Simultaneous assessment of heart and lungs with gated high-pitch ultra-low dose chest CT using artificial intelligence-based calcium scoring.

Purpose: The combined testing for coronary artery and pulmonary diseases is of clinical interest as risk factors are shared. In this study, a novel ECG-gated tin-filtered ultra-low dose chest CT protocol (GCCT) for integrated heart and lung acquisition and the applicability of artificial intelligence (AI)-based coronary artery calcium scoring were assessed. Methods: In a clinical registry of 10481 patients undergoing heart and lung CT, GCCT was applied in 44 patients on a dual-source CT. Coronary calcium scans (CCS) with 120 kVp, 100 kVp, and tin-filtered 100 kVp (Sn100) of controls, matched with regard to age, sex, and body-mass index, were retrieved from the registry (ntotal=176, 66.5 (59.4-74.0) years, 52 men). Automatic tube current modulation was used in all scans. In 20 patients undergoing GCCT and Sn100 CCS, Agatston scores were measured both semi-automatically by experts and by AI, and classified into six groups (0, <10, <100, <400, <1000, ≥1000). Results: Effective dose decreased significantly from 120 kVp CCS (0.50 (0.41-0.61) mSv) to 100 kVp CCS (0.34 (0.26-0.37) mSv) to Sn100 CCS (0.14 (0.11-0.17) mSv). GCCT showed higher values (0.28 (0.21-0.32) mSv) than Sn100 CCS but lower than 120 kVp and 100 kVp CCS (all p < 0.05) despite greater scan length. Agatston scores correlated strongly between GCCT and Sn100 CCS in semi-automatic and AI-based measurements (both ρ = 0.98, p < 0.001) resulting in high agreement in Agatston score classification (κ = 0.97, 95% CI 0.92-1.00; κ = 0.89, 95% CI 0.79-0.99). Regarding chest findings, further diagnostic steps were recommended in 28 patients. Conclusions: GCCT allows for reliable coronary artery disease and lung cancer screening with ultra-low radiation exposure. GCCT-derived Agatston score shows excellent agreement with standard CCS, resulting in equivalent risk stratification.

Prognostic value of novel imaging parameters derived from standard cardiovascular magnetic resonance in high risk patients with systemic light chain amyloidosis.

BACKGROUND: The differentiated assessment of functional parameters besides morphological changes is essential for the evaluation of prognosis in systemic immunoglobulin light chain (AL) amyloidosis. METHODS: Seventy-four subjects with AL amyloidosis and presence of late gadolinium enhancement (LGE) pattern typical for cardiac amyloidosis were analyzed. Long axis strain (LAS) and myocardial contraction fraction (MCF), as well as morphological and functional markers, were measured. The primary endpoint was death, while death and heart transplantation served as a composite secondary endpoint. RESULTS: After a median follow-up of 41 months, 29 out of 74 patients died and 10 received a heart transplant. Left ventricular (LV) functional parameters were reduced in patients, who met the composite endpoint (LV ejection fraction 51% vs. 61%, LAS - 6.9% vs - 10%, GLS - 12% vs - 15% and MCF 42% vs. 69%; p <  0.001 for all). In unadjusted univariate analysis, LAS (HR = 1.05, p <  0.001) and MCF (HR = 0.96, p <  0.001) were associated with reduced transplant-free survival. Kaplan-Meier analyses showed a significantly lower event-free survival in patients with reduced MCF. MCF and LAS performed best to identify high risk patients for secondary endpoint (Log-rank test p <  0.001) in a combined model. Using sequential Cox regression analysis, the addition of LAS and MCF to LV ejection fraction led to a significant increase in the predictive power of the model (χ2 (df = 1) = 28.2, p <  0.001). CONCLUSIONS: LAS and MCF as routinely available and robust CMR-derived parameters predict outcome in LGE positive AL amyloidosis. Patients with impaired LV function in combination with reduced LAS and MCF are at the highest risk for death and heart transplantation.

Syncope in a female patient. Echocardiography and cardiac computed tomography reveal an unexpected diagnosis.

Papillary fibroelastoma is a benign cardiac tumor with a high potential of embolization. Coronary computed tomography is a valuable tool for the work-up of patients with papillary fibroelastoma, providing accurate information regarding the coronary circulation and morphology of the cardiac mass.

Value of adenosine stress cardiovascular magnetic resonance in the evaluation of vessels supplying previously infarcted territories.

