known coronary artery disease undergoing CACS and Rubidium-82 PET. Abnormal perfusion was defined as summed stress score ≥ 4. Using Bayes' formula, pre-test probabilities and CACS were combined into post-test probabilities. RESULTS: We included 2050 participants (54% male, mean age 64.6 years) with median CACS 62 (IQR 0-380), pre-test-ESC 17% (11-26), pre-test-AHA/ACC 27% (16-44), and abnormal perfusion in 437 participants (21%). To predict abnormal perfusion, area under the curve of CACS was 0.81, pre-test-AHA/ACC 0.68, pre-test-ESC 0.69, post-test-AHA/ACC 0.80, and post-test-ESC 0.81 (P < 0.001 for CACS vs. each pre-test, and each post-test vs. pre-test). CACS = 0 had 97% negative predictive value (NPV), pre-test-AHA/ACC ≤ 5% 100%, pre-test-ESC ≤ 5% 98%, post-test-AHA/ACC ≤ 5% 98%, and post-test-ESC ≤ 5% 96%. Among participants, 26% had CACS = 0, 2% pre-test-AHA/ACC ≤ 5%, 7% pre-test-ESC ≤ 5%, 23% post-test-AHA/ACC ≤ 5%, and 33% post-test-ESC ≤ 5% (all P < 0.001). CONCLUSIONS: CACS and post-test probabilities are excellent predictors of abnormal perfusion and can rule it out with very high NPV in a substantial proportion of participants. CACS and post-test probabilities may be used as gatekeepers before advanced imaging. Coronary artery calcium score (CACS) predicted abnormal perfusion (SSS ≥ 4) in myocardial positron emission tomography (PET) better than pre-test probabilities of coronary artery disease (CAD), while pre-test-AHA/ACC and pre-test-ESC performed similarly (left). Using Bayes' formula, pre-test-AHA/ACC or pre-test-ESC were combined with CACS into post-test probabilities (middle). This calculation reclassified a substantial proportion of participants to low probability of CAD (0-5%), not needing further imaging, as shown for AHA/ACC probabilities (2% with pre-test-AHA/ACC to 23% with post-test-AHA/ACC, P < 0.001, right). Very few participants with abnormal perfusion were classified under pre-test or post-test probabilities 0-5%, or under CACS 0. AUC: area under the curve. Pre-test-AHA/ACC: Pre-test probability of the American Heart Association/American College of Cardiology. Post-test-AHA/ACC: Post-test probability combining pre-test-AHA/ACC and CACS. Pre-test-ESC: Pre-test probability of the European Society of Cardiology. SSS: Summed stress score.

The power of zero calcium in 82-Rubidium PET irrespective of sex and age.

BACKGROUND: Despite clinical suspicion, many non-invasive tests for coronary artery disease (CAD) are normal. Coronary artery calcification score (CACS) is a well-validated method to detect and risk stratify CAD. Patients with zero calcium score (ZCS) rarely have abnormal tests. Therefore, aims were to evaluate CACS as a gatekeeper to further functional downstream testing for CAD and estimate potential radiation and cost savings. METHODS: Consecutive patients with suspected CAD referred for PET were included (n = 2640). Prevalence and test characteristics of ZCS were calculated in different groups. Summed stress score ≥ 4 was considered abnormal and summed difference score ≥ 7 equivalent to ≥ 10% ischemia. To estimate potential radiation/cost reduction, PET scans were hypothetically omitted in ZCS patients. RESULTS: Mean age was 65 ± 11 years, 46% were female. 21% scans were abnormal and 26% of patients had ZCS. CACS was higher in abnormal PET (median 561 vs 27, P < 0.001). Abnormal PET was significantly less frequent in ZCS patients (2.6% vs 27.6%, P < 0.001). Sensitivity/negative predictive value (NPV) of ZCS to detect/exclude abnormal PET and ≥ 10% ischemia were 96.8% (95%-CI 95.0%-97.9%)/97.4% (95.9%-98.3%) and 98.9% (96.7%-99.6%)/99.6% (98.7%-99.9%), respectively. Radiation and cost reduction were estimated to be 23% and 22%, respectively. CONCLUSIONS: ZCS is frequent, and most often consistent with normal PET scans. ZCS offers an excellent NPV to exclude an abnormal PET and ≥ 10% ischemia across different gender and age groups. CACS is a suitable gatekeeper before advanced cardiac imaging, and potential radiation/cost savings are substantial. However, further studies including safety endpoints are needed.

