Wolfgang Dichtl

Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy

BACKGROUND The natural history, management, and outcome of takotsubo (stress) cardiomyopathy are incompletely understood. METHODS The International Takotsubo Registry, a consortium of 26 centers in Europe and the United States, was established to investigate clinical features, prognostic predictors, and outcome of takotsubo cardiomyopathy. Patients were compared with age- and sex-matched patients who had an acute coronary syndrome. RESULTS Of 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age, 66.8 years). Emotional triggers were not as common as physical triggers (27.7% vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%) (P<0.001 for both comparisons). Rates of severe in-hospital complications including shock and death were similar in the two groups (P=0.93). Physical triggers, acute neurologic or psychiatric diseases, high troponin levels, and a low ejection fraction on admission were independent predictors for in-hospital complications. During long-term follow-up, the rate of major adverse cardiac and cerebrovascular events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year. CONCLUSIONS Patients with takotsubo cardiomyopathy had a higher prevalence of neurologic or psychiatric disorders than did those with an acute coronary syndrome. This condition represents an acute heart failure syndrome with substantial morbidity and mortality. (Funded by the Mach-Gaensslen Foundation and others; ClinicalTrials.gov number, NCT01947621.).

HMG-CoA Reductase Inhibitors Regulate Inflammatory Transcription Factors in Human Endothelial and Vascular Smooth Muscle Cells

Objective—Pleiotropic atheroprotective effects of HMG-CoA reductase inhibitors may be mediated on the level of vascular gene transcription. The aim of this study was to characterize the effects of statins on the activation of transcription factors known to regulate inflammation and cell proliferation/differentiation. Methods and Results—Simvastatin, atorvastatin, and lovastatin (0.1 to 10 &mgr;mol/L) inhibited the binding of nuclear proteins to both the nuclear factor-kappa B (NF-&kgr;B) and activator protein-1 (AP-1) DNA consensus oligonucleotides in human endothelial and vascular smooth muscle cells as assessed by electrophoretic mobility shift assay (EMSA). The inhibitory effects of statins on NF-&kgr;B or AP-1–dependent transcriptional activity were examined by transient transfection studies. HMG-CoA reductase inhibitors upregulated I&kgr;B-&agr; protein levels in endothelial cells and decreased c-Jun mRNA expression in smooth muscle cells as analyzed by Western and Northern blotting, respectively. Furthermore, statins inhibited DNA binding of hypoxia-inducible factor-1&agr;. Downstream effects of statins included inhibition of plasminogen activator inhibitor-1 and vascular endothelial growth factor-A mRNA levels in endothelial cells. Conclusions—HMG-CoA reductase inhibitors downregulate the activation of transcription factors NF-&kgr;B, AP-1, and hypoxia-inducible factor-1&agr;. These findings support the concept that statins have antiinflammatory and antiproliferative effects that are relevant in the treatment of atherosclerotic diseases.

Multislice Computed Tomography in Infective Endocarditis Comparison With Transesophageal Echocardiography and Intraoperative Findings

OBJECTIVES The aim of this study was to assess the value of multislice computed tomography (CT) for the assessment of valvular abnormalities in patients with infective endocarditis (IE) in comparison with transesophageal echocardiography (TEE) and intraoperative findings. BACKGROUND Multislice CT has recently shown promising data regarding valvular imaging in a 4-dimensional fashion. METHODS Thirty-seven consecutive patients with clinically suspected IE were examined with TEE and 64-slice CT or dual-source CT. Twenty-nine patients had definite IE and underwent surgery. RESULTS The diagnostic performance of CT for the detection of evident valvular abnormalities for IE compared with TEE was: sensitivity 97%, specificity 88%, positive predictive value (PPV) 97%, and negative predictive value (NPV) 88% on a per-patient basis (n = 37; excellent intermodality agreement kappa = 0.84). CT correctly identified 26 of 27 (96%) patients with valvular vegetations and 9 of 9 (100%) patients with abscesses/pseudoaneurysms compared with the intraoperative specimen. On a per-valve-based analysis, diagnostic accuracy for the detection of vegetations and abscesses/pseudoaneurysms compared with surgery was: sensitivity 96%, specificity 97%, PPV 96%, NPV 97%, and sensitivity 100%, specificity 100%, PPV 100%, NPV 100%, respectively, without significant differences as compared with TEE. Vegetation size measurements by CT correlated (r = 0.95; p <0.001) with TEE (mean 7.6 +/- 5.6 mm). The mobility of vegetations was accurately diagnosed in 21 of 22 (96%) patients with CT, but all of 4 leaflet perforations (<or=2 mm) were missed. CT provided more accurate anatomic information regarding perivalvular extent of abscess/pseudoaneurysms than TEE. CONCLUSIONS Multislice CT shows good results in detecting valvular abnormalities in IE and could be applied in pre-operative planning and exclusion of coronary artery disease before surgery.

