Static CT myocardial perfusion imaging: image quality, artifacts including distribution and diagnostic performance compared to 82Rb PET

Background Rubidium-82 positron emission tomography (82Rb PET) MPI is considered a noninvasive reference standard for the assessment of myocardial perfusion in coronary artery disease (CAD) patients. Our main goal was to compare the diagnostic performance of static rest/ vasodilator stress CT myocardial perfusion imaging (CT-MPI) to stress/ rest 82Rb PET-MPI for the identification of myocardial ischemia. Methods Forty-four patients with suspected or diagnosed CAD underwent both static CT-MPI and 82Rb PET-MPI at rest and during pharmacological stress. The extent and severity of perfusion defects on PET-MPI were assessed to obtain summed stress score, summed rest score, and summed difference score. The extent and severity of perfusion defects on CT-MPI was visually assessed using the same grading scale. CT-MPI was compared with PET-MPI as the gold standard on a per-territory and a per-patient basis. Results On a per-patient basis, there was moderate agreement between CT-MPI and PET-MPI with a weighted 0.49 for detection of stress induced perfusion abnormalities. Using PET-MPI as a reference, static CT-MPI had 89% sensitivity (SS), 58% specificity (SP), 71% accuracy (AC), 88% negative predictive value (NPV), and 59% positive predictive value (PPV) to diagnose stress-rest perfusion deficits on a per-patient basis. On a per-territory analysis, CT-MPI had 73% SS, 65% SP, 67% AC, 90.8% NPV, and 34% PPV to diagnose perfusion deficits. Conclusions CT-MPI has high sensitivity and good overall accuracy for the diagnosis of functionally significant CAD using 82Rb PET-MPI as the reference standard. CT-MPI may play an important role in assessing the functional significance of CAD especially in combination with CCTA.

Dynamic Handgrip Exercise: Feasibility and Physiologic Stress Response of a Potential Needle-Free Cardiac Magnetic Resonance Stress Test

Background: Cardiac magnetic resonance (CMR) pharmacological stress-testing is a well-established technique for detecting myocardial ischemia. Although stressors and contrast agents seem relatively safe, contraindications and side effects must be considered. Substantial costs are further limiting its applicability. Dynamic handgrip exercise (DHE) may have the potential to address these shortcomings as a physiological stressor. We therefore evaluated the feasibility and physiologic stress response of DHE in relation to pharmacological dobutamine-stimulation within the context of CMR examinations.Methods: Two groups were prospectively enrolled: (I) volunteers without relevant disease and (II) patients with known CAD referred for stress-testing. A both-handed, metronome-guided DHE was performed over 2 min continuously with 80 contractions/minute by all participants, whereas dobutamine stress-testing was only performed in group (II). Short axis strain by fast-Strain-ENCoded imaging was acquired at rest, immediately after DHE and during dobutamine infusion.Results: Eighty middle-aged individuals (age 56 ± 17 years, 48 men) were enrolled. DHE triggered significant positive chronotropic (HRrest: 68 ± 10 bpm, HRDHE: 91 ± 13 bpm, p < 0.001) and inotropic stress response (GLSrest: −19.4 ± 1.9%, GLSDHE: −20.6 ± 2.1%, p < 0.001). Exercise-induced increase of longitudinal strain was present in healthy volunteers and patients with CAD to the same extent, but in general more pronounced in the midventricular and apical layers (p < 0.01). DHE was aborted by a minor portion (7%) due to peripheral fatigue. The inotropic effect of DHE appears to be non-inferior to intermediate dobutamine-stimulation (GLSDHE= −19.5 ± 2.3%, GLSDob= −19.1 ± 3.1%, p = n.s.), whereas its chronotropic effect was superior (HRDHE= 89 ± 14 bpm, HRDob= 78 ± 15 bpm, p < 0.001).Conclusions: DHE causes positive ino- and chronotropic effects superior to intermediate dobutamine-stimulation, suggesting a relevant increase of myocardial oxygen demand. DHE appears to be safe and timesaving with broad applicability. The data encourages further studies to determine its potential to detect obstructive CAD.