BACKGROUND: The diagnostic performance of adenosine stress cardiovascular magnetic resonance (CMR) for the detection of significant stenosis in infarct-related arteries is widely unknown. Two different types of perfusion defects can be observed: (a) larger than or (b) equal size as scar.We hypothesized that: (a) defect>scar predicts significant coronary stenosis, and (b) defect=scar predicts an unobstructed infarct-related artery, and (c) angina symptoms might be of additional value in stratification. PATIENTS AND METHODS: Patients with previous myocardial infarction referred for work-up of myocardial ischemia undergoing adenosine stress CMR were included if they had coronary angiography within 4 weeks of CMR. RESULTS: Two hundred patients with a mean age of 66±11 years, ischemic scars (subendocardial/transmural), and a mean left ventricular ejection fraction of 53% were included. In patients with defect>scar, the positive predictive value was excellent (88%) and typical angina was reported only in the stenosis group (P=0.002). However, patients with defect=scar (with 50% showing subendocardial scar) had a prevalence of 37% for stenosis, yielding a low negative predictive value of 63%. In this group, symptoms of typical angina were independent of stenosis (P=1.0). CONCLUSION: A perfusion defect larger than scar is highly predictive for significant stenosis in infarct-related arteries. However, more than a third of the patients with perfusion defect of equal size as scar also showed significant coronary stenosis. As half of these patients showed still viable (subendocardial) scars, there is a high-risk of reinfarction. The addition of angina symptoms seems to increase diagnostic accuracy only in patients with perfusion defects larger than scar.

Establishment Success of the Beetle Tapeworm Hymenolepis diminuta Depends on Dose and Host Body Condition.

Parasite effects on host fitness and immunology are often intensity-dependent. Unfortunately, only few experimental studies on insect-parasite interactions attempt to control the level of infection, which may contribute substantial variation to the fitness or immunological parameters of interest. The tapeworm Hymenolepis diminuta-flour beetle Tenebrio molitor model-has been used extensively for ecological and evolutionary host-parasite studies. Successful establishment of H. diminuta cysticercoids in T. molitor relies on ingestion of viable eggs and penetration of the gut wall by the onchosphere. Like in other insect models, there is a lack of standardization of the infection load of cysticercoids in beetles. The aims of this study were to: (1) quantify the relationship between exposure dose and establishment success across several H. diminuta egg concentrations; and (2) test parasite establishment in beetles while experimentally manipulating host body condition and potential immune response to infection. Different egg concentrations of H. diminuta isolated from infected rat feces were fed to individual beetles 7-10 days after eclosion and beetles were exposed to starvation, wounding, or insertion of a nylon filament one hour prior to infection. We found that the establishment of cysticercoids in relation to exposure dose could be accurately predicted using a power function where establishment success was low at three lowest doses and higher at the two highest doses tested. Long-term starvation had a negative effect on cysticercoid establishment success, while insertion of a nylon filament and wounding the beetles did not have any effect compared to control treatment. Thus, our results show that parasite load may be predicted from the exposure dose within the observed range, and that the relationship between dose and parasite establishment success is able to withstand some changes in host body condition.

Regional differences in prognostic value of cardiac valve plane displacement in systemic light-chain amyloidosis.

BACKGROUND: To compare the prognostic value of cardiac valve plane displacement (CVPD) on various locations in cardiac light chain (AL) amyloidosis. METHODS: Consecutive patients with biopsy-proven cardiac involvement in AL amyloidosis who had undergone cardiovascular magnetic resonance (CMR) between 2005 and 2014 in our institution, were retrospectively identified and data analyzed. The primary combined endpoint was all-cause mortality or heart transplantation. Systolic CVPD were obtained from standard cine bSSFP in 2-, 3- and 4-chamber views at anterior aortic plane systolic excursion (AAPSE); anterior, anterolateral, inferolateral, inferior, inferoseptal mitral (MAPSE); and lateral tricuspid (TAPSE) annular segments. RESULTS: We identified 68 patients (58 ± 10 years; 59% male). Median follow-up period was 1.2 years (IQR, 0.3-4.1). Significant differences in CVPD between patients who reached a primary endpoint (n = 44) and transplant-free survivors were found only for AAPSE (6.1 mm (IQR, 4.6-9.4) vs. 8.8 mm (IQR, 6.9-10.4); p = 0.02) and MAPSEanterolateral (7.3 mm (IQR, 5.4-11.7) vs. 10.5 mm (IQR, 8.1-13.4); p = 0.03). AAPSE (χ2 = 15.6; p = 0.0002) provided the best predictive value for transplant-free survival compared to all other valvular plane locations. A high-risk cutoff (AAPSE ≤ 7.6 mm) was calculated by ROC analysis to predict all-cause death or heart transplantation within 6 months from index examination (AUC = 0.80; CI: 0.68 to 0.89; p < 0.0001). AAPSE added incremental prognostic power to an imaging prediction model of late gadolinium enhancement and global longitudinal strain (GLS) (∆χ2 = 5.8, p = 0.02) as well as to a clinical model including Karnofsky index and NT-proBNP (∆χ2 = 6.2, p = 0.01). CONCLUSION: In patients with cardiac involvement in AL amyloidosis, systolic CVPD obtained from standard long axis cine views appear to indicate outcome better, when obtained in the anterior aortic plane (AAPSE) and provide incremental prognostic value to LGE and strain measurements.