Low-dose coronary artery calcium scoring compared to the standard protocol.

BACKGROUND: We aimed to compare coronary artery calcium scoring (CACS) with computed tomography (CT) with 80 and 120 kVp in a large patient population and to establish whether there is a difference in risk classification between the two scores. METHODS: Patients with suspected CAD undergoing MPS were included. All underwent standard CACS assessment with 120-kVp tube voltage and with 80 kVp. Two datasets (low-dose and standard) were generated and compared. Risk classes (0 to 25, 25 to 50, 50 to 75, 75 to 90, and > 90%) were recorded. RESULTS: 1511 patients were included (793 males, age 69 ± 9.1 years). There was a very good correlation between scores calculated with 120 and 80 kVp (R = 0.94, R2 = 0.88, P < .001), with Bland-Altman limits of agreement of - 563.5 to 871.9 and a bias of - 154.2. The proportion of patients assigned to the < 25% percentile class (P = .03) and with CACS = 0 differed between the two protocols (n = 264 vs 437, P < .001). CONCLUSION: In a large patient population, despite a good correlation between CACS calculated with standard and low-dose CT, there is a systematic underestimation of CACS with the low-dose protocol. This may have an impact especially on the prognostic value of the calcium score, and the established "power of zero" may no longer be warranted if CACS is assessed with low-dose CT.

Quantitative myocardial perfusion 82Rb-PET assessed by hybrid PET/coronary-CT: Normal values and diagnostic performance.

PURPOSE: We aimed to assess normal values for quantified myocardial blood flow (MBF) on a hybrid PET/coronary-CT scanner and to test their diagnostic performance in patients with suspected CAD. MATERIALS AND METHODS: Patients underwent 82Rb-PET/CT and integrated CT-based coronary angiography (CCTA) and were classified as normal (no stenosis), with non-obstructive stenosis (< 50%) and with CAD (≥ 50%). Global and regional stress MBF (sMBF), rest MBF and myocardial flow reserve (MFR) were calculated. Ischemia was defined as SDS ≥ 2, severe ischemia as SDS ≥ 7. RESULTS: 357 consecutive patients were included. Global sMBF and MFR were higher in normal patients than in patients with CAD (3.61 ± 0.71 vs 3.04 ± 0.77, P < 0.0001; 3.08 ± 0.84 vs 2.68 ± 0.79, P = 0.0001), but not different compared to patients with non-obstructive stenosis (3.61 ± 0.71 vs 3.43 ± 0.69, P = 0.052; 3.08 ± 0.84 vs 2.99 ± 0.82, P = 0.45). sMBF yielded superior accuracy over MFR in identifying both ischemia (AUC 0.74 vs 0.62, P = 0.003) and severe ischemia (AUC 0.88 vs 0.78, P = 0.012). Optimal threshold for global sMBF to rule out myocardial ischemia was 3.5 mL g-1 min-1. CONCLUSIONS: Normal quantitative values are provided. Global sMBF provided higher diagnostic accuracy than MFR. Using sMBF-threshold of 3.5 mL·g-1·min-1 on 82Rb-PET/CT yielded similar NPV (96%) as CCTA to rule out CAD. Hence, resting scan could be omitted in patients with sMBF values above reference.

Left ventricular ejection fraction, myocardial blood flow and hemodynamic variables in adenosine and regadenoson vasodilator 82-Rubidium PET.

