Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST).

BACKGROUND: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. AIMS: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. METHODS: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. BASELINE RESULTS: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021. CONCLUSION: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856).

Influence of dose reduction and iterative reconstruction on CT calcium scores: a multi-manufacturer dynamic phantom study.

To evaluate the influence of dose reduction in combination with iterative reconstruction (IR) on coronary calcium scores (CCS) in a dynamic phantom on state-of-the-art CT systems from different manufacturers. Calcified inserts in an anthropomorphic chest phantom were translated at 20 mm/s corresponding to heart rates between 60 and 75 bpm. The inserts were scanned five times with routinely used CCS protocols at reference dose and 40 and 80% dose reduction on four high-end CT systems. Filtered back projection (FBP) and increasing levels of IR were applied. Noise levels were determined. CCS, quantified as Agatston and mass scores, were compared to physical mass and scores at FBP reference dose. For the reference dose in combination with FBP, noise level variation between CT systems was less than 18%. Decreasing dose almost always resulted in increased CCS, while at increased levels of IR, CCS decreased again. The influence of IR on CCS was smaller than the influence of dose reduction. At reference dose, physical mass was underestimated 3-30%. All CT systems showed similar CCS at 40% dose reduction in combinations with specific reconstructions. For some CT systems CCS was not affected at 80% dose reduction, in combination with IR. This multivendor study showed that radiation dose reductions of 40% did not influence CCS in a dynamic phantom using state-of-the-art CT systems in combination with specific reconstruction settings. Dose reduction resulted in increased noise and consequently increased CCS, whereas increased IR resulted in decreased CCS.

Diagnostic Value of Urinary Steroid Profiling in the Evaluation of Adrenal Tumors.

Radiological examination may unexpectedly reveal an adrenal mass. Current algorithms for differentiating between benign and malignant lesions mainly rely on size and densitometry on unenhanced CT, which have limited specificity. We examined the diagnostic value of urinary steroid profiling by gas chromatography/mass-spectrometry (GC/MS) in differentiating between benign and malignant adrenal tumors. A retrospective study in two referral centers for patients with adrenal disease was performed. All urinary steroid profiles ordered for evaluation of an adrenal tumor between January 2000 and November 2011 were examined. Patients were diagnosed with adrenal cortical carcinoma (ACC), adrenal cortical adenoma (ACA), or other adrenal mass. Results of hormonal measurements, imaging studies, pathology reports, and clinical outcome were retrieved from medical records. The diagnostic value of individual urinary steroid metabolites was determined by receiver operating characteristics analysis. Cut-off values were compared to reference values from an age and gender-standardized population of healthy controls. Eighteen steroid metabolites were excreted in significantly higher concentrations in patients with ACC (n = 27) compared to patients with ACA (n = 107) or other adrenal conditions (n = 18). Tetrahydro-11-deoxycortisol (THS) at a cut-off value of 2.35 µmol/24 h differentiated ACC from other adrenal disorders with 100% sensitivity and 99% specificity. Elevated urinary excretion of THS was associated with a very high sensitivity and specificity to differentiate between an ACC and a benign adrenal mass. Urinary steroid profiling might be a useful diagnostic test for the evaluation of patients with an adrenal incidentaloma.

Calcification as a risk factor for rupture of abdominal aortic aneurysm.

OBJECTIVES: Abdominal aortic aneurysm (AAA) is a major cause of death in developed countries. The AAA diameter is still the only validated prognostic measure for rupture, and therapeutic interventions are initiated accordingly. This still leads to unnecessary interventions in some cases or unidentified impending ruptures. Vascular calcification has been validated abundantly as a risk factor in the cardiovascular field and may strengthen the rupture risk assessment of the AAA. With this study we aim to assess the correlation between AAA calcification and rupture risk in a retrospective unmatched case-control population. METHODS: A database of 334 AAA patients was evaluated. Three groups were formed: elective (eAAA; n = 233), ruptured (rAAA; n = 73) and symptomatic non-ruptured (sAAA; n = 28) AAA patients. The Abdominal Aortic Calcification-8 score (AAC-8) was used to measure the severity of vascular calcification. RESULTS: The AAA diameter (61 ± 12 mm vs. 74 ± 21 mm; p < .001) and AAC-8 score (3.4 ± 2 points vs. 4.9 ± 2.3 points; p < .001) of the eAAA and the combined rAAA and sAAA groups, respectively, were significantly different after univariate analysis. Multivariate analysis showed that larger AAA diameter (odds ratio [OR]: 1.048/mm increase; 95% confidence interval [CI]: 1.042-1.082; p < .001) and a higher AAC-8 score (OR: 1.34/point increase; 95% CI: 1.19-1.53; p < .001) were significantly associated with development into a sAAA or rAAA. Peripheral artery disease was significantly correlated to eventual elective treatment (OR: 0.39; 95% CI: .15-1; p = .049). CONCLUSION: This study suggests a trend of an increased degree of calcification in symptomatic or even ruptured AAA patients compared with elective AAA patients.