Arrhythmogenic Hearts in PKD2 Mutant Mice Are Characterized by Cardiac Fibrosis, Systolic, and Diastolic Dysfunctions

Autosomal dominant polycystic kidney disease (PKD) is a hereditary disorder affecting multiple organs, including the heart. PKD has been associated with many cardiac abnormalities including the arrhythmogenic remodeling in clinical evaluations. In our current study, we hypothesized that Pkd2 gene mutation results in structural and functional defects in the myocardium. The structural and functional changes of Pkd2 mutant hearts were analyzed in the myocardial-specific Pkd2 knockout (KO) mouse. We further assessed a potential role of TGF-b1 signaling in the pathology of Pkd2-KO hearts. Hearts from age-matched 6-month-old MyH6•Pkd2wt/wt (control or wild-type) and MyH6•Pkd2flox/flox (mutant or Pkd2-KO) mice were used to study differential heart structure and function. Cardiac histology was used to study structure, and the “isolated working heart” system was adapted to mount and perfuse mouse heart to measure different cardiac parameters. We found that macrophage1 (M1) and macrophage 2 (M2) infiltration, transforming growth factor (TGF-b1) and TGF-b1 receptor expressions were significantly higher in Pkd2-KO, compared to wild-type hearts. The increase in the extracellular matrix in Pkd2-KO myocardium led to cardiac hypertrophy, interstitial and conduction system fibrosis, causing cardiac dysfunction with a predisposition to arrhythmia. Left ventricular (LV) expansion or compliance and LV filling were impaired in fibrotic Pkd2-KO hearts, resulted in diastolic dysfunction. LV systolic contractility and elastance decreased in fibrotic Pkd2-KO hearts, resulted in systolic dysfunction. Compared to wild-type hearts, Pkd2-KO hearts were less responsive to the pharmacological stress-test and changes in preload. In conclusion, Pkd2-KO mice had systolic and diastolic dysfunction with arrhythmogenic hearts.

Prognostic value of ABCDE stress echocardiography

Background Stress echocardiography (SE) was recently upgraded to the ABCDE protocol: step A, regional wall motion abnormalities; step B, B-lines; step C, left ventricular contractile reserve; step D, Doppler-based coronary flow velocity reserve in left anterior descending coronary artery; and step E, EKG-based heart rate reserve. Aim: to assess the prognostic value of ABCDE-SE in a prospective, large scale, multicenter, international, effectiveness study. Methods From July 2016 to November 2020, we enrolled 3,574 all-comers (age 65±11 years, 2,070 males, 58%; ejection fraction 60±10%) with known or suspected chronic coronary syndromes referred from 13 certified laboratories. All patients underwent ABCDE-SE. The employed stress modality was exercise (n=952, with semi-supine bike, n=887, or treadmill, n=65 with adenosine for step D) or pharmacological stress (n=2,622, with vasodilator, n=2,151; or dobutamine, n=471). SE response ranged from score 0 (all steps normal) to score 5 (all steps abnormal). All-cause death was the only end-point. Results Rate of abnormal results was 16% for A, 30% for B, 36% for C, 28% for D and 37% for E step. During a median follow-up of 21 months, 73 deaths occurred. At univariable analysis, predictors of all-cause mortality were step B (hazard ratio, HR: 2.621, 95% Confidence Intervals, CI: 1.654–4.152, p<0.001), step D (HR: 2.578, 95% CI: 1.624–4.093, p<0.001), and step E (HR: 2.955, 95% CI: 1.848–4.725, p<0.001), but not step A (HR: 1.333, 95% CI: 0.731–2.430, p=0.349) and step C (HR1.581, 95% CI: 0.997–2.506, p=0.051). At multivariable analysis, ABCDE-SE was an independent predictor of mortality with score 3 (HR: 3.472, 95% CI: 1.483–8.135, p=0.004), 4 (HR: 4.045, 95% CI: 1.595–10.259, p=0.003) and 5 (HR: 5.678, 95% CI: 2.106–15.313, p=0.001) (Figure). Annual mortality rate ranged from 0.4% person/year for score 0 up to 2.4% person/year for score 5. Conclusion ABCDE-SE allows an effective risk stratification of patient global vulnerability. FUNDunding Acknowledgement Type of funding sources: None. Survival curves based on ABCDE score

Comparison of coronary flow reserve feasibility and values in different stress echocardiography protocols: dobutamine, dipyridamole, exercise and rapid pacing

Background and aims To compare the feasibility of Coronary Flow Velocity Reserve (CFVR) assessment in the left anterior descending (LAD) artery in four types of stress echocardiography (SE): dobutamine (DOB), dipyridamole (DIP), rapid pacing (PAC) and bicycle exercise (EXE). Methods and results We subjected 369 patients (mean age: 67±11 years) to SE with DOB (up to 40 mcg/kg/min, n=230), DIP (0.84 mg/kg, n=73), PAC (n=22) or EXE (n=44). CFVR was measured as the ratio of peak diastolic coronary flow velocity (CFV) during exercise, pharmacological stress or pacing and peak diastolic CFV at rest in distal or mid LAD. The feasibility was excellent during PAC (100%), DOB (95%) and DIP (95%) and lower during EXE (73%, p<0.01 vs other groups) when assessed in all consecutive patients. When assessed in patients having readable LAD flow at rest the feasibility achieved even higher values, being however still lowered in EXE group, see Figure 1. In multivariate analysis only the EXE protocol was a predictor of LAD flow loss during SE, with OR = 8.23 (95% CI 2.17 – 31.33), p=0.0019. CFVR was lower with PAC (1.8±0.4) as compared to DIP (2.2±0.6, p=0.0061) and DOB (2.2±0.6, p=0.0025), but similar to EXE (2.0±0.6, p=0.178), and correlated best with the peak heart rate in EXE and PAC, see Figure 2. Conclusion CFVR in LAD can be obtained during all forms of SE, but the feasibility is significantly higher with PAC and pharmacological tests as compared to EXE, which was identified in our study as the independent predictor of the loss of LAD flow recording at the peak of stress test. Moreover, CFVR values were the lowest in PAC group which however encompassed the older patients with more advanced coronary artery disease. Significant correlation between HR and CFVR observed in EXE and PAC suggests that in this type of SE cut-off value of CFVR should be probably indexed to maximal HR achieved. FUNDunding Acknowledgement Type of funding sources: None. Figure 1 Figure 2

