Andreas Hoffmeier

Differentiation of Malignant and Benign Cardiac Tumors Using 18F-FDG PET/CT

In the diagnostic algorithm of cardiac tumors, the noninvasive determination of malignancy and metastatic spread is of major interest to stratify patients and to select and monitor therapies. In the diagnostic work-up, morphologic imaging modalities such as echocardiography or magnetic resonance tomography offer information on, for example, size, invasiveness, and vascularization. However, preoperative assessment of malignancy may be unsatisfactory. The aim of this study was to evaluate the diagnostic value of 18F-FDG PET and the incremental diagnostic value of an optimized CT score in this clinical scenario. Methods: 18F-FDG PET/CT scans (whole-body imaging with low-dose CT) of 24 consecutive patients with newly diagnosed cardiac tumors were analyzed (11 men, 13 women; mean age ± SD, 59 ± 13 y). The maximum standardized uptake values (SUVmax) of the tumors were measured. Patients were divided into 2 groups: benign cardiac tumors (n = 7) and malignant cardiac tumors (n = 17) (cardiac primaries [n = 8] and metastases [n = 9]). SUVmax was compared between the 2 groups. Results were compared with contrast-enhanced CT, using standardized criteria of malignancy. Histology served as ground truth. Results: Mean SUVmax was 2.8 ± 0.6 in benign cardiac tumors and significantly higher both in malignant primary and in secondary cardiac tumors (8.0 ± 2.1 and 10.8 ± 4.9, P < 0.01). Malignancy was determined with a sensitivity of 100% and specificity of 86% (accuracy, 96%), after a cutoff with high sensitivity (SUVmax of 3.5) was chosen to avoid false-negatives. Morphologic imaging reached a sensitivity of 82% and a specificity of 86% (accuracy, 83%). Both false-positive and false-negative decisions in morphology could be corrected in all but 1 case using a metabolic threshold with an SUVmax of 3.5. In addition, extracardiac tumor manifestations were detected in 4 patients by whole-body 18F-FDG PET/CT. Conclusion: 18F-FDG PET/CT can aid the noninvasive preoperative determination of malignancy and may be helpful in detecting metastases of malignant cardiac tumors.

Systematic Analysis of Gene Expression Differences between Left and Right Atria in Different Mouse Strains and in Human Atrial Tissue

Background Normal development of the atria requires left-right differentiation during embryonic development. Reduced expression of Pitx2c (paired-like homeodomain transcription factor 2, isoform c), a key regulator of left-right asymmetry, has recently been linked to atrial fibrillation. We therefore systematically studied the molecular composition of left and right atrial tissue in adult murine and human atria. Methods We compared left and right atrial gene expression in healthy, adult mice of different strains and ages by employing whole genome array analyses on freshly frozen atrial tissue. Selected genes with enriched expression in either atrium were validated by RT-qPCR and Western blot in further animals and in shock-frozen left and right atrial appendages of patients undergoing open heart surgery. Results We identified 77 genes with preferential expression in one atrium that were common in all strains and age groups analysed. Independent of strain and age, Pitx2c was the gene with the highest enrichment in left atrium, while Bmp10, a member of the TGFβ family, showed highest enrichment in right atrium. These differences were validated by RT-qPCR in murine and human tissue. Western blot showed a 2-fold left-right concentration gradient in PITX2 protein in adult human atria. Several of the genes and gene groups enriched in left atria have a known biological role for maintenance of healthy physiology, specifically the prevention of atrial pathologies involved in atrial fibrillation, including membrane electrophysiology, metabolic cellular function, and regulation of inflammatory processes. Comparison of the array datasets with published array analyses in heterozygous Pitx2c+/− atria suggested that approximately half of the genes with left-sided enrichment are regulated by Pitx2c. Conclusions Our study reveals systematic differences between left and right atrial gene expression and supports the hypothesis that Pitx2c has a functional role in maintaining “leftness” in the atrium in adult murine and human hearts.