Improved image quality with simultaneously reduced radiation exposure: Knowledge-based iterative model reconstruction algorithms for coronary CT angiography in a clinical setting.

BACKGROUND: The aim of this study was to assess the potential for radiation dose reduction using knowledge-based iterative model reconstruction (K-IMR) algorithms in combination with ultra-low dose body mass index (BMI)-adapted protocols in coronary CT angiography (coronary CTA). METHODS: Forty patients undergoing clinically indicated coronary CTA were randomly assigned to two groups with BMI-adapted (I: <25.0 kg/m2, II: <28.0 kg/m2, III: <30.0 kg/m2, IV: ≥30.0 kg/m2) low dose (LD, I: 100kVp/75 mAs, II: 100kVp/100 mAs, III: 100kVp/150 mAs, IV: 120kVp/150 mAs, n = 20) or ultra-low dose (ULD, I: 100kVp/50 mAs, II: 100kVp/75 mAs, III: 100kVp/100 mAs, IV: 120kVp/100 mAs, n = 20) protocols. Prospectively-triggered coronary CTA was performed using a 256-MDCT with the lowest reasonable scan length. Images were generated with filtered back projection (FBP), a noise-reducing hybrid iterative algorithm (iD, levels 2/5) and K-IMR using cardiac routine (CR) and cardiac sharp settings, levels 1-3. RESULTS: Groups were comparable regarding anthropometric parameters, heart rate, and scan length. The use of ULD protocols resulted in a significant reduction of radiation exposure (0.7 (0.6-0.9) mSv vs. 1.1 (0.9-1.7) mSv; p < 0.02). Image quality was significantly better in the ULD group using K-IMR CR 1 compared to FBP, iD 2 and iD 5 in the LD group, resulting in fewer non-diagnostic coronary segments (2.4% vs. 11.6%, 9.2% and 6.1%; p < 0.05). CONCLUSIONS: The combination of K-IMR with BMI-adapted ULD protocols results in significant radiation dose savings while simultaneously improving image quality compared to LD protocols with FBP or hybrid iterative algorithms. Therefore, K-IMR allows for coronary CTA examinations with high diagnostic value and very low radiation exposure in clinical routine.

Incremental value of cardiac magnetic resonance for the evaluation of cardiac tumors in adults: experience of a high volume tertiary cardiology centre.

To assess the value of cardiac magnetic resonance imaging (CMR) in evaluating cardiac tumours in a tertiary cardiology centre. Between 2004 and 2014, 125 patients (pts.) from a total of 17000 who received a CMR examination in our institution were referred with the suspicion of cardiac tumours. A dedicated protocol was used that included standard cine SSFP acquisitions as well as tissue characterization using T1 and T2 black-blood (T1 BB and T2 BB respectively) with and without fat suppression, perfusion of the structure and late gadolinium enhancement. Patients' files were retrospectively analysed and data related to clinical status, results from other examinations (echocardiography), therapeutic approach and histology results, when performed, were collected. In 65 pts., a diagnosis of cardiac tumour was reached. 45 Pts had a biopsy. The CMR examination was concordant with the histology results in 35 (76%) pts. superior to that showed by echocardiography, 26 (58%) pts., p = 0.03. Forty-two (65%) pts. had a benign tumour and 23 (35%) a malignant process. Myxoma was the most frequent benign tumour, 27 (65%) and cardiac metastases were the most frequent form of malignancies, 21 (91%), with B cell non-Hodgkin lymphoma being the most frequent one, 4 (19%). Benign tumours were mostly located in the left atrium, 27 (64%) versus 6 (26%), p = 0.007, whereas malignant tumours had a predilection for the right atrium und left ventricle [11 (48%) vs. 3 (7%), p = 0.001 and 8 (35%) vs. 3 (7%), p = 0.03]. All benign cardiac tumours were single and did not show signs of infiltration. Conversely, malignant cardiac tumours were larger (43 ± 35 vs. 24 ± 16, p = 0.007) with a significant proportion (65%) showing myocardial infiltration. Pts with malignant cardiac tumours had a higher proportion of LGE (82 vs. 60%, p = 0.05) and exhibited more frequently an isointense signal in T1 BB images (78 vs. 61%, p = 0.04). Both groups showed similar proportion of perfusion and signal intensity in the T2 BB acquisitions (p = NS). CMR is a valuable tool in evaluating cardiac tumours, proving superior to echocardiography in establishing the type of cardiac tumour.