Very Low-Density Lipoprotein Activates Nuclear Factor-κB in Endothelial Cells

High plasma levels of VLDL are associated with increased risk for atherosclerosis. Here we show that VLDL (75 to 150 microg/mL) activates nuclear factor-kappaB (NF-kappaB), a transcription factor known to play a key role in regulation of inflammation. Oxidation of VLDL reduced its capacity to activate NF-kappaB in vitro, whereas free fatty acids such as linoleic and oleic acid activated NF-kappaB to the same extent as did VLDL. Intravenous injection of human VLDL (6 mg protein per kg) into rats resulted in arterial activation of NF-kappaB as assessed by electrophoretic mobility shift assay. Aortic endothelial cells showed positive nuclear staining for the activated RelA (p65) subunit of NF-kappaB at 6 to 24 hours after injection. There was also a parallel expression of the adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, as well as the cytokine tumor necrosis factor-alpha. Pretreatment of the rats with diet containing 1% of the antioxidant probucol for 8 weeks did not inhibit arterial activation of NF-kappaB in response to injection of VLDL. Moreover, injection of triglycerides (10% Intralipid, 5 mL/kg) activated arterial expression of NF-kappaB to the same extent as VLDL. Our results suggest that VLDL may promote the development of atherosclerotic lesions by activation of the proinflammatory transcription factor NF-kappaB. The effect appears to be mediated by a release of VLDL fatty acids but not to involve VLDL oxidation.

Sixty-four slice CT evaluation of aortic stenosis using planimetry of the aortic valve area.

OBJECTIVE The purpose of our study was to evaluate planimetry of the aortic valve area with 64-slice CT in comparison with transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) in patients with aortic stenosis. MATERIALS AND METHODS Thirty-six patients with aortic valve disease referred for coronary 64-slice CT angiography were examined. Planimetry of the aortic valve area with 64-slice CT was compared with TTE using the Doppler continuity equation for calculation of the aortic valve area and with planimetric measurement of the aortic valve area using TEE. RESULTS Planimetry of the aortic valve area with CT (1.11 +/- 0.42 cm2) showed a good correlation with TTE (1.05 +/- 0.42 cm2) (r = 0.88, p < 0.001) in 32 patients and a good correlation with TEE (1.41 +/- 1.61 cm2) (r = 0.99, p < 0.0001) in 10 patients. The mean and maximum transvalvular pressure gradients were correlated with the aortic valve area as measured with CT (r = -0.68, p = 0.0001; and r = -0.67, p = 0.0001, respectively). Beta-blockers were not given (mean heart rate, 62.5 +/- 10.7 beats per minute). CONCLUSION MDCT allows accurate planimetry of the aortic valve area in patients with aortic stenosis. In patients referred for 64-slice CT coronary angiography, concomitant aortic stenosis can be identified and evaluated.

64-MDCT for Diagnosis of Aortic Regurgitation in Patients Referred to CT Coronary Angiography