Calcium score of small coronary calcifications on multidetector computed tomography: results from a static phantom study.

INTRODUCTION: Multi detector computed tomography (MDCT) underestimates the coronary calcium score as compared to electron beam tomography (EBT). Therefore clinical risk stratification based on MDCT calcium scoring may be inaccurate. The aim of this study was to assess the feasibility of a new phantom which enables establishment of a calcium scoring protocol for MDCT that yields a calcium score comparable to the EBT values and to the physical mass. MATERIALS AND METHODS: A phantom containing 100 small calcifications ranging from 0.5 to 2.0mm was scanned on EBT using a standard coronary calcium protocol. In addition, the phantom was scanned on a 320-row MDCT scanner using different scanning, reconstruction and scoring parameters (tube voltage 80-135 kV, slice thickness 0.5-3.0mm, reconstruction kernel FC11-FC15 and threshold 110-150 HU). The Agatston and mass score of both modalities was compared and the influence of the parameters was assessed. RESULTS: On EBT the Agatston and mass scores were between 0 and 20, and 0 and 3mg, respectively. On MDCT the Agatston and mass scores were between 0 and 20, and 0 and 4 mg, respectively. All parameters showed an influence on the calcium score. The Agatston score on MDCT differed 52% between the 80 and 135kV, 65% between 0.5 and 3.0mm and 48% between FC11 and FC15. More calcifications were detected with a lower tube voltage, a smaller slice thickness, a sharper kernel and a lower threshold. Based on these observations an acquisition protocol with a tube voltage of 100 kV and two reconstructions protocols were defined with a FC12 reconstruction kernel; one with a slice thickness of 3.0mm and a one with a slice thickness of 0.5mm. This protocol yielded an Agatston score as close to the EBT as possible, but also a mass score as close to the physical phantom value as possible, respectively. CONCLUSION: With the new phantom one acquisition protocol and two reconstruction protocols can be defined which produces Agatston scores comparable to EBT values and to the physical mass.

Prosthetic valves in adult patients with congenital heart disease: Rationale and design of the Dutch PROSTAVA study.

BACKGROUND: Data on long-term complications in adult patients with congenital heart disease (ACHD) and a prosthetic valve are scarce. Moreover, the influence of prosthetic valves on quality of life (QoL) and functional outcome in ACHD patients with prosthetic valves has not been studied. OBJECTIVES: The primary objective of the PROSTAVA study is to investigate the relation between prosthetic valve characteristics (type, size and location) and functional outcome as well as QoL in ACHD patients. The secondary objectives are to investigate the prevalence and predictors of prosthesis-related complications including prosthesis-patient mismatch. METHODS: The PROSTAVA study, a multicentre cross-sectional observational study, will include approximately 550 ACHD patients with prosthetic valves. Primary outcome measures are maximum oxygen uptake during cardiopulmonary exercise testing and QoL. Secondary outcomes are the prevalence and incidence of valve-related complications including prosthesis-patient mismatch. Other evaluations are medical history, physical examination, echocardiography, MRI, rhythm monitoring and laboratory evaluation (including NT-proBNP). IMPLICATIONS: Identification of the relation between prosthetic valve characteristics in ACHD patients on one hand and functional outcome, QoL, the prevalence and predictors of prosthesis-related complications on the other hand may influence the choice of valve prosthesis, the indication for more extensive surgery and the indication for re-operation.

Is there an indication for computed tomography and magnetic resonance imaging in the evaluation of coronary artery bypass grafts?