Myocardial contraction fraction derived from cardiovascular magnetic resonance cine images-reference values and performance in patients with heart failure and left ventricular hypertrophy.

AIMS: Left ventricular hypertrophy (LVH) has strong prognostic implications and is associated with heart failure. Recently, myocardial contraction fraction (MCF) was identified as a useful marker for specifically identifying cardiac amyloidosis (CA). The purpose of this study was to evaluate the diagnostic accuracy of MCF for the discrimination of different forms of LVH. METHODS AND RESULTS: We analysed cardiovascular magnetic resonance (CMR) scans of patients with CA (n = 132), hypertrophic cardiomyopathy (HCM, n = 60), hypertensive heart disease (HHD, n = 38) and in 100 age- and gender-matched healthy controls. MCF was calculated by dividing left ventricular (LV) stroke volume by LV myocardial volume. The diagnostic accuracy of MCF was compared to that of LV ejection fraction (EF) and the mass index (MI). Compared with controls (136.3 ± 24.4%, P < 0.05), mean values for MCF were significantly reduced in LVH (HHD:92.6 ± 20%, HCM:80 ± 20.3%, transthyretin CA:74.9 ± 32.2% and light-chain (AL) CA:50.5 ± 21.4%). MCF performed better than LVEF (AUC = 0.96 vs. AUC = 0.6, P < 0.001) and was comparable to LVMI (AUC = 0.95, P = 0.4) in discriminating LVH from controls. There was a significant yet weak correlation between MCF and LVEF (r = 0.43, P < 0.0001). MCF outperformed LVEF and LVMI in discriminating between different etiologies of LVH and between AL and other forms of LVH (AUC = 0.84, P < 0.0001). Moreover, cut-off values for MCF <50% and LVEF <60% allowed to identify patients with high probability for CA. CONCLUSION: In patients with heart failure MCF discriminates CA from other forms of LVH. As it can easily be derived from standard, non-contrast cine images, it may be a very useful marker in the diagnostic workup of patients with LVH.

Galectin-3 binding protein plasma levels are associated with long-term mortality in coronary artery disease independent of plaque morphology.

BACKGROUND AND AIMS: Galectin-3 binding protein (Gal-3BP) is a secreted protein associated with inflammation and carotid atherosclerosis. We hypothesized that high Gal-3BP levels may indicate unfavorable plaque morphology and outcome in coronary artery disease (CAD). METHODS: Gal-3BP plasma levels were measured by ELISA in 233 patients (63 ± 10 years, 50.2% male) undergoing computed coronary angiography tomography (CCTA). RESULTS: In 149 patients, CCTA confirmed CAD (stenosis grade >20%). Mean Gal-3BP plasma levels were 5.9 ± 2.7 µg/mL and did not differ between patients with or without CAD. Over a follow-up time of up to 4.4 years (median 2.5 years), there were 17 cases of revascularization, five cases of myocardial infarction, and five deaths (four non-cardiac, one fatal myocardial infarction). Kaplan-Meier analysis revealed that high Gal-3BP levels were significantly associated with long-term mortality (p < 0.001). Cox proportional hazards regression analysis showed that this association was independent of cardiovascular risk factors (HR 1.238, 95%-CI 1.012-1.514, p = 0.038). After adjustment for troponin T and C-reactive protein (hs-CRP) levels, significance was lost (p = 0.123). Further analysis revealed that Gal-3BP levels were significantly related to body mass index and hs-CRP levels indicating an association with metabolic and inflammatory distress. There was no correlation between Gal-3BP and calcium score, plaque volume, or vascular remodeling. CONCLUSIONS: While high Gal-3BP plasma levels are associated with long-term mortality, we could not confirm it as a marker of cardiac mortality or unstable plaque morphology.

Myocardial Perfusion Reserve and Strain-Encoded CMR for Evaluation of Cardiac Allograft Microvasculopathy.