Skeletonization Versus Pedicle Preparation of the Radial Artery With and Without the Ultrasonic Scalpel

BACKGROUND The radial artery (RA) is increasingly used for myocardial revascularization because of its presumed advantageous long-term patency rates. The vessel can be harvested as a pedicle or skeletonized. The aim of this study was to compare the skeletonization technique with pedicle preparation using either an ultrasonic scalpel or scissors. METHODS Forty consecutive patients with coronary artery disease undergoing complete arterial revascularization were included in the study. In 20 patients the RAs were prepared using scissors and clips (group 1: skeletonization; group 2: pedicle). In another 20 patients the arteries harvested were prepared using an ultrasonic scalpel (group 3: skeletonization; group 4: pedicle). The RA was treated with papaverine to prevent spasm of the vessel during and after harvesting. Tissue specimens of each RA were taken to analyze endothelial morphology by scanning electron microscopy. After implantation of the RA, graft perfusion was measured with a flow probe. RESULTS Harvesting the RA as a skeletonized vessel took more time as compared with pedicle preparation (group 1 vs group 2: 37.1 +/- 3.5 minutes vs 24.4 +/- 3.9 minutes; p < 0.001 and group 3 vs group 4: 31.1 +/- 3.5 minutes vs 25.6 +/- 3.7 minutes; p < 0.01). The number of hemostatic titanium clips was similarly higher in group 1 as opposed to group 2 (58.7 +/- 7.1 vs 38.7 +/- 7.1; p < 0.01). However, there was no difference between groups 3 and 4 (p = 0.086). The length of the RA after skeletonization with scissors and clips was 20.8 +/- 1.5 cm in contrast with 19.1 +/- 0.9 cm (p < 0.01) after dissection as a pedicle. In the groups using the ultrasonic scalpel, there was no difference in graft length (p = 0.062). Mean blood flow through the graft after establishing the proximal anastomosis was similar among all groups (groups 1, 2, 3, and 4: 50 +/- 20.1 mL/min, 53.8 +/- 24.3 mL/min, 56.3 +/- 25.1 mL/min, and 51.8 +/- 23 mL/min, respectively). Scanning electron microscopy demonstrated endothelial damage in all patients in groups 1, 2, and 3 and in 7 patients of group 4. Most endothelial lesions were minor except in group 3 in which 1 of 5 endothelial lesions were severe. Statistically significant differences was found between groups 1 and 2, and 3 and 4 with respect to the degree of endothelial damage (p < 0.01). CONCLUSIONS Skeletonization using scissors and clips is more time consuming and technically more difficult, but yield significantly longer grafts. Skeletonization with an ultrasonic scalpel did not result in additional length and was more frequently associated with severe endothelial damage. Pedicle preparation using scissors or an ultrasonic scalpel is much simpler and faster, and does not jeopardize endothelial integrity.

Clinical and echocardiographic outcomes after implantation of the Trifecta aortic bioprosthesis: an initial single-centre experience.

OBJECTIVES The Trifecta valve (St. Jude Medical) was introduced into clinical practice as a tri-leaflet stented pericardial valve designed for supra-annular placement in the aortic position. The present study aims to evaluate the preliminary results with this new bioprosthesis. METHODS Seventy patients underwent aortic valve replacement (AVR) with the Trifecta valve between August 2010 and December 2011. Thirty-three patients were male and 37 were female (52.9%). Mean age was 74.65 ± 7.63 (range 47-90 years). Prevalent cause of AVR was aortic stenosis in 64 (91.43%) patients. The mean preoperative pressure gradient was 50 ± 17 (range 20-84 mmHg), and the mean aortic valve area was 0.77 ± 0.33. Five (7.14%) patients were operated on due to aortic valve endocarditis. One patient was operated on due to isolated, severe aortic insufficiency. All patients were in New York Heart Association functional class III or IV. Twenty-eight (40%) patients underwent concomitant procedures. RESULTS Concomitant procedures were coronary artery bypass grafting (n = 25), mitral valve replacement (n = 1), ablation of atrial fibrillation (n = 1) and septal myomectomy (n = 1). There were no intraoperative deaths. The 30-day in-hospital mortality was 2.85% (2 of 70). One late death occurred during the in-hospital stay due to a multiorgan failure on postoperative day 60. There were 2 (2.85%) perioperative strokes. Mean pressure gradient decreased significantly from a preoperative value of 50 ± 17 mmHg to an intraoperative gradient of 9 ± 4 mmHg (Table 3). The mean gradients were 14, 11, 11, 8 and 6 mmHg for the 19, 21, 23, 25 and 27 mm valve size, respectively. No prosthesis dislocation, endocarditis, valve thrombosis or relevant aortic regurgitation was observed at discharge. CONCLUSIONS The initial experience with the Trifecta valve bioprosthesis shows excellent outcomes with favourable early haemodynamics. Further studies with longer follow-up are needed to confirm those preliminary results.