AIMS: In most Rubidium-(Rb)-positron emission tomography (PET) studies, dipyridamole was used as vasodilator. The aim was to evaluate vasodilator PET left ventricular ejection fraction (LVEF), myocardial blood flow (MBF), hemodynamics, and the influence of adenosine and regadenoson on these variables. METHODS AND RESULTS: Consecutive patients (N = 2299) with prior coronary artery disease (CAD) or no prior CAD undergoing adenosine/regadenoson 82Rb-PET were studied and compared according to CAD status and normal/abnormal PET (summed stress score 0-3 vs. ≥4). Rest and stress LVEF differed significantly depending on CAD status and scan results. In patients with no prior CAD, rest/stress LVEF were 68% and 72%, in patients with prior CAD 60% and 63%. LVEF during stress increased 5 ± 6% in normal compared to 1 ± 8% in abnormal PET (P<0.001). Global rest myocardial blood flow(rMBF), stress MBF(sMBF) and myocardial flow reserve (sMBF/rMBF) were significantly higher in no prior CAD patients compared to prior CAD patients(1.3 ± 0.5, 3.3 ± 0.9, 2.6 ± 0.8 and 1.2 ± 0.4, 2.6 ± 0.8, 2.4 ± 0.8 ml/g/min, respectively, P<0.001) and in normal versus abnormal scans, irrespective of CAD status(no prior CAD: 1.4 ± 0.5, 3.5 ± 0.8, 2.8 ± 0.8 and 1.2 ± 0.8, 2.5 ± 0.8, 2.2 ± 0.7; prior CAD: 1.3 ± 0.4, 3.1 ± 0.8, 2.7 ± 0.8 and 1.1 ± 0.4, 2.3 ± 0.7, 2.2 ± 0.7 ml/g/min, respectively, P<0.001). LVEF and hemodynamic values were similar for adenosine and regadenoson stress. Stress LVEF ≥70% excluded relevant ischemia (≥10%) with a negative predictive value (NPV) of 94% (CI 92-95%). CONCLUSIONS: Rest/stress LVEF, LVEF reserve and MBF values are lower in abnormal compared to normal scans. Adenosine and regadenoson seem to have similar effect on stress LVEF, MBF and hemodynamics. A stress LVEF ≥70% has a high NPV to exclude relevant ischemia.

Prognostic value of myocardial perfusion scintigraphy in asymptomatic patients with diabetes mellitus at high cardiovascular risk: 5-year follow-up of the prospective multicenter BARDOT trial.

BACKGROUND: The Basel Asymptomatic High-Risk Diabetics' Outcome Trial (BARDOT) demonstrated that asymptomatic diabetic patients with an abnormal myocardial perfusion scintigraphy (MPS) were at increased risk of major adverse cardiovascular events (MACEs) at 2-year follow-up. It remains unclear whether this finding holds true even for a longer follow-up. METHODS: Four hundred patients with type 2 diabetes, neither history nor symptoms of coronary artery disease (CAD), were evaluated clinically and with MPS. Patients were followed up for 5 years. Major adverse cardiovascular events (MACEs) were defined as all-cause death, myocardial infarction, or late coronary revascularization. RESULTS: At baseline, an abnormal MPS (SSS ≥ 4 or SDS ≥ 2) was found in 87 of 400 patients (22%). MACE within 5 years occurred in 14 patients with abnormal MPS (16.1%) and in 22 with normal scan (1.7%), p = 0.009; 15 deaths were recorded. Patients with completely normal MPS (SSS and SDS = 0) had lower rates of MACEs than patients with abnormal scans (2.5% vs. 7.0%, p = 0.032). Patients with abnormal MPS who had undergone revascularization had a lower mortality rate and a better event-free survival from MI and revascularization than patients with abnormal MPS who had either undergone medical therapy only or could not be revascularized (p = 0.002). CONCLUSIONS: MPS may have prognostic value in asymptomatic diabetic patients at high cardiovascular risk over a follow-up period of 5 years. Patients with completely normal MPS have a low event rate and may not need retesting within 5 years. Patients with an abnormal MPS have higher event rates and may benefit from a combined medical and revascularization approach.

Quantitative 99mTc-DPD SPECT/CT in patients with suspected ATTR cardiac amyloidosis: Feasibility and correlation with visual scores.