OBJECTIVES: This study sought to evaluate myocardial perfusion reserve index (MPRI) and diastolic strain rate, both assessed by cardiac magnetic resonance (CMR) as a noninvasive tool for the detection of microvasculopathy. BACKGROUND: Long-term survival of cardiac allograft recipients is limited primarily by cancer and cardiac allograft vasculopathy (CAV). Besides epicardial CAV, diagnosed by coronary angiography, stenotic microvasculopathy was found to be an additional independent risk factor for survival after heart transplantation. METHODS: Sixty-three consecutive heart transplant recipients who underwent CMR, coronary angiography, and myocardial biopsy were enrolled. Stenotic vasculopathy in microvessels was considered in myocardial biopsies by immunohistochemistry and CAV was graded during coronary angiography according to International Society of Heart and Lung Transplantation criteria. In addition, by CMR microvasculopathy was assessed by myocardial perfusion reserve during pharmacologic hyperemia with adenosine and strain-encoded magnetic resonance using a modified spatial modulation of magnetization tagging pulse sequence in all patients. RESULTS: Decreasing MPRI and diastolic strain rates were observed in patients with decreasing microvessel luminal radius to wall thickness ratio and decreasing capillary density (r = 0.45 and r = 0.61 for MPRI and r = 0.50 and r = 0.38 for diastolic strain rate, respectively; p < 0.005 for all). Using multivariable analysis, both MPRI and diastolic strain rate were robust predictors of stenotic microvasculopathy, independent of age, organ age, and CAV by International Society of Heart and Lung Transplantation criteria (hazard ratio: 0.07, p = 0.006 for MPRI; hazard ratio: 0.91, p = 0.002 for diastolic strain rate). Patients without stenotic microvasculopathy in the presence of no or mild CAV (n = 36) exhibited significantly higher median survival free of events, compared with patients with stenotic microvasculopathy in the presence of no or mild CAV (n = 18; p = 0.04 by log rank). CONCLUSIONS: CMR represents a valuable noninvasive diagnostic tool, which may be used for the early detection of transplant microvasculopathy before the manifestation of CAV during surveillance coronary angiographic procedures.

Cardiac Effects of Attenuating Gsα - Dependent Signaling.

AIMS: Inhibition of ß-adrenergic signalling plays a key role in treatment of heart failure. Gsα is essential for ß-adrenergic signal transduction. In order to reduce side-effects of beta-adrenergic inhibition diminishing ß-adrenergic signalling in the heart at the level of Gsα is a promising option. METHODS AND RESULTS: We analyzed the influence of Gsα on regulation of myocardial function and development of cardiac hypertrophy, using a transgenic mouse model (C57BL6/J mice) overexpressing a dominant negative Gsα-mutant under control of the α-MHC-promotor. Cardiac phenotype was characterized in vivo and in vitro and under acute and chronic ß-adrenergic stimulation. At rest, Gsα-DN-mice showed bradycardia (602 ± 13 vs. 660 ± 17 bpm, p<0.05) and decreased dp/dtmax (5037 ± 546- vs. 6835 ± 505 mmHg/s, p = 0.02). No significant differences were found regarding ejection fraction, heart weight and cardiomyocyte size. ß-blockade by propranolol revealed no baseline differences of hemodynamic parameters between wildtype and Gsα-DN-mice. Acute adrenergic stimulation resulted in decreased ß-adrenergic responsiveness in Gsα-DN-mice. Under chronic adrenergic stimulation, wildtype mice developed myocardial hypertrophy associated with increase of LV/BW-ratio by 23% (4.4 ± 0.2 vs. 3.5 ± 0.1 mg/g, p<0.01) and cardiac myocyte size by 24% (14927 ± 442 px vs. 12013 ± 583 px, p<0.001). In contrast, both parameters were unchanged in Gsα-DN-mice after chronic isoproterenol stimulation. CONCLUSION: Overexpression of a dominant negative mutant of Gsα leads to decreased ß-adrenergic responsiveness and is protective against isoproterenol-induced hypertrophy. Thus, Gsα-DN-mice provide novel insights into ß-adrenergic signal transduction and its modulation in myocardial overload and failure.

Anterior Aortic Plane Systolic Excursion: A Novel Indicator of Transplant-Free Survival in Systemic Light-Chain Amyloidosis.

BACKGROUND: Anterior aortic plane systolic excursion (AAPSE) was evaluated in the present pilot study as a novel echocardiographic indicator of transplant-free survival in patients with systemic light-chain amyloidosis. METHODS: Eighty-nine patients with light-chain amyloidosis were included in the post-hoc analysis. A subgroup of 54 patients with biopsy-proven cardiac amyloid infiltration were compared with 41 healthy individuals to evaluate the discriminative ability of echocardiographic findings. AAPSE is defined as the systolic excursion of the anterior aortic margin. To quantify AAPSE, the M-mode cursor was placed on the aortic valve plane in parasternal long-axis view at end-diastole. Index echocardiography had been performed before chemotherapy. Median follow-up duration was 2.4 years. The primary combined end point was heart transplantation or overall death. RESULTS: Mean AAPSE was 14 ± 2 mm in healthy individuals (mean age=57 ± 10 years; 56% men; BMI=25 ± 4 kg/m2). AAPSE < 11 mm separated patients from age-, gender-, and BMI-matched control subjects with 93% sensitivity and 97% specificity. Median transplant-free survival of patients with AAPSE < 5 mm was 0.7 versus 4.8 years (P = .0001). AAPSE was an independent indicator of transplant-free survival in multivariate Cox regression (echocardiographic model: hazard ratio=0.72 [P = .03]; biomarker model: hazard ratio=0.62 [P = .0001]). Sequential regression analysis suggested incremental power of AAPSE as a marker of transplant-free survival. An ejection fraction-based model with an overall χ2 value of 22.8 was improved by the addition of log NT-proBNP (χ2 = 32.6, P < .005), troponin-T (χ2 = 39.6, P < .01), and AAPSE (χ2 = 54.0, P < .0001). CONCLUSIONS: AAPSE is suggested as an indicator of transplant-free survival in patients with systemic light-chain amyloidosis. AAPSE provided significant incremental value to established staging models.

