Transient apical ballooning syndrome--clinical characteristics, ballooning pattern, and long-term follow-up in a Swiss population

BACKGROUND: Transient apical ballooning syndrome (TABS) or Takotsubo cardiomyopathy mimics acute ST-elevation myocardial infarction, but is considered to have a good prognosis with only moderate elevation of myocardial enzymes and full recovery of left ventricular function. Although it is increasingly reported, its exact incidence, clinical presentation, and prognosis in non-Asian populations remain largely unknown. OBJECTIVE: To describe the clinical characteristics and long-term follow-up of patients who presented with TABS at our institution over a 3 year-period. METHODS: Patients were retrospectively retrieved from our local database. Patient charts were carefully reviewed and the diagnosis of TABS was based on the Mayo Clinic diagnostic criteria. Moreover, psychosocial stress or gastrointestinal disease was recorded. RESULTS: During the study period, 13,715 coronary angiographies were performed at our institution, including 2459 patients presenting with an acute coronary syndrome (ACS). Forty-one TABS were diagnosed, which represents an incidence of 1.7% of ACS-patients and 0.3% of all coronary angiographies performed, respectively. Mean age was 65 years, with 85% women. Clinical presentations included chest pain, dyspnoea, and cardiogenic shock. A preceding psychological or physical condition perceived as "stress" was reported in 61%. At a mean follow-up of 675+/-288 days, none of the patients died of cardiac causes, but two patients had a recurrence of symptoms. CONCLUSIONS: This is the largest cohort of TABS patients reported out of Europe so far. The good overall prognosis and low likelihood of recurrence were confirmed.

Proteomic analysis in aortic media of patients with Marfan syndrome reveals increased activity of calpain 2 in aortic aneurysms

BACKGROUND: Marfan syndrome (MFS) is a heritable disorder of connective tissue, affecting principally skeletal, ocular, and cardiovascular systems. The most life-threatening manifestations are aortic aneurysm and dissection. We investigated changes in the proteome of aortic media in patients with and without MFS to gain insight into molecular mechanisms leading to aortic dilatation. METHODS AND RESULTS: Aortic samples were collected from 46 patients. Twenty-two patients suffered from MFS, 9 patients had bicuspid aortic valve, and 15 patients without connective tissue disorder served as controls. Aortic media was isolated and its proteome was analyzed in 12 patients with the use of 2-dimensional difference gel electrophoresis and mass spectrometry. We found higher amounts of filamin A C-terminal fragment, calponin 1, vinculin, microfibril-associated glycoprotein 4, and myosin-10 heavy chain in aortic media of MFS aneurysm samples than in controls. Regulation of filamin A C-terminal fragmentation was validated in all patient samples by immunoblotting. Cleavage of filamin A and the calpain substrate spectrin was increased in the MFS and bicuspid aortic valve groups. Extent of cleavage correlated positively with calpain 2 expression and negatively with the expression of its endogenous inhibitor calpastatin. CONCLUSIONS: Our observation demonstrates for the first time upregulation of the C-terminal fragment of filamin A in dilated aortic media of MFS and bicuspid aortic valve patients. In addition, our results present evidence that the cleavage of filamin A is highly likely the result of the protease calpain. Increased calpain activity might explain, at least in part, histological alterations in dilated aorta.

[ECG-gated chest CT angiography: value for atypical chest pain evaluation]