PURPOSE: While a visual interpretation of 99mTc-DPD scintigraphy by means of Perugini score can provide a reliable diagnosis of transthyretin-related (ATTR) cardiac amyloidosis (CA), a quantitative approach is expected to play a major role in risk stratification and therapy evaluation. The aim of our study was to test the feasibility of a quantitative assessment and to correlate various parameters to Perugini score. METHODS: in this retrospective study, consecutive patients underwent a 99mTc-DPD whole-body bone scintigraphy and a SPECT/CT of the thorax. XSPECT-QUANT software was used to quantify the DPD uptake in the heart. RESULTS: Thirteen patients were included. CA was confirmed in 8 and rejected in 5. Myocardial SUVmax and SUVpeak showed a fairly strong correlation with Perugini score (both ρ = .71, P = .006). Same held true for to-bone normalized values (both ρ = .75, P = .003). There was a great degree of overlap for quantitative values in patients with Perugini score 2 and 3. CONCLUSION: Quantitative 99mTc-DPD SPECT/CT in suspected ATTR CA patients is feasible and allows for a more accurate assessment of myocardial uptake.

[A heart murmur - a frequent incidental finding]. / Das Herzgeräusch als Zufallsbefund.

A heart murmur - a frequent incidental finding Abstract. Heart murmurs are very common and are present in up to 80 % of school children and 52 % of adults. They originate from the transition from laminar to turbulent blood flow in patients with a structural cardiomyopathy (so-called "organic" murmurs) or in patients with normal hearts (so-called "innocent" murmurs). A detailed history and physical examination help to discriminate innocent from organic murmurs. With the wide availability of transthoracic echocardiography (TTE) cardiac auscultation has lost a lot of its importance, although it remains an important skill for the initial evaluation and triage. An innocent murmur is a minor (1 / 6 - 2 / 6), crescendo-decrescendo, mostly position-dependent, mid-systolic murmur without radiation, which needs no further workup in asymptomatic patients with normal physical capacity. A TTE should be ordered if signs for a cardiac disease are present based on history, physical examination or other tests. Diastolic and continuous murmurs are mostly pathologic and warrant further workup.

Quality of life as predictor for the development of cardiac ischemia in high-risk asymptomatic diabetic patients.

BACKGROUND: Ischemia induced by psychological stress and depression is a common phenomenon in stable coronary artery disease (CAD). We evaluated the quality of life (QoL) of diabetic patients screened for CAD and assessed the prognostic value of mental and physical QoL scores to predict the development of new cardiac ischemia. METHODS: Prospective multicentre outcome study. The study comprised 400 asymptomatic diabetic patients without history or symptoms of CAD. They underwent myocardial perfusion single-photon emission computed tomography (MPS) and assessment of QoL by two questionnaires: Hospital Depression and Anxiety Scale (HADS-D and HADS-A) and Medical Outcomes Study Short Form 36 (SF-36) at baseline and after 2 years. Patients with normal MPS received usual care; those with abnormal MPS received medical or combined invasive and medical management. RESULTS: Only mental QoL scores but not physical QoL scores or traditional cardiovascular risk factors were predictive of new ischemia (n = 11/306) during follow-up. The prognostic value for new ischemia as quantified by the area under the receiver operating characteristics curve (AUC) amounted to 0.784 (95% confidence interval (CI) 0.654-0.914, P = 0.002) for HADS-D and to 0.737 (95% CI 0.580-0.893, P = 0.011) for HADS-A. This finding was confirmed by SF-36 mental sum score (AUC 0.688, 95% CI 0.539-0.836, P = 0.036), but not SF-36 physical sum score. QoL scores did not change after 2 years in patients with ischemia at baseline. CONCLUSIONS: QoL scores assessing mental health, particularly depression and anxiety, predicted the development of new cardiac ischemia in asymptomatic diabetic patients. The study is limited by a small number of events (new ischemia) and so the results should be considered hypothesis generating rather than conclusive.

Clinical benefit of high-sensitivity cardiac troponin I in the detection of exercise-induced myocardial ischemia.