OBJECTIVE In clinical practice, 64-MDCT coronary angiography is increasingly being used for exclusion of coronary artery disease. Therefore, the purpose of this study was to evaluate whether aortic valve regurgitation can be diagnosed with 64-MDCT in comparison with transthoracic echocardiography. MATERIALS AND METHODS Eighty-one consecutive patients were examined with ECG-gated CT coronary angiography using image reconstruction during end-diastole. The diagnostic criterion for aortic valve regurgitation by CT was an incomplete coadaptation of aortic valve leaflets, the central aortic regurgitation area (ARA), which was quantified. All patients underwent transthoracic echocardiography using semiquantitative grading of aortic valve regurgitation (i.e., mild, moderate, or severe). RESULTS Of the 81 patients, 45 had aortic valve regurgitation by transthoracic echocardiography. The diagnostic accuracy of CT in detecting aortic valve regurgitation was as follows: sensitivity of 73% (33/45), specificity of 97% (35/36), positive predictive value (PPV) of 97% (33/34), and negative predictive value (NPV) of 74% (35/47). All 12 false-negative findings by CT were graded as mild regurgitation by transthoracic echocardiography and were caused by severe valve calcification (mean, 3,053.1 +/- 1,700 Agatston units; range, 937.7-5,632.5 Agatston units), bicuspid valves, or both. The sensitivity, specificity, PPV, and NPV of CT for the detection of moderate and severe aortic valve regurgitation were 95%, 100%, 100%, and 98%, respectively. Quantification of the ARA by CT (mean, 0.25 cm(2) +/- 0.34 cm(2) [SD]) was significantly correlated with the severity of aortic valve regurgitation by trans thoracic echocardiography (p < 0.001). CONCLUSION Although 64-MDCT accurately detects moderate and severe aortic regurgitation in patients referred to coronary CT angiography, mild aortic regurgitation can be missed on 64-MDCT in the presence of severe valve calcification or bicuspid valves.

Diagnostic Performance of MDCT for Detecting Aortic Valve Regurgitation

OBJECTIVE This study evaluates whether ECG-gated 16-MDCT coronary angiography provides a reliable imaging technique for detecting aortic regurgitation (AR). SUBJECTS AND METHODS We examined 71 patients prospectively with 16-MDCT angiography using retrospective ECG gating during the mid-to-end diastolic phase. A visible central valvular leakage area was considered as a diagnostic criterion for AR. The central valvular leakage area was quantified in patients with positive transthoracic echocardiography (TTE). We compared 16-MDCT to Doppler TTE, the accepted diagnostic standard based on semiquantitative regurgitation jet analysis (grade 0-3+ for mild, moderate, and severe). RESULTS The overall sensitivity of 16-MDCT for the identification of patients with AR was 81%. The specificity was 91%, the negative predictive value was 70%, and the positive predictive value was 95%. Of the 71 patients, 48 had AR determined by TTE, and 16-MDCT correctly detected AR in 39 of those 48 patients. The sensitivity of 16-MDCT for the detection of patients with moderate and severe AR (grade > or = 1.5+) was 95%, and the specificity was 96% (20 of 21 patients). The sensitivity of 16-MDCT for identification of patients with mild AR (grade < or = 1+) was 70%, and the specificity was 92% (19 of 27 patients). Quantification of the central valvular leakage area was not possible in 50% of cases with AR by TTE because of valve calcifications. CONCLUSION Sixteen-MDCT coronary angiography provides an accurate, noninvasive imaging technique to detect moderate and severe aortic regurgitation (grade > or = 1.5+). However, severe valve calcifications and mild AR limit its results.

Functional Recovery of a Human Neonatal Heart After Severe Myocardial Infarction

RATIONALE Cardiac remodeling and subsequent heart failure remain critical issues after myocardial infarction despite improved treatment and reperfusion strategies. Recently, cardiac regeneration has been demonstrated in fish and newborn mice after apex resection or cardiac infarctions. Two key issues remain to translate findings in model organisms to future therapies in humans: what is the mechanism and can cardiac regeneration indeed occur in newborn humans? OBJECTIVE To assess whether human neonatal hearts can functionally recover after myocardial infarction. METHODS AND RESULTS Here, we report the case of a newborn child having a severe myocardial infarction due to coronary artery occlusion. The child developed massive cardiac damage as defined by serum markers for cardiomyocyte cell death, electrocardiograms, echocardiography, and cardiac angiography. Remarkably, within weeks after the initial ischemic insult, we observed functional cardiac recovery, which translated into long-term normal heart function. CONCLUSIONS These data indicate that, similar to neonatal rodents, newborn humans might have the intrinsic capacity to repair myocardial damage and completely recover cardiac function.