PURPOSE: The aim of this study was to evaluate ECG-gated whole chest CTA as a routine triage tool for patients with acute chest pain. MATERIAL AND METHODS: Whole chest CTA with retrospective ECG-gating was performed in 30 patients with acute atypical chest pain. The ten main segments of the coronary arteries, the pulmonary arteries, the aorta, and the myocardium (function, morphology) were independently analyzed by a resident and two senior radiologists. The inter-observer agreement between resident and senior radiologists was calculated. A final diagnosis was determined by consensus. RESULTS: Thirty patients were included. The coronary artery segments, myocardium and pulmonary arteries were considered analyzable in 84%, 90% and 97% of cases respectively. A final diagnosis for the cause of pain was retained in 19 patients: significant coronary artery stenosis (5), pulmonary embolus (5), aortic dissection (1), hypokinetic cardiomyopathy (2), lung parenchymal abnormalities (5), and hiatus hernia (1). Inter-observer agreement ranged from 0.76 to 1 between senior radiologists and from 0.76 to 1 between resident and senior radiologists. The average time of image interpretation ranged from 14 to 15 minutes. CONCLUSION: ECG-gated whole chest CT angiography appears as a promising tool for the evaluation of acute chest pain. Combined evaluation of appearance and function of the myocardium can reveal additional interesting information.

The role of the sinuses of Valsalva in aortic root flow dynamics and aortic root surgery: evaluation by magnetic resonance imaging

BACKGROUND AND AIM OF THE STUDY: Combined replacement of the aortic valve and ascending aorta using a composite graft represents the standard treatment for dilated aortic root with concomitant structural damage of the aortic valve, especially when the aortic valve cannot be preserved. Unfortunately, hemodynamic changes associated with prosthetic replacement of the aortic root have not been fully elucidated. The study aim was to compare hemodynamics within the replaced aortic root using either a prosthetic vascular graft with bulges mimicking the sinuses of Valsalva and including a stented pericardial valve, or a straight xenopericardial conduit and a stentless porcine valve. METHODS: Between July 2004 and March 2006, a total of 35 patients (mean age 65.2 years: range: 32-80 years) was enrolled into the present study. Aortic root replacement was performed in nine patients with a Valsalva graft (Gelweave Valsalva; Vascutek, Renfrewshire, UK) including a stented pericardial valve, and in 19 patients with a xenopericardial conduit containing a stentless porcine valve. All patients underwent postoperative magnetic resonance imaging (MRI). A control group of seven patients allowed for comparison with native aortic root hemodynamics. RESULTS: Maximum flow-velocity above the aortic valve as one marker of compliance of the aortic root was slightly higher in patients with a Valsalva graft compared to native aortic roots (1.9 m/s versus 1.3 m/s, p = 0.001), but was significantly lower than in patients with the xenopericardial graft without neo-sinuses (1.3 m/s versus 2.4 m/s, p < 0.001). CONCLUSION: The pre-shaped bulges in the prosthetic Valsalva graft effectively mimic the native sinuses of Valsalva, improve compliance of the aortic root, and result in a more physiologic flow pattern, as demonstrated by postoperative MRI.

Rare retinal haemorrhages in translational accidental head trauma in children

PURPOSE: The characteristic findings in accidental head injury consist of linear skull fracture, epidural haematoma, localized subdural haematoma, or cortical contusion because of a linear or translational impact force. Retinal haemorrhages have been found, although uncommon, in accidental head trauma. METHODS: We performed a retrospective study of 24 consecutive cases of children with severe head injuries caused by falls. Inclusion criteria were skull fractures and/or intracranial haemorrhages documented by computerized tomography. All patients underwent a careful ophthalmic examination including dilated indirect fundoscopy within the first 48 h following admission. RESULTS: No retinal haemorrhages could be found in patients whose accidents were plausible and physical and imaging findings were compatible with reported histories. Excessive bilateral retinal haemorrhages were found in only three children with the typical signs of shaken baby syndrome. In eight children, trauma had led to orbital roof fractures. CONCLUSIONS: Retinal haemorrhages were not found in any of the patients with accidental trauma despite the severity of their head injuries. Hence, we add more evidence that there are strong differences between the ocular involvement in accidental translational trauma and those in victims of non-accidental trauma. Fall-related injuries carry a very low risk of retinal haemorrhages.