Rest/Stress Myocardial Perfusion Imaging by Positron Emission Tomography with 18F-Flurpiridaz: A Feasibility Study in Mice

Background: Myocardial perfusion imaging by positron emission tomography (PET-MPI) is the current gold standard for quantification of myocardial blood flow. 18F-flurpiridaz was recently introduced as a valid alternative to currently used PET-MPI probes. Nonetheless, optimum scan duration and time interval for image analysis are currently unknown. Further, it is unclear whether rest/stress PET-MPI with 18F-flurpiridaz is feasible in mice. Methods: Rest/stress PET-MPI was performed with 18F-flurpiridaz (0.6-3.0 MBq) in 29 mice aged 7-8 months. Regadenoson (0.1 μg/g) was used for induction of vasodilator stress. Kinetic modeling was performed using a metabolite-corrected arterial input function. Image-derived myocardial 18F-flurpiridaz uptake was assessed for different time intervals by placing a volume of interest in the left ventricular myocardium. Results: Tracer kinetics were best described by a two-tissue compartment model. K1 ranged from 6.7-20.0 mL/cm3/min, while myocardial volumes of distribution (VT) were between 34.6 and 83.6 mL/cm3. Of note, myocardial 18F-flurpiridaz uptake (%ID/g) was significantly correlated with K1 at rest and following pharmacological stress testing for all time intervals assessed. However, while Spearman coefficients (rs) ranged between 0.478 and 0.672, R2 values were generally low. In contrast, an excellent correlation of myocardial 18F-flurpiridaz uptake with VT was obtained, particularly when employing the averaged myocardial uptake from 20-40 min post tracer injection (R2 ≥0.98). Notably, K1 and VT were similarly sensitive to pharmacological stress induction. Further, mean stress-to-rest ratios of K1, VT, and %ID/g 18F-flurpiridaz were virtually identical, suggesting that %ID/g 18F-flurpiridaz can be used to estimate CFR in mice. Conclusion: Our findings suggest that a simplified assessment of relative myocardial perfusion and coronary flow reserve (CFR), based on image-derived tracer uptake, is feasible with 18F-flurpiridaz in mice, enabling high-throughput mechanistic CFR studies in rodents.

Non-invasive CMR-Based Quantification of Myocardial Power and Efficiency Under Stress and Ischemic Conditions in Landrace Pigs

Background: Myocardial efficiency should be maintained stable under light-to-moderate stress conditions, but ischemia puts the myocardium at risk for impaired functionality. Additionally, the measurement of such efficiency typically requires invasive heart catheterization and exposure to ionizing radiation. In this work, we aimed to non-invasively assess myocardial power and the resulting efficiency during pharmacological stress testing and ischemia induction.Methods: In a cohort of n = 10 healthy Landrace pigs, dobutamine stress testing was performed, followed by verapamil-induced ischemia alongside cardiac magnetic resonance (CMR) imaging. External myocardial power, internal myocardial power, and myocardial efficiency were assessed non-invasively using geometrical and functional parameters from CMR volumetric as well as blood flow and pressure measurements.Results: External myocardial power significantly increased under dobutamine stress [2.3 (1.6–3.1) W/m2 vs. 1.3 (1.1–1.6) W/m2, p = 0.005] and significantly decreased under verapamil-induced ischemia [0.8 (0.5–0.9) W/m2, p = 0.005]. Internal myocardial power [baseline: 5.9 (4.6–8.5) W/m2] was not affected by dobutamine [7.5 (6.9–9.0) W/m2, p = 0.241] nor verapamil [5.8 (4.7–8.8) W/m2, p = 0.878]. Myocardial efficiency did not change from baseline to dobutamine [21% (15–27) vs. 31% (20–44), p = 0.059] but decreased significantly during verapamil-induced ischemia [10% (8–13), p = 0.005].Conclusion: In healthy Landrace pigs, dobutamine stress increased external myocardial power, whereas myocardial efficiency was maintained stable. On the contrary, verapamil-induced ischemia substantially decreased external myocardial power and myocardial efficiency. Non-invasive CMR was able to quantify these efficiency losses and might be useful for future clinical studies evaluating the effects of therapeutic interventions on myocardial energetics.