Cardiac hepatopathy before and after heart transplantation

Chronic cardiac hepatopathy is a common entity in patients evaluated for heart transplantation (HTX). Hepatic injury is caused by severe heart failure resulting from prolonged recurrent congestion and/or impaired arterial perfusion. No data are available on the reversibility of cardiac hepatopathy in patients undergoing HTX. Data of 56 consecutive adult patients undergoing HTX during 2000–02 at the University Hospital of Innsbruck were analysed retrospectively. The following parameters were evaluated at the time of listing and 3, 6 and 12 months after HTX. Plasma levels of gamma‐glutamyl transferase (γ‐GT), alkaline phosphatase (AP), bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and total plasma protein. When listed for HTX, only 12% of all patients analysed had physiological values throughout the seven laboratory parameters assessed. Elevated levels of γ‐GT, AP, bilirubin, AST, ALT, LDH and total plasma protein were detected in 66.6%, 29%, 50%, 16.7%, 10%, 40% and 18% of all patients respectively. Accordingly, median plasma levels of γ‐GT, bilirubin and LDH were elevated, whereas the mean plasma level of AP was at the upper normal range. In contrast, median plasma level of AST and mean plasma levels of ALT and total plasma protein were within the normal range: γ‐GT (median, 109.0; range, 634.0 U/l; n = 36), AP (mean, 120.2 ± 78.9 U/l; n = 29), bilirubin (median, 1.3; range, 16.1 mg/dl; n = 32), LDH (median, 226.0; range, 2355.0 U/l; n = 33), AST (median, 29.0; range, 145.0 U/l; n = 36), ALT (mean, 28.3 ± 20.8 U/l; n = 36) and total plasma protein (mean, 7.2 ± 1.1 g/dl; n = 25). Within 3 months after HTX, elevated parameters except LDH significantly ameliorated: γ‐GT (median, 59.0; range, 1160.0 U/l; P = 0.011), AP (92.2 ± 75.2 U/l; P = 0.016), bilirubin (median, 0.9; range, 8.1 mg/dl; P = 0.004), LDH slightly increased (median, 281.0; range, 543.0 U/l; P = 0.039), but there was a delayed improvement of this parameter after 6 and 12 months post‐HTX. End‐stage heart failure is characterized by a cholestatic liver enzyme profile with elevated plasma levels of γ‐GT and bilirubin. These parameters significantly improve within 3 months after HTX. Therefore, chronic cardiac hepatopathy seems to be a benign, potentially reversible disease.

Oxidized LDL and lysophosphatidylcholine stimulate plasminogen activator inhibitor-1 expression in vascular smooth muscle cells

Plasminogen activator inhibitor-1 (PAI-1) functions as an important regulator of fibrinolysis by inhibiting both tissue-type and urokinase-type plasminogen activator. PAI-1 is produced by smooth muscle cells (SMCs) in atherosclerotic arteries, but the mechanisms responsible for induction of PAI-1 in SMCs are less well understood. In cultured human aortic SMCs, PAI-1 mRNA expression and protein secretion were increased after incubation with oxidized low-density lipoprotein (LDL) and the lipid peroxidation product lysophosphatidylcholine, whereas the effects of native LDL on PAI-1 production and release were more variable and did not reach statistical significance. The effect of LDL on arterial expression of PAI-1 in vivo was also studied in an animal model. Intravenous injection of human LDL in Sprague-Dawley rats resulted in accumulation of apolipoprotein B in the aorta within 12 hours as assessed by immunohistochemical testing. Epitopes specific for oxidized LDL began to develop in the aorta 12 hours after injection of LDL and peaked at 24 hours; this peak was accompanied by intense expression of PAI-1 immunoreactivity in the media. Also, increased aortic expression of PAI-1 mRNA after LDL injection was detected by using in situ hybridization. The transcription factor activator protein-1, which is known to bind to the promoter of the PAI-1 gene, was activated in the aortic wall 24 hours after LDL injection as assessed by electrophoretic mobility shift assay. Pretreatment of LDL with the antioxidant probucol decreased expression of oxidized LDL and PAI-1 immunoreactivity and activator protein-1 induction in the aorta but did not affect expression of apolipoprotein B immunoreactivity. These findings demonstrate that LDL oxidation enhances secretion of PAI-1 from cultured SMCs and that a similar mechanism may be involved in vascular expression of PAI-1.