Green tea extract as a treatment for patients with wild-type transthyretin amyloidosis: an observational study.

BACKGROUND: Causative treatment of patients with wild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) is lacking. Recent reports indicate the potential use of epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea, to inhibit amyloid fibril formation. We sought to investigate changes of cardiac function and morphology in patients with wtATTR-CM after consumption of green tea extract (GTE). METHODS: Twenty-five male patients (71 [64; 80] years) with wtATTR-CM were submitted to clinical examination, echocardiography, cardiac magnetic resonance imaging (cMRI) (n=14), and laboratory testing before and after daily consumption of GTE capsules containing 600 mg epigallocatechin-3-gallate for at least 12 months. RESULTS: A significant decrease of left ventricular (LV) myocardial mass by 6% (196 [100; 247] vs 180 [85; 237] g; P=0.03) by cMRI and total cholesterol by 8.4% (191 [118; 267] vs 173 [106; 287] mg/dL; P=0.006) was observed after a 1-year period of GTE consumption. LV ejection fraction by cMRI (53% [33%; 69%] vs 54% [28%; 71%]; P=0.75), LV wall thickness (17 [13; 21] vs 18 [14; 25] mm; P=0.1), and mitral annular plane systolic excursion (10 [5; 23] vs 8 [4; 13] mm; P=0.3) by echocardiography remained unchanged. CONCLUSION: This study supports LV mass stabilization in patients with wtATTR-CM consuming GTE potentially indicating amyloid fibril reduction.

Comparison of different types of cardiac amyloidosis by cardiac magnetic resonance imaging.

OBJECTIVES: We sought to determine cardiac morphological and functional differences between light-chain (AL), mutant-type transthyretin (ATTRmt) and wild-type TTR (ATTRwt) amyloidosis using contrast-enhancement cardiac magnetic resonance imaging (CE-CMR). Finally, we attempted to establish the diagnostic and prognostic impact of these findings. INTRODUCTION: The most common forms of cardiac amyloid are AL and ATTR amyloidosis, but the clinical courses of these variants are quite heterogeneous. While CE-CMR is used to evaluate patients with cardiac amyloidosis, its ability to predict prognosis in these patients is debatable. METHODS: About 130 patients with cardiac amyloidosis (AL, n = 62; ATTRmt, n = 30, ATTRwt, n = 33) were assessed by CE-CMR (cardiac morphology, cardiac function, late gadolinium enhancement). RESULTS: Left ventricular (LV) mass, basal and mid-ventricular maximal wall thickness, and thickness of the inter-atrial septum were higher in ATTRwt when compared to AL and ATTRmt amyloidosis. Tricuspid annular excursion was lower in ATTRwt amyloidosis than in AL amyloidosis. CE was observed in 94.6% of the patients (AL 80.6%; ATTRmt 90%; ATTRwt 87.9%) with significant differences in quality and intensity between the groups. Differentiation of amyloid types was achieved by combination of age, number of organs, the presence of inferolateral CE-CMR, thickness of inter-atrial septum and troponin T. Overall 1-year-survival rates were 93.3, 93.9 and 70.5% in ATTRwt, ATTRmt and AL amyloidosis, respectively. LV mass, mitral annular excursion and NT-proBNP in AL amyloidosis, LV mass maximal apical wall thickness and troponin T in ATTRwt amyloidosis, and finally NT-proBNP and renal function in ATTRmt amyloidosis were independent predictors of outcome. CONCLUSIONS: This study demonstrates that CE-CMR can highlight morphological and functional differences between different types of cardiac amyloidosis. In addition, CE-CMR and cardiac biomarkers provide useful prognostic information in patients with cardiac amyloidosis.

Extracellular remodeling in patients with wild-type amyloidosis consuming epigallocatechin-3-gallate: preliminary results of T1 mapping by cardiac magnetic resonance imaging in a small single center study.