Quantitative contrast echocardiographic assessment of collateral derived myocardial perfusion during elective coronary angioplasty

OBJECTIVE To determine whether myocardial contrast echocardiography can be used to quantify collateral derived myocardial flow in humans. METHODS In 25 patients undergoing coronary angioplasty, a collateral flow index (CFI) was determined using intracoronary wedge pressure distal to the stenosis to be dilated, with simultaneous mean aortic pressure measurements. During balloon occlusion, echo contrast was injected into both main coronary arteries simultaneously. Echocardiography of the collateral receiving myocardial area was performed. The time course of myocardial contrast enhancement in images acquired at end diastole was quantified by measuring pixel intensities (256 grey units) within a region of interest. Perfusion variables, such as background subtracted peak pixel intensity and contrast transit rate, were obtained from a fitted gamma variate curve. RESULTS 16 patients had a left anterior descending coronary artery stenosis, four had a left circumflex coronary artery stenosis, and five had a right coronary artery stenosis. The mean (SD) CFI was 19 (12)% (range 0-47%). Mean contrast transit rate was 11 (8) seconds. In 17 patients, a significant collateral contrast effect was observed (defined as peak pixel intensity more than the mean + 2 SD of background). Peak pixel intensity was linearly related to CFI in patients with a significant contrast effect (p = 0.002, r = 0.69) as well as in all patients (p = 0.0003, r = 0.66). CONCLUSIONS Collateral derived perfusion of myocardial areas at risk can be demonstrated using intracoronary echo contrast injections. The peak echo contrast effect is directly related to the magnitude of collateral flow.

Integration of merged delayed-enhanced magnetic resonance imaging and multidetector computed tomography for the guidance of ventricular tachycardia ablation: a pilot study

BACKGROUND Delayed enhancement (DE) MRI can assess the fibrotic substrate of scar-related VT. MDCT has the advantage of inframillimetric spatial resolution and better 3D reconstructions. We sought to evaluate the feasibility and usefulness of integrating merged MDCT/MRI data in 3D-mapping systems for structure-function assessment and multimodal guidance of VT mapping and ablation. METHODS Nine patients, including 3 ischemic cardiomyopathy (ICM), 3 nonischemic cardiomyopathy (NICM), 2 myocarditis, and 1 redo procedure for idiopathic VT, underwent MRI and MDCT before VT ablation. Merged MRI/MDCT data were integrated in 3D-mapping systems and registered to high-density endocardial and epicardial maps. Low-voltage areas (<1.5 mV) and local abnormal ventricular activities (LAVA) during sinus rhythm were correlated to DE at MRI, and wall-thinning (WT) at MDCT. RESULTS Endocardium and epicardium were mapped with 391 ± 388 and 1098 ± 734 points per map, respectively. Registration of MDCT allowed visualization of coronary arteries during epicardial mapping/ablation. In the idiopathic patient, integration of MRI data identified previously ablated regions. In ICM patients, both DE at MRI and WT at MDCT matched areas of low voltage (overlap 94 ± 6% and 79 ± 5%, respectively). In NICM patients, wall-thinning areas matched areas of low voltage (overlap 63 ± 21%). In patients with myocarditis, subepicardial DE matched areas of epicardial low voltage (overlap 92 ± 12%). A total number of 266 LAVA sites were found in 7/9 patients. All LAVA sites were associated to structural substrate at imaging (90% inside, 100% within 18 mm). CONCLUSION The integration of merged MDCT and DEMRI data is feasible and allows combining substrate assessment with high-spatial resolution to better define structure-function relationship in scar-related VT.

The effectiveness and safety of d,l-sotalol in the ambulatory treatment of atrial fibrillation and flutter