This meta-analysis evaluates the diagnostic accuracy of multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) for bypass graft occlusion and stenosis detection compared with coronary angiography in post-coronary artery bypass graft patients. The indication for noninvasive imaging in post-coronary artery bypass graft patients with these techniques is discussed. Overall, MRI had significantly lower sensitivity (81%) and specificity (91%) for occlusion detection than MDCT (96% and 98%, respectively). Only 2 studies assessed the accuracy of stenosis detection with MRI. Stenosis detection with MDCT had a pooled sensitivity of 89% and specificity of 97%. Multidetector computed tomography is therefore superior to MRI for the noninvasive detection of coronary bypass graft occlusion and stenosis. For stenosis detection, the accuracy of MDCT is, however, not sufficient to warrant a wide clinical use. The remaining indication for MRI-guided bypass graft assessment is in combination with myocardial evaluation such as magnetic resonance perfusion, wall motion, and stress test as a "one-stop-shop" procedure.

Coronary revascularization treatment based on dual-source computed tomography.

Therapy advice based on dual-source computed tomography (DSCT) in comparison with coronary angiography (CAG) was investigated and the results evaluated after 1-year follow-up. Thirty-three consecutive patients (mean age 61.9 years) underwent DSCT and CAG and were evaluated independently. In an expert reading (the "gold standard"), CAG and DSCT examinations were evaluated simultaneously by an experienced radiologist and cardiologist. Based on the presence of significant stenosis and current guidelines, therapy advice was given by all readers blinded from the results of other readings and clinical information. Patients were treated based on a multidisciplinary team evaluation including all clinical information. In comparison with the gold standard, CAG had a higher specificity (91%) and positive predictive value (PPV) (95%) compared with DSCT (82% and 91%, respectively). DSCT had a higher sensitivity (96%) and negative predictive value (NPV) (89%) compared with CAG (91% and 83%, respectively). The DSCT-based therapy advice did not lead to any patient being denied the revascularization they needed according to the multidisciplinary team evaluation. During follow-up, two patients needed additional revascularization. The high NPV for DSCT for revascularization assessment indicates that DSCT could be safely used to select patients benefiting from medical therapy only.

The benefit of 64-MDCT prior to invasive coronary angiography in symptomatic post-CABG patients.

PURPOSE: The purpose of this study is to assess the diagnostic accuracy of 64-MDCT in symptomatic patients after CABG and to explore the advantages of the 64-MDCT results on the CAG procedure. MATERIAL AND METHODS: From December 2004 until August 2005, 34 post-CABG patients (29 men, mean age 63.5 +/- 8.5 years) with 69 coronary artery bypass grafts were scanned on a 64-MDCT (Somatom Sensation 64, Siemens AG, Forchheim, Germany) prior to CAG. Angiograms and 64-MDCT images were evaluated for the existence of occlusions or significant stenosis (>or=50% lumen reduction) in bypass grafts and native coronary arteries. RESULTS: 64-MDCT had a sensitivity, a specificity, and a diagnostic accuracy of 100% for occlusion detection. For stenosis detection, sensitivity was 100%, specificity 98.7% and diagnostic accuracy 98.7%. For detecting significant stenosis in native coronary arteries, 64-MDCT had a sensitivity of 80.0%, specificity of 90.8%, and a diagnostic accuracy of 87.1%. Seventeen patients (50.0%) did not need invasive treatment, 14 patients (41.2%) underwent a percutaneous coronary intervention (PCI), and 3 patients (8.8%) underwent surgery. Treatment advice based on 64-MDCT was correct in 88.2% of patients and when 64-MDCT results would have been known 58.8% of diagnostic CAG procedures could have been prevented. CONCLUSION: In conclusion, 64-MDCT has a high diagnostic accuracy in detecting bypass graft stenosis and occlusions, and 64-MDCT based treatment advice was correct in 88.2% of patients.

A 16-slice multidetector computed tomography protocol for evaluation of the gastroepiploic artery grafts in patients after coronary artery bypass surgery.