BACKGROUND: A pilot study using a novel high-sensitivity cardiac troponin I (hs-cTnI) assay suggested that cTnI might be released into blood during exercise-induced myocardial ischemia. We investigated the potential clinical value of this signal. METHODS: We included 819 patients with suspected exercise-induced myocardial ischemia referred for rest/bicycle myocardial perfusion single-photon emission computed tomography. The treating cardiologist used all available clinical information to quantify clinical judgment regarding the presence of myocardial ischemia using a visual analog scale twice: prior and after stress testing. High-sensitivity cTnI measurements were obtained before, immediately after peak stress, and 2 hours after stress testing in a blinded manner. Myocardial ischemia was adjudicated using perfusion single-photon emission computed tomography and coronary angiography findings. RESULTS: Exercise-induced myocardial ischemia was detected in 278 (34%) patients. High-sensitivity cTnI levels were significantly higher at all time points in patients with myocardial ischemia as compared with those without (P < .001 for all). Combining clinical judgment prior exercise testing with baseline hs-cTnI levels increased diagnostic accuracy as quantified by the area under the receiver operating characteristics curve (AUC) from 0.672 to 0.757 (P < .001). Combining clinical judgment after exercise testing (AUC 0.704) with baseline or poststress hs-cTnI levels also increased the diagnostic accuracy (AUC 0.761-0.771, P < .001 for all). In contrast, exercise-induced changes in hs-cTnI during exercise did not seem useful, as they were small and similar in patients with or without myocardial ischemia. CONCLUSIONS: High-sensitivity cTnI concentrations at rest and after exercise, but not its exercise-induced changes, provide substantial incremental value to clinical judgment including exercise electrocardiography regarding the presence of myocardial ischemia.

Enhancing the diagnosis of functionally relevant coronary artery disease with machine learning.

Functionally relevant coronary artery disease (fCAD) can result in premature death or nonfatal acute myocardial infarction. Its early detection is a fundamentally important task in medicine. Classical detection approaches suffer from limited diagnostic accuracy or expose patients to possibly harmful radiation. Here we show how machine learning (ML) can outperform cardiologists in predicting the presence of stress-induced fCAD in terms of area under the receiver operating characteristic (AUROC: 0.71 vs. 0.64, p = 4.0E-13). We present two ML approaches, the first using eight static clinical variables, whereas the second leverages electrocardiogram signals from exercise stress testing. At a target post-test probability for fCAD of <15%, ML facilitates a potential reduction of imaging procedures by 15-17% compared to the cardiologist's judgement. Predictive performance is validated on an internal temporal data split as well as externally. We also show that combining clinical judgement with conventional ML and deep learning using logistic regression results in a mean AUROC of 0.74.

Combining anatomical and biochemical markers in the detection and risk stratification of coronary artery disease.

AIM: We aimed to test the hypothesis if combining coronary artery calcium score (Ca-score) as a quantitative anatomical marker of coronary atherosclerosis with high-sensitive cardiac troponin as a quantitative biochemical marker of myocardial injury provided incremental value in the detection of functional relevant CAD (fCAD) and risk stratification. METHODS AND RESULTS: Consecutive patients undergoing myocardial perfusion SPECT (MPS) without prior CAD were enrolled. The diagnosis of fCAD was based on the presence of ischemia on MPS and coronary angiography- fCAD was centrally adjudicated in the diagnostic and prognostic domain. Diagnostic accuracy was evaluated using the area under receiver-operating characteristic curve. The composite of cardiovascular death and non-fatal acute myocardial infarction (AMI) within 730 days were the primary prognostic endpoints.Among 1715 patients eligible for the diagnostic analysis, 399 patients had fCAD. The combination of Ca-Score and hs-cTnT had good diagnostic accuracy for the diagnosis of fCAD, AUC 0.79 (95 % CI 0.77-0.81), but no incremental value compared to the Ca-score alone (AUC 0.79 (95%CI 0.77-0.81, p=0.965). Similar results were observed using hs-cTnI (AUC 0.80, 95%CI 0.77-0.82) instead of hs-cTnT.Among 1709 patients (99.7%) with available follow-up, 59 patients (3.5%) suffered the composite primary prognostic endpoint (nonfatal AMI n=34, CV death n=28).Both, Ca-score and hs-cTnT had independent prognostic value. Increased risk was restricted to patients with elevation in both markers. CONCLUSION: The combination of the Ca-score with hs-cTnT increases the prognostic accuracy for future events defining fCAD, but does not provide incremental value versus the Ca-Score alone for the diagnosis of fCAD.

Diagnostic and prognostic value of mannan-binding lectin associated protein (MAp19) for functionally relevant coronary artery disease.