Data on short and long term efficacy and safety of d,l sotalol in patients with atrial fibrillation or atrial flutter is limited. The aims of this study were to (1) assess the antiarrhythmic efficacy of d,l sotalol maintaining normal sinus rhythm in patients with refractory atrial fibrillation or flutter, (2) evaluate the efficacy of d,l sotalol in preventing recurrences of paroxysmal atrial fibrillation or flutter, (3) evaluate the control of ventricular rate in patients with paroxysmal or refractory atrial fibrillation or flutter unsuccessfully treated with other antiarrhythmic agents, (4) determine predictors of efficacy (5) assess the safety of d,l sotalol in this setting. Two hundred patients with chronic or paroxysmal atrial fibrillation or atrial flutter or both, who had failed one to six previous antiarrhythmic drug trials were treated with d,l sotalol 80 to 440 mg/day orally. Fifty four percent was female, age 47 +/- 16 years (range 7-79), follow up period 7 +/- 7 months (range 1 to 14 months), 79% of patients had the arrhythmia for more than one year. The atrial fibrillation in 37.5% of patients was chronic and paroxysmal in 23.5. The atrial flutter was chronic in 31% of patients and paroxysmal in 8%. Eighty two percent of patients was in functional class I (NYHA) and 82% had cardiac heart disease: left atrial (LA) size 44 +/- 10 mm, right atrial (RA) size 37 +/- 7 mm and left ventricular ejection fraction (LVEF) 58 +/- 8%. Total success was achieved in 58% of patients (atrial fibrillation 40% and 18% in atrial flutter), partial success in 38% (atrial fibrillation in 18% and 20% in atrial flutter) and 4% of patients failure. It was p < 0.07 when compared total success vs partial success among atrial fibrillation and atrial flutter groups. Patients with cardiac heart disease responded worst (p = 0.10) to the drug than those without it, specially if the heart was dilated. We concluded that d,l sotalol has moderate efficacy to convert and maintain normal sinus rhythm, as well as it acts controlling paroxysmal relapses and ventricular heart rate.

Pulmonary thromboembolism as cause of death on unenhanced postmortem 3T MRI

OBJECTIVES: To investigate unenhanced postmortem 3-T MR imaging (pmMRI) for the detection of pulmonary thrombembolism (PTE) as cause of death. METHODS: In eight forensic cases dying from a possible cardiac cause but with homogeneous myocardium at cardiac pmMRI, additional T2w imaging of the pulmonary artery was performed before forensic autopsy. Imaging was carried out on a 3-T MR system in the axial and main pulmonary artery adapted oblique orientation in situ. In three cases axial T2w pmMRI of the lower legs was added. Validation of imaging findings was performed during forensic autopsy. RESULTS: All eight cases showed homogeneous material of intermediate signal intensity within the main pulmonary artery and/or pulmonary artery branches. Autopsy confirmed the MR findings as pulmonary artery thrombembolism. At lower leg imaging unilateral dilated veins and subcutaneous oedema with or without homogeneous material of intermediate signal intensity within the popliteal vein were found. CONCLUSIONS: Unenhanced pmMRI demonstrates pulmonary thrombembolism in situ. PmMR may serve as an alternative to clinical autopsy, especially when consent cannot be obtained. KEY POINTS: • Postmortem MRI (pmMRI) provides an alternative to clinical autopsy • Fatal pulmonary thrombembolism (PTE) can now be diagnosed using postmortem MRI (pmMRI). • Special attention has to be drawn to the differentiation of postmortem clots.

Left ventricular torsion abnormalities in septic shock and corrective effect of volume loading: a pilot study

BACKGROUND Ventricular torsion is an important component of cardiac function. The effect of septic shock on left ventricular torsion is not known. Because torsion is influenced by changes in preload, we compared the effect of fluid loading on left ventricular torsion in septic shock with the response in matched healthy control subjects. METHODS We assessed left ventricular torsion parameters using transthoracic echocardiography in 11 patients during early septic shock and in 11 age- and sex-matched healthy volunteers before and after rapid volume loading with 250 mL of a Ringer's lactate solution. RESULTS Peak torsion and peak apical rotation were reduced in septic shock (10.2 ± 5.2° and 5.6 ± 5.4°) compared with healthy volunteers (16.3 ± 4.5° and 9.6 ± 1.5°; P = 0.009 and P = 0.006 respectively). Basal rotation was delayed and diastolic untwisting velocity reached its maximum later during diastole in septic shock patients than in healthy volunteers (104 ± 16% vs 111 ± 14% and 13 ± 5% vs 21 ± 10%; P = 0.03 and P = 0.034, respectively). Fluid challenge increased peak torsion in both groups (septic shock, 10.2 ± 5.3° vs 12.6 ± 3.9°; healthy volunteers, 16.3 ± 4.5° vs 18.1 ± 6°; P = 0.01). Fluid challenge increased left ventricular stroke volume in septic shock patients (P = 0.003). CONCLUSIONS Compared with healthy volunteers, left ventricular torsion is impaired in septic shock patients. Fluid loading attenuates torsion abnormalities in parallel with increasing stroke volume. Reduced torsional motion might constitute a relevant component of septic cardiomyopathy, a notion that merits further testing in larger populations.