Initial Clinical Experience With the HeartWare Left Ventricular Assist System: A Single-Center Report

BACKGROUND The HeartWare ventricular assist device (HVAD) system (HeartWare International Inc, Framingham, MA) is a new centrifugal continuous-flow ventricular assist device. The aim of the present study is to review our institutional experience with this novel device. METHODS We reviewed the files of 50 patients (39 men, 11 women) with a mean age of 50.6 ± 11.8 years (range, 19 to 70 years) who underwent HVAD implantation between July 2009 and November 2011. Two patients underwent HeartWare BIVAD implantation. The underlying heart diseases were end-stage ischemic heart disease (n = 12), acute myocardial infarction (n = 9), dilated cardiomyopathy (n = 27) and acute myocarditis (n = 2). Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles were level 1 (n = 11), 2 (n = 5), 3 (n = 10), and 4 (n = 24). RESULTS After a cumulative support duration of 11,086 days, Kaplan-Meier analysis revealed a survival of 82.0%, 77.9%, 75.5%, at 1, 12, and 24 months, respectively. Causes of early death were right heart failure (n = 4), multiorgan failure (n = 2), septic shock (n = 2), and major neurologic complications (n = 4). One late death occurred due to a right heart failure. Comparison between patients operated on in cardiogenic shock (INTERMACS 1 and 2) and patients who underwent elective HVAD implantation (INTERMACS 3 and 4) revealed a survival of 61.5% and 44.1% for the INTERMACS 1 and 2 group and 90.3% and 87.1% for the INTERMACS 3 and 4 group at 1 and 12 months, respectively (odds ratio, 4.67; p = 0.003). One patient was weaned from the system after 2 years. Eleven patients (22%) were successfully bridged to transplantation. Mean time to transplantation was 209 days (range, 72 to 427 days). Posttransplant survival at the 1-year follow-up was 90.9% (11 patients). CONCLUSIONS Our experience with HVAD shows satisfying results with an excellent posttransplantation survival. Moreover, the stratified survival based on the level of preoperative stability shows better outcomes in patients undergoing elective HVAD implantation.

Whole-heart coronary magnetic resonance angiography: value for the detection of coronary artery stenoses in comparison to multislice computed tomography angiography

Background: Coronary magnetic resonance imaging and computed tomography are being discussed as alternatives to catheter angiography in the detection of coronary artery disease. Yet, only few comparative validations have been performed. Purpose: To compare steady-state free precession whole heart coronary magnetic resonance imaging (MRI) with multidetector coronary computed tomography angiography (CTA) for the detection of coronary artery disease using catheter angiography as the standard of reference. Material and Methods: Twenty patients with known CAD were examined with navigator (NAV) gated and corrected free-breathing 3D balanced gradient echo whole heart coronary MRI and coronary CTA. Subjective overall image quality (4 point scale, 1 = excellent), visibility of vessel segments and accuracy for the detection of significant coronary stenoses (>50%) were compared to coronary x-ray angiography by two blinded readers. Results: Median of subjective image quality was 3 for coronary MRI and 2 for coronary CTA. Of a total of 209 segments, 67 segments (32%) had to be excluded from the evaluation by coronary MRI (61 due to insufficient image quality and 6 due to stent artifacts). For coronary CTA, 31 segments (15%) had to be excluded from the evaluation (12 due to insufficient image quality, 15 due to severe calcifications superimposing the vessel lumen and 4 due to stent artifacts. Segment based values for the detection of ⩾50% diameter coronary x-ray angiographic stenoses were: specificity: MRI 88%, CTA 95%; sensitivity: MRI 82%, CTA 84%; diagnostic accuracy: MRI 87%, CTA 93%; positive predictive value: MRI 68%, CTA 77% and negative predictive value: MRI 94%, CTA 95%. Conclusion: Coronary WH-MRI was inferior to coronary CTA regarding image quality and number of evaluable segments but both had similar diagnostic value for the detection and exclusion of CAD when only evaluable segments were included.

A Recurrent Activating PLCG1 Mutation in Cardiac Angiosarcomas Increases Apoptosis Resistance and Invasiveness of Endothelial Cells