Arterial coronary bypass grafts [internal mammary arteries and gastroepiploic artery (GEA)] are in widespread use for coronary surgery. Since selective catheterisation of the GEA graft to monitor patency, is often unsuccessful, a non-invasive protocol to visualise the GEA-graft from origin to anastomosis is presented using 16-slice multidetector computed tomography (MDCT). Twenty-six male patients (mean age 58.1+/-6.7 years) with GEA grafts were scanned according to a protocol of an ECG-synchronised cardiac scan followed by a thoracoabdominal scan. To terminate the scan at the correct anatomical level, the lowest level of the GEA was coded based on the lumbar vertebrae level. Scores ranging from one (excellent) to four (bad) were assigned to evaluate visualisation quality of the grafts. GEA grafts were assessable in 62% of the thoracoabdominal scans and 69% of the cardiac scans. On average, the lowest part of the GEA corresponded with a level between L1 and L2, in two cases in the upper part of L3. Mean visualisation score in the thoracoabdominal scans and cardiac scans was good (respectively 1.4+/-0.6 and 1.4+/-1.0). Sixteen-slice MDCT is a promising alternative for catheterisation in evaluating patency of GEA grafts, using the presented protocol with thoracoabdominal scan including L3 for complete coverage of the GEA graft.

Human tissue valves in aortic position: determinants of reoperation and valve regurgitation.

BACKGROUND: Human tissue valves for aortic valve replacement have a limited durability that is influenced by interrelated determinants. Hierarchical linear modeling was used to analyze the relation between these determinants of durability and valve regurgitation measured by serial echocardiography. METHODS AND RESULTS: In adult patients, 218 cryopreserved aortic allografts were implanted with the subcoronary (85) or the root replacement technique (133), and 81 patients had root replacement with a pulmonary autograft. Mean follow-up was 4.2 years (SD 2.7; range, 0 to 10.5). Patient age, operator experience with subcoronary implantation, and allograft diameter were independent predictors for reoperation. With repeated color Doppler echocardiography, the severity of aortic regurgitation was assessed by the jet length method and the jet diameter ratio. Multilevel hierarchical linear modeling was used to estimate initial aortic regurgitation (intercept), its change over time (slope), and the effect of 11 potential determinants of durability on aortic regurgitation. With the jet length method, the intercept was 0.94 grade and the slope was 0.11 grade per year. With the jet diameter ratio, the intercept was 0.34 and the annual increase was 0.01. Subcoronary implanted valves had more initial aortic regurgitation, but progression of aortic valve regurgitation did not differ from root replacement. At midterm follow-up, recipient age <40 years was the only independent predictor of aortic regurgitation. CONCLUSIONS: Subcoronary implantation has a learning curve, resulting in more initial aortic regurgitation and early reoperation compared with root replacement. In both techniques, progression of aortic regurgitation over time is small but accelerated in young adults.

Aortic allograft implantation techniques: pathomorphology and regurgitant jet patterns by Doppler echocardiographic studies.

BACKGROUND: The diagnosis of allograft-specific pathology by echocardiography has important consequences for patient counseling and research. This study describes the pathomorphologic findings and color Doppler jet patterns in a consecutive series of patients after allograft placement with either the subcoronary implantation or root replacement technique. METHODS: From 1987 to July 1996, the subcoronary allograft implantation technique and root replacement technique were used in 82 patients and 70 patients, respectively. These patients comprised the study group. RESULTS: The incidence of paravalvular leaks and eccentric regurgitant jets was higher with subcoronary implantation (41%) than with root replacement (11%). Patients with a subcoronary implanted allograft had a higher incidence of eccentric jets. CONCLUSIONS: These findings support the concept of preservation of valve geometry after root replacement, as allograft-specific pathomorphologic abnormalities and eccentric jets are more common after subcoronary implantation of allografts. Learning effects, however, cannot be excluded as the cause of these abnormalities.

Allograft reconstruction of the right ventricular outflow tract.