BACKGROUND: This study aimed to evaluate the diagnostic and prognostic potential of MAp19, a regulating component of the lectin pathway of the complement system, in patients with suspected functionally relevant coronary artery disease (fCAD) as well as the determinants of MAp19 levels. METHODS: The presence of fCAD was adjudicated using myocardial perfusion imaging with single-photon emission tomography and, where available, coronary angiography. MAp19 levels were measured in participants at rest, at peak stress tests, and two hours after the stress. The study also tracked major cardiovascular events, including non-fatal myocardial infarction and cardiovascular death, over a five-year follow-up period. RESULTS: Among the 1,571 patients analyzed (32.3 % women), fCAD was identified in 462 individuals (29.4 %). MAp19 demonstrated no diagnostic significance, yielding an area under the curve (AUC) of 0.51 (0.47-0.55). Throughout the five-year follow-up, 107 patients (6.8 %) experienced non-fatal myocardial infarctions, 99 (6.3 %) had cardiovascular death, 194 (12.3 %) experienced all cause death and 50 (3.1 %) suffered a stroke. Cox and Kaplan-Meier analysis confirmed prognostic value of MAp19 for myocardial infarction, but not for cardiovascular death. Significant increases in the concentration of MAp19 were observed during bicycle (p = 0.001) and combined stress tests (p = 0.001). CONCLUSION: MAp19 demonstrated an association with the risk of myocardial infarction. Increases in MAp19 concentration were observed during bicycle and combined stress-tests.

Microalbuminuria predicts silent myocardial ischaemia in type 2 diabetes patients.

PURPOSE: Myocardial ischaemia is frequently silent in patients with type 2 diabetes. Although it has been proposed as a potential screening tool, the role of myocardial perfusion single photon emission computed tomography (MPS) has recently been questioned, due to the low prevalence of positive scans and the low rate of cardiac events. The aim of this study was to assess if pretest clinical variables can identify a subgroup of asymptomatic patients with type 2 diabetes at risk of silent myocardial ischaemia and a subsequent poor outcome METHODS: This prospective study included 77 patients (50 men, mean age 63 ± 9 years) with type 2 diabetes and no known coronary artery disease (CAD) or angina pectoris who underwent gated MPS to screen for CAD between March 2006 and October 2008. MPS images were interpreted using a semiquantitative visual 20-segment model to define summed stress, rest and difference scores. Ischaemia was defined as a sum difference score (SDS) ≥2. Patients were followed-up (median 4.1 years, range 0.8 - 6.1 years) and cardiac hard events (cardiac death or nonfatal myocardial infarction) were recorded. RESULTS: Silent ischaemia was detected in 25 of the 77 patients (32 %). Specifically, 10 patients (13 %) had mild ischaemia (SDS 2 to ≤4) and 15 patients (19 %) had severe ischaemia (SDS >4). In univariate binary logistic analysis, microalbuminuria was the only significant predictor of silent ischaemia on MPS (odds ratio 4.42, 95 % CI 1.27 - 15.40; P = 0.019). The overall accuracy of microalbuminuria for predicting silent ischaemia was 71.4 % and was 89.6 % for predicting severe ischaemia. Kaplan-Meier curves showed no significant group differences in 5-year cardiac event-free survival between patients with and those without microalbuminuria, or between patients with SDS ≥2 and those with SDS <2. In contrast, 5-year event-free survival was significantly lower in patients with SDS >4 than in patients with SDS ≤4: 55.6 % (95 % CI 39.0 - 72.2 %) vs. 94.5 % (95 % CI: 91.4 - 97.6 %), respectively (Breslow test, chi-square 20.9, P < 0.001). Median cardiac event-free survival was not observed in the whole group, while the 25th percentile of cardiac event-free survival was reached only in patients with SDS >4 (2.3 years). In univariate Cox regression analysis, SDS >4 predicted cardiac event-free survival (hazard ratio 12.87, 95 % CI 2.86 - 27.98; P = 0.001), while SDS ≥2 did not (hazard ratio 2.78, 95 % CI 0.62 - 12.46, P = 0.16). CONCLUSION: In this group of patients with type 2 diabetes, microalbuminuria was the only predictor of silent ischaemia on MPS. Assessment of microalbuminuria should be routinely considered among the first risk stratification steps for CAD in patients with type 2 diabetes, even though severe ischaemia on MPS is a major predictor of cardiac event-free survival.