Do mature pulmonary lobes grow after transplantation into an immature recipient?

BACKGROUND The use of reduced-size adult lung transplants could help solve the profound pediatric donor lung shortage. However, adequate long-term function of the mature grafts requires growth in proportion to the recipient's development. METHODS Mature left lower lobes from adult mini-pigs (age: 7 months; mean body weight: 30 kg) were transplanted into 14-week-old piglets (mean body weight: 15 kg). By the end of the 14-week holding period, lungs of the recipients (n = 4) were harvested. After volumetric measurements, the lung morphology was studied using light microscopy, scanning, and transmission electron microscopy. Changes of alveolar airspace volume were determined using a computer aided image analysis system. Comparisons were made to age- and weight-matched controls. RESULTS Volumetric studies showed no significant differences (p = 0.49) between the specific volume (mL/kg body weight) of lobar grafts and left lower lobes of adult controls. Morphologic studies showed marked structural differences between the grafts and the right native lungs of the recipients, with increased average alveolar diameter of the grafts. On light microscopy and scanning electron microscopy, alveoli appeared dilated and rounded compared to the normal polygonal shape in the controls. The computer generated semi-quantitative data of relative alveolar airspace volume tended to be higher in transplanted lobes. CONCLUSIONS The mature pulmonary lobar grafts have filled the growing left hemithorax of the developing recipient. Emphysema-like alterations of the grafts were observed without evidence of alveolar growth in the mature lobar transplants. Thus, it can be questioned whether mature pulmonary grafts can guarantee sufficient long-term gas exchange in growing recipients.

Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis

Septic shock is characterized by increased vascular permeability and hypotension despite increased cardiac output. Numerous vasoactive cytokines are upregulated during sepsis, including angiopoietin 2 (ANG2), which increases vascular permeability. Here we report that mice engineered to inducibly overexpress ANG2 in the endothelium developed sepsis-like hemodynamic alterations, including systemic hypotension, increased cardiac output, and dilatory cardiomyopathy. Conversely, mice with cardiomyocyte-restricted ANG2 overexpression failed to develop hemodynamic alterations. Interestingly, the hemodynamic alterations associated with endothelial-specific overexpression of ANG2 and the loss of capillary-associated pericytes were reversed by intravenous injections of adeno-associated viruses (AAVs) transducing cDNA for angiopoietin 1, a TIE2 ligand that antagonizes ANG2, or AAVs encoding PDGFB, a chemoattractant for pericytes. To confirm the role of ANG2 in sepsis, we i.p. injected LPS into C57BL/6J mice, which rapidly developed hypotension, acute pericyte loss, and increased vascular permeability. Importantly, ANG2 antibody treatment attenuated LPS-induced hemodynamic alterations and reduced the mortality rate at 36 hours from 95% to 61%. These data indicate that ANG2-mediated microvascular disintegration contributes to septic shock and that inhibition of the ANG2/TIE2 interaction during sepsis is a potential therapeutic target.

Intussusceptive microvascular growth: a common alternative to capillary sprouting.