OBJECTIVES: T1 mapping by cardiac magnetic resonance imaging (CMR) is able to determine the extracellular volume fraction. Wild-type transthyretin amyloidosis (WT-ATTR) is characterized by extracellular amyloid deposition in the heart. Recent reports indicated a reduction of left ventricular (LV) myocardial mass in WT-ATTR after consumption of epigallocatechin-3-gallate, the main catechin in green tea. It remained unclear, whether reduction of LV myocardial mass reflects decrease of amyloid load or progressive atrophy of cardiomyocytes. METHODS: This study included 7 male patients with CMR repetitively performed before and 12 months after daily consumption of green tea extract (600 mg epigallocatechin-3-gallate). Short axis slices as well as 2-, 3-, and 4-chamber views were acquired using SSFP sequences. T1 mapping was created out of 11 mid-ventricular short axis views with increasing inversion times using a single breath-hold modified look-locker inversion recovery sequence before and 15 min after Gadolinium contrast administration. RESULTS: After 12 months, a significant decrease of LV myocardial mass [198 (160; 212) vs. 180 (142; 204) g; p < 0.05] was observed. Moreover, a significant decrease of native [T1 1110 (1072; 1150) ms vs. 1080 (970; 1101), p < 0.05 or p = 0.03] was noticed. The calculated extracellular volume decreased in 5 patients (62.5%) by 7% and increased in 2 patients (37.5%) by 9.5%, in trend resulting in a (not significant) decrease of median ECV by 2.4%. Left ventricular ejection fraction (LVEF) [57 (48; 65) vs. 55 (47; 64) %; p = 0.3] remained unchanged. CONCLUSIONS: This study provided further evidence of LV myocardial mass reduction in patients with WT-ATTR daily consuming green tea extract. Additionally, this study gave first insights into the histomorphological correlate of LV mass reduction using T1 mapping. LV mass reduction appeared to be rather due to a decrease of amyloid load than atrophy of cardiomyocytes.

T1 mapping in dilated cardiomyopathy with cardiac magnetic resonance: quantification of diffuse myocardial fibrosis and comparison with endomyocardial biopsy.

AIM: The aim of this study was to determine the value of extracellular volume fraction (ECV) for the non-invasive assessment of diffuse myocardial fibrosis (MF) in different stages of systolic left ventricular (LV) dysfunction in dilated cardiomyopathy (DCM) in comparison with endomyocardial biopsy. BACKGROUND: Non-invasive ECV assessment using cardiovascular magnetic resonance (CMR) T1 mapping reflects diffuse MF in patients with severe DCM, but earlier stages of DCM with mild LV functional impairment have not been investigated yet. METHODS: Forty-five subjects with mild functional impairment and LV dilation ['early DCM', ejection fraction (EF) 45-55%], 29 with LV dysfunction and volume dilatation ('DCM', EF <45%) and 56 healthy volunteers (controls) underwent standard CMR imaging, late gadolinium enhancement (LGE) and T1 mapping for the calculation of ECV. The collagen volume fraction (CVF) was quantified histologically from endomyocardial biopsies of 24 DCM patients out of the study cohort. RESULTS: The ECV between 'early DCM' (25 ± 4%), 'DCM' (27 ± 4%), and controls (23 ± 3; P < 0.05 for all) differed significantly. There was a weak inverse correlation between ECV and EF (r = -0.35; P < 0.01). A strong correlation between ECV and CVF could be detected (r = 0.85; P = 0.01). The cut-off value for ECV to differentiate between healthy myocardium and DCM was 26% (specificity 91.1%, sensitivity 62.1%, area under the curve 0.8, P < 0.0001). ECV is already elevated at early stages of functional impairment, whereby an overlap between early DCM and controls is present. But 31% of the early DCM patients had an ECV fraction above the mean ±2 SD ECV of controls. CONCLUSIONS: ECV measurement with CMR reflects myocardial collagen content in DCM. Therefore, CMR-based assessment of ECV may have the potential to serve as a non-invasive tool for the quantification of diffuse MF in order to monitor therapy response and aid risk stratification in different stages of DCM.

Prognostic significance of semiautomatic quantification of left ventricular long axis shortening in systemic light-chain amyloidosis.