OBJECTIVE: Evaluation of allograft reconstruction of the right ventricular outflow tract (RVOT). METHODS: From 1986 to April 1995, 201 allografts (146 pulmonary, 55 aortic) were implanted in 189 patients for conduit reconstruction of the RVOT in congenital heart disease or in the pulmonary autograft procedure. The mean age at allograft implantation was 16 years (range 2 weeks - 54 years). The primary diagnoses of these patients were truncus arterious (n = 19, 10%), transposition of the great arteries (TGA) with ventricular septal defect (VSD) and pulmonary atresia (PA) or stenosis (PS) (n = 14, 7%), PA with VSD (n = 26, 14%), PA or PS with intact septum (n = 7, 4%), tetralogy of Fallot (n = 44, 23%), corrected TGA with PA or PS (n = 11, 6%), tricuspid atresia (n = 9, 5%), aortic valve pathology for pulmonary autograft procedure (n = 55, 29%), and miscellaneous (n = 4, 2%). The allograft implantation was a reoperation in 54 patients (29%). RESULTS: The mean follow-up was 2.5 years (range 4 weeks-9 years). Six patients died in hospital (3.2%). Patient survival at 5 years was 91% (95% CL 86-95%). Freedom from all valve-related events (2 deaths, 17 reoperations, one endocarditis), as determined during reoperation or autopsy at 5 years was 78% (95% CL 65-86%). Freedom from structural allograft failure was 83% (2 deaths, 12 reoperations, 95% CL 70-90%). Allografts implanted for congenital right heart defects failed earlier than allografts used for pulmonary autograft procedures (P = 0.05). Aortic allografts showed structural failure more often than pulmonary allografts (P = 0.05). There were more valve-related events in patients of a younger age at implantation (P = 0.02) and in those allograft valves from younger donors (P = 0.004). CONCLUSIONS: Allograft RVOT reconstruction is an adequate surgical therapy. The allograft should preferably be pulmonary. A younger age at implantation is a risk factor for allograft failure. Donor age may be a thus-far underestimated risk factor for allograft degeneration.

Subcoronary implantation or aortic root replacement for human tissue valves: sufficient data to prefer either technique?

The aortic root replacement technique with aortic allograft or pulmonary autograft might be superior to the subcoronary allograft implantation technique with regard to aortic regurgitation. We explored the influence of the learning process on the incidence of reoperation and the severity of postoperative aortic regurgitation as assessed by color Doppler echocardiography. The subcoronary implantation technique was used in 81 patients, and root replacement was done in 63 patients. The first 30 patients of each group were considered as the surgeons' learning curve. Reoperations were more common in the subcoronary implantation group. After exclusion of early reoperations, the median regurgitation score based on echocardiographic examination was 0.22 in the first 30 patients from the subcoronary implantation group and 0.14 in the root replacement group. The subsequent patients from these groups had regurgitation scores of 0.20 and 0.17, respectively. Statistical analysis of these data showed no significant difference. This interim report suggests that the learning curve for the surgical procedure and the grouping of echocardiographic data influence the interpretation of follow-up studies. The superiority of either technique with regard to aortic regurgitation has yet to be proved.

Aortic root replacement with a pulmonary autograft.

A series of 42 consecutive patients with exclusively aortic root replacement using the pulmonary autograft is presented. The mean age at operation was 19.3 years (range 0.3-41.4). Two patients died in hospital (4.8%; 70% CL: 0.0-8.2). This mortality was not related to the autograft procedure. The mean follow-up time was 30 months (range 3-70; SD: 20). Late mortality consisted of two patients; in one of these severe autograft failure occurred due to chronic juvenile rheumatoid arthritis. The estimated survival rate at 4 years was 88.8% (70% CL: 83.3-94.5). Morbidity involved three patients. One had a total heart block after operation, requiring pacemaker implantation and two patients were reoperated: one for severe autograft failure due to recurrent acute rheumatic fever and the other for severe stenosis at the distal anastomosis of the pulmonary allograft. Thromboembolic complications and endocarditis were not registered. Reoperations for technical or degenerative reasons were not necessary. The estimated event-free survival rate at 4 years was 78.7% (70% CL: 71.0-86.4). Serial echocardiography (n = 28) showed a significant increase of the autograft annulus diameter of 2.9 mm (SD: 2.7). Thirty-five of the 37 patients with an autograft in situ were in NYHA class I, and 2 in class II. At last follow-up precordial color Doppler echocardiography showed moderate aortic regurgitation in one patient and no, trivial or mild aortic regurgitation in 36 patients. Stenosis of the autograft was not observed. These medium-term results are promising with respect to mortality, morbidity and functional results.(ABSTRACT TRUNCATED AT 250 WORDS)