Intussusceptive capillary growth represents a new principle for microvascular growth as described in the lungs of growing rats. According to this concept, the capillary network expands by the formation of slender transcapillary tissue pillars, which give rise to new vascular meshes. The process was first observed in Mercox casts of the lung microvasculature, which revealed the existence of multiple tiny holes with diameters around 1.5 microns. Consecutive transmission electron microscopic investigation of serial sections demonstrated that the holes corresponded to slender tissue pillars (Burri and Tarek, 1990). The corrosion cast technique thus appears to be an adequate screening method for intussusceptive growth. In the present investigation, Mercox casts of various vascular systems, namely, those of the eye, submandibular gland, heart, liver, stomach, small and large intestine, trachea, kidney, uterus and ovary were prepared from rats aged between 4 and 9 weeks in order to screen them for the existence of the typical tiny holes representing tissue pillars. In all organs investigated, these structures were observed in various locations to a variable degree. They were mainly encountered within dilated vascular segments or at triple or quadruple branching points of the circulation. Even in capillary networks with a three-dimensional arrangement could these pillars be detected. Intussusception thus appears to be a principle of growth appertaining to many vascular systems.

Swiss national guideline for reimbursement of enzyme replacement therapy in late-onset Pompe disease.

Glycogen storage disease type II is a rare multi-systemic disorder characterised by an intracellular accumulation of glycogen due a mutation in the acid alpha glucosidase (GAA) gene. The level of residual enzyme activity, the genotype and other yet unknown factors account for the broad variation of the clinical phenotype. The classical infantile form is characterised by severe muscle hypotonia and cardiomyopathy leading to early death. The late-onset form presents as a limb girdle myopathy with or without pulmonary dysfunction. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) in infants is life saving. In contrast, therapeutic efficacy of rhGAA in the late-onset form is modest. High expenses of rhGAA, on-going infusions and poor pharmacokinetic efficacy raised a discussion of the cost effectiveness of ERT in late-onset Pompe disease in Switzerland. This discussion was triggered by a Swiss federal court ruling which confirmed the reluctance of a health care insurer not to reimburse treatment costs in a 67-year-old female suffering from Pompe disease. As a consequence of this judgement ERT was stopped by all insurance companies in late-onset Pompe patients in Switzerland regardless of their clinical condition. Subsequent negotiations lead to the release of a national guideline of the management of late-onset Pompe disease. Initiation and limitation of ERT is outlined in a national Pompe registry. Reimbursement criteria are defined and individual efficacy of ERT with rhGAA is continuously monitored.

Apoptotic enteropathy caused by antimetabolites and TNF-α antagonists.

AIMS To investigate whether drugs others than mycophenolic acid and ipilimumab might cause graft-versus-host-like apoptotic enteropathy, the clinicopathological findings in four patients were examined who had developed watery diarrhoea and apoptotic enteropathy (three cases from colon and one case from ileal pouch) after intake of antimetabolites (methotrexate and capecitabine) and/or tumour necrosis factor-α inhibitors (etanercept and infliximab). METHODS The clinical charts, endoscopy reports and intestinal biopsies from all endoscopies were reviewed for all patients. Biopsies were evaluated semiquantitatively for apoptosis of basal crypts, dilated damaged crypts, defined as cystically dilated crypts with flattened degenerated epithelium containing apoptotic debris and few neutrophils, and mucosal architecture. Further, the presence of intraepithelial lymphocytes, chronic inflammatory cells in the lamina propria and mucosal ulcerations was recorded and immunohistochemical analysis for human cytomegalovirus and herpes simplex virus was performed. RESULTS Endoscopic examination revealed normal mucosa in two patients, whereas the other two showed focal ulcerations. Histological changes included increased apoptosis of basal crypts, the presence of dilated damaged crypts and architecture distortion. In all cases, a temporal association between drug intake and/or dose increase, and onset of diarrhoea, was observed, and no convincing evidence of other potentially underlying causes of colitis/enteritis was found, including infections. CONCLUSIONS Pathologists should be aware of the expanding spectrum of drugs that can cause apoptotic enteropathy, including antimetabolites and tumour necrosis factor-α inhibitors.