Design and Clinical Evaluation of Pharmacologic Stress-Test with Dalargin for SPECT Detection of Viable Myocardium in Patients after Myocardial Infarction

Purpose: To develop a functional stress-test with Dalargin used as a pharmacological stress agent and to study its diagnostic capabilities for quantifying the general and segmental systolic function of the left ventricle in patients with IHD using SPECT and echo methods. Material and methods: The study comprised 29 male patients with CHD-angina of 2-3 functional classes, studied on 15–25 days (on average 20 ± 2.8 days) after a large-focal myocardial infarction. A fractional step-wise injection of Dalargin was performed with step doses as 0.1 mg / kg (1 ml up to a total of 8 ml, with intervals of 90 seconds, for a total of 12 minutes), in a supine position. After each dose of Dalargin, blood pressure, heart rate, ECG were recorded, and an echocardiographic assessment of hemodynamic parameters and local contractility was carried out. At the peak of the effect of dalargin, 99mTc-Tetrofosmin was administered intravenously (370 – 540 MBq), followed by chest SPECT. Results: The optimal dose of dalargin for assessing the contractility of the LV was 0.3 mg/kg. From the data of myocardial perfusion SPECT, at dalargin test, the number of segments with normal regional blood supply increased statistically significantly from 56,0 % to 64,7 %, the number of hypoperfused segments decreased from 41.0% to 33.7% as compared to rest, and the number of non-perfused ones – from 3.0 % to 1.6 %. Spearman’s correlation coefficient between segmental contractility and local perfusion at the top dalargin inotropic effect was high and significant (R=0.67, p<0.01). The sensitivity and specificity of the pharmacological test with intravenous administration of dalargin for prediction of postoperative improvement of perfusion and contractility of the viable myocardium were: sensitivity 78.8 %, specificity 76.4 %, diagnostic accuracy 77.6 %. Conclusion. The use of the agonist of the μ - and δ-opioid receptors dalargin as a pharmacological stress-agent at perfusion SPECT and Stress Echocardiography to assess the contractile reserve of a dysfunctional viable myocardium is informative and appropriate. In patients with IHD who have suffered a myocardial infarction and are referred to myocardial revascularization, dalargin can be employed as an effective stress-agent for assessing the reserve of perfusion and contractility of dysfunctional left ventricular myocardium using perfusion SPECT and echocardiography.

Dynamic Handgrip Exercise: Feasibility and Physiologic Stress Response of a Needle-Free Cmr Stress Test

Purpose: CMR pharmacological stress-testing is well-established to detect myocardial ischemia. Despite stressor and contrast agents appear rather save, contraindications and side effects have to be considered. Substantial costs are further limiting its applicability. Dynamic handgrip exercise(DHE) may have the potential to address these shortcomings as a physiological stressor. We therefore evaluated the feasibility and physiologic stress response of DHE in relation to pharmacological dobutamine-stimulation by cardiac magnetic resonance(CMR).Methods: Two subgroups were prospectively enrolled: (i)volunteers without relevant disease and (ii)patients with known CAD referred for stress-testing. A both-handed, metronome-guided DHE was performed over 2 minutes continuously with 80 contractions/minute by all participants, whereas dobutamine stress-testing was only performed in group(ii). Short axis strain by fast-Strain-ENCoded imaging was acquired at rest, immediately after DHE and during dobutamine infusion. Results: Eighty middle-aged individuals(age 56±17years, 48males) were enrolled. DHE triggered significant positive chronotropic(HRrest:68±10bpm, HRDHE:91±13bpm, p<0.001) and inotropic stress response(GLSrest:-19.4±1.9%, GLSDHE:-20.6±2.1%, p<0.001). Exercise-induced increase of longitudinal strain was present in healthy volunteers and CAD patients to the same extent, but in general pronounced from basal to apical layers(p<0.01). DHE was aborted by a minor portion(7%) due to peripheral fatigue. The inotropic effect of DHE appears to be non-inferior to intermediate dobutamine-stimulation(GLSDHE=-19.5±2.3%, GLSDob=-19.1±3.1%, p=n.s.), whereas its chronotropic effect was superior (HRDHE=89±14bpm, HRDOB=78±15bpm, p<0.001). Conclusions: DHE causes positive ino- and chronotropic effects superior to intermediate dobutamine-stimulation, suggesting a relevant increase of myocardial oxygen demand. DHE appears safe and timesaving with broad applicability. The data encourages further studies to determine its potential to detect obstructive CAD.