Primary cardiac angiosarcomas are rare tumors with unfavorable prognosis. Pathogenic driver mutations are largely unknown. We therefore analyzed a collection of cases for genomic aberrations using SNP arrays and targeted next-generation sequencing (tNGS) of oncogenes and tumor-suppressor genes. Recurrent gains of chromosome 1q and a small region of chromosome 4 encompassing KDR and KIT were identified by SNP array analysis. Repeatedly mutated genes identified by tNGS were KDR with different nonsynonymous mutations, MLL2 with different nonsense mutations, and PLCG1 with a recurrent nonsynonymous mutation (R707Q) in the highly conserved autoinhibitory SH2 domain in three of 10 cases. PLCγ1 is usually activated by Y783 phosphorylation and activates protein kinase C and Ca(2+)-dependent second messengers, with effects on cellular proliferation, migration, and invasiveness. Ectopic expression of the PLCγ1-R707Q mutant in endothelial cells revealed reduced PLCγ1-Y783 phosphorylation with concomitant increased c-RAF/MEK/ERK1/2 phosphorylation, increased IP3 amounts, and increased Ca(2+)-dependent calcineurin activation compared with ectopic expressed PLCγ1-wild-type. Furthermore, cofilin, whose activation is associated with actin skeleton reorganization, showed decreased phosphorylation, and thus activation after expression of PLCγ1-R707Q compared with PLCγ1-wild-type. At the cellular level, expression of PLCγ1-R707Q in endothelial cells had no influence on proliferation rate, but increased apoptosis resistance and migration and invasiveness in in vitro assays. Together, these findings indicate that the PLCγ1-R707Q mutation causes constitutive activation of PLCγ1 and may represent an alternative way of activation of KDR/PLCγ1 signaling besides KDR activation in angiosarcomas, with implications for VEGF/KDR targeted therapies.

Left ventricular dilation and functional impairment assessed by gated SPECT are indicators of cardiac allograft vasculopathy in heart transplant recipients

BACKGROUND Coronary angiography (CA) is the standard method for diagnosis of cardiac allograft vasculopathy (CAV). Little is known about the value of measuring left ventricular function over time, which can be derived from gated myocardial perfusion single-photon emission computed tomography (SPECT). We evaluated the potential of measuring myocardial perfusion and left ventricular function with gated SPECT, as compared with CA, to detect CAV in the follow-up of heart transplantation. METHODS One hundred sixty-one heart transplant recipients (137 men, 24 women, age 50.7 ± 12.2 years) were followed-up for 4.2 ± 2.0 years by annual routine gated perfusion SPECT and consecutive CA. Myocardial perfusion was quantified by summed stress, rest and difference scores (SSS, SRS and SDS, respectively). Left ventricular function (ESV, EDV and LVEF) was derived from gated SPECT. Both were compared with angiographically defined stages of CAV. RESULTS ESV/EDV derived from gated SPECT increased from 61 ± 25 ml/169 ± 39 ml in patients with no CAV over 74 ± 38 ml/188 ± 55 ml in patients with moderate CAV to 153 ± 75 ml/278 ± 86 ml in patients with severe CAV (p < 0.01 and p < 0.001), whereas LVEF decreased from 64 ± 10% over 62 ± 11% to 47 ± 13% in patients with severe CAV (p < 0.001). Perfusion quantified by SRS and SSS increased from 1.2 ± 1.5/1.9 ± 2.3 over 1.9 ± 1.4/2.8 ± 2.0 to 6.5 ± 5.1/7.7 ± 5.8 in patients with severe CAV (p < 0.01). Overall, for the prediction of severe CAV, accuracy was found to be higher for gated SPECT functional analysis as compared with perfusion analysis. CONCLUSIONS Impaired left ventricular function, as assessed by gated SPECT, correlated significantly with CAV. Thus, for this purpose, gated SPECT offers higher sensitivity than analysis of perfusion while having a comparable specificity.

Primary left atrial angiosarcoma mimicking severe mitral valve stenosis

Primary cardiac tumours are quite rare and most of these tumours are benign. In this report, a patient presented with heart failure symptoms attributable to severe mitral valve stenosis. Echocardiography showed a dense left atrial mass causing functional mitral valve obstruction. The morphological and intraoperative presentation was highly suggestive of a myxoma but histopathological examination found a primary pedunculated cardiac angiosarcoma. The role of two dimensional and transoesophageal echocardiography in the assessment of cardiac masses and tumours is discussed.

Aortic dissection associated with cogans's syndrome: deleterious loss of vascular structural integrity is associated with GM-CSF overstimulation in macrophages and smooth muscle cells

BackgroundCogans syndrome is a rare disorder of unknown origin characterized by inflammatory ocular disease and vestibuloauditory symptoms. Systemic vasculitis is found in about 10% of cases.Case presentationA 46-year-old female with Coganss syndrome and a history of arterial hypertension presented with severe chest pain caused by an aneurysm of the ascending aorta with a dissection membrane located a few centimeters distal from the aortic root. After surgery, histopathological analysis revealed that vascular matrix integrity and expression of the major matrix molecules was characterized by elastolysis and collagenolysis and thus a dramatic loss of structural integrity. Remarkably, exceeding matrix deterioration was associated with massively increased levels of granulocyte macrophage colony stimulating factor (GM-CSF).ConclusionOur data suggest that the persistently increased secretion of the inflammatory mediator GM-CSF by resident inflammatory cells but also by SMC may be the trigger of aortic wall structural deterioration.