AIMS: To assess left ventricular long axis shortening (LAS) in patients with AL amyloidosis as a potential predictor for outcome. METHODS AND RESULTS: We performed a de novo echocardiographic analysis of LAS in 120 patients with biopsy-proven AL amyloidosis evaluated at first presentation before specific treatment. Additionally, 47 control subjects were analyzed retrospectivly. LAS was measured using a semiautomatic tissue motion annular displacement software algorithm (TMAD). LAS was significantly better than ejection fraction (EF) (p < 0.0001) and M-mode-derived mitral annular plane systolic excursion (MAPSE) (p < 0.05) discriminating AL patients from control subjects, while being non-inferior compared to tissue Doppler-derived peak systolic mitral annular velocity. One year outcome analysis in patients with AL amyloidosis showed that LAS remained the only significant echocardiographic parameter (HR:0.76; p < 0.005) in a multivariable Cox regression model of echocardiographic values. In a comprehensive clinical model, LAS (HR:0.72, p < 0.0001), cardiac troponin-T (HR:2.86, p < 0.01) and free light chain difference (HR:1.00; p < 0.05) were independently associated with the outcome. Assessment of LAS led to a significant integrated discrimination improvement and offered incremental information compared to EF and biomarkers. The cut-off value for LAS discriminating the endpoint was 5.8%. CONCLUSION: LAS was an independent predictor of survival within the first year and offers incremental information in patients with AL amyloidosis evaluated prior to specific treatment.

The "Wagshurst study": p.Val40Ile transthyretin gene variant causes late-onset cardiomyopathy.

BACKGROUND: Transthyretin-related amyloidosis (ATTR) is characterized by a wide heterogeneity of genotypes and predominantly neurological and cardiac phenotypes. This study aims to characterize a cohort of patients with the rare transthyretin (TTR) Val20Ile (p.TTRVal40Ile) variant. METHODS AND RESULTS: This study comprises a single-center cohort of 59 individuals subsequently evaluated for TTRVal20Ile variant due to clinical (n = 13) or predictive (n = 46) reasons. All patients were mainly related to Wagshurst, a small village in the South of Germany. Clinical assessment was performed by neurological evaluation, echocardiography, electrocardiography, cardiac biomarkers, cardiac MRI (n = 13), and (99m)Tc-DPD scintigraphy (n = 16). The rare TTRVal20Ile variant was found in 41 patients; evidence of cardiac amyloidosis was present in 22 patients. Evidence of pulmonary involvement was obtained by (99m)Tc-DPD scintigraphy in eight patients. No further organ involvement was observed in any of the patients carrying TTRVal20Ile variant. Correlation of inter-ventricular septum thickness as well as decrease of left ventricular longitudinal contractility with age was observed. Moreover, thickness of inter-ventricular septum correlated with NT-proBNP plasma levels and decrease in mitral annular plane systolic excursion. Cardiac manifestation started during the early sixth life decade indicated by higher left ventricular septum thickness and NT-proBNP plasma levels as compared to patients in fifth decade of life. All patients of the seventh and eighth life decade (n = 10) presented with cardiac amyloidosis. During median follow-up of 26 (0-108) months, eight patients underwent heart transplantation with 1-year mortality rate of 25%. CONCLUSIONS: This large cohort of individuals carrying the TTRVal20Ile mutation reveals a predominantly cardiac phenotype with high penetrance and late onset of symptoms. Cardiac manifestation progressed to end-stage heart failure within a few years, finally requiring heart transplantation with promising long-term survival rates.

The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.

BACKGROUND: Inherited arrhythmias were originally considered isolated electrical defects. There is growing evidence that ion channel dysfunction also contributes to myocardial disorders, but genetic overlap has not been reported for sinus node dysfunction (SND) and noncompaction cardiomyopathy (NCCM). OBJECTIVES: The study sought to investigate a familial electromechanical disorder characterized by SND and NCCM, and to identify the underlying genetic basis. METHODS: The index family and a cohort of unrelated probands with sinus bradycardia were examined by electrocardiography, Holter recording, exercise stress test, echocardiography, and/or cardiac magnetic resonance imaging. Targeted next-generation and direct sequencing were used for candidate gene analysis and mutation scanning. Ion channels were expressed in HEK293 cells and studied using patch-clamp recordings. RESULTS: SND and biventricular NCCM were diagnosed in multiple members of a German family. Segregation analysis suggested autosomal-dominant inheritance of the combined phenotype. When looking for potentially disease-causing gene variants with cosegregation, a novel hyperpolarization-activated cyclic nucleotide channel 4 (HCN4)-G482R mutation and a common cysteine and glycine-rich protein 3 (CSRP3)-W4R variant were identified. HCN4-G482R is located in the highly conserved channel pore domain. Mutant subunits were nonfunctional and exerted dominant-negative effects on wild-type current. CSRP3-W4R has previously been linked to dilated and hypertrophic cardiomyopathy, but was also found in healthy subjects. Moreover, different truncation (695X) and missense (P883R) HCN4 mutations segregated with a similar combined phenotype in an additional, unrelated family and a single unrelated proband respectively, which both lacked CSRP3-W4R. CONCLUSIONS: The symptom complex of SND and NCCM is associated with heritable HCN4 defects. The NCCM phenotype may be aggravated by a common CSRP3 variant in one of the families.