Alexander Hess

Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy

Z-disks, the mechanical integration sites of heart and skeletal muscle cells, link anchorage of myofilaments to force reception and processing. The key molecules that enable the Z-disk to persistently withstand the extreme mechanical forces during muscle contraction have not yet been identified. Here we isolated nexilin (encoded by NEXN) as a novel Z-disk protein. Loss of nexilin in zebrafish led to perturbed Z-disk stability and heart failure. To evaluate the role of nexilin in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found several mutations in NEXN associated with the disease. Nexilin mutation carriers showed the same cardiac Z-disk pathology as observed in nexilin-deficient zebrafish. Expression in zebrafish of nexilin proteins encoded by NEXN mutant alleles induced Z-disk damage and heart failure, demonstrating a dominant-negative effect and confirming the disease-causing nature of these mutations. Increasing mechanical strain aggravated Z-disk damage in nexilin-deficient skeletal muscle, implying a unique role of nexilin in protecting Z-disks from mechanical trauma.

A Single Serine in the Carboxyl Terminus of Cardiac Essential Myosin Light Chain-1 Controls Cardiomyocyte Contractility In Vivo

Although it is well known that mutations in the cardiac essential myosin light chain-1 (cmlc-1) gene can cause hypertrophic cardiomyopathy, the precise in vivo structural and functional roles of cMLC-1 in the heart are only poorly understood. We have isolated the zebrafish mutant lazy susan (laz), which displays severely reduced contractility of both heart chambers. By positional cloning, we identified a nonsense mutation within the zebrafish cmlc-1 gene to be responsible for the laz phenotype, leading to expression of a carboxyl-terminally truncated cMLC-1. Whereas complete loss of cMLC-1 leads to cardiac acontractility attributable to impaired cardiac sarcomerogenesis, expression of a carboxyl-terminally truncated cMLC-1 in laz mutant hearts is sufficient for normal cardiac sarcomerogenesis but severely impairs cardiac contractility in a cell-autonomous fashion. Whereas overexpression of wild-type cMLC-1 restores contractility of laz mutant cardiomyocytes, overexpression of phosphorylation site serine 195–deficient cMLC-1 (cMLC-1S195A) does not reconstitute cardiac contractility in laz mutant cardiomyocytes. By contrast, introduction of a phosphomimetic amino acid on position 195 (cMLC-1S195D) rescues cardiomyocyte contractility, demonstrating for the first time an essential role of the carboxyl terminus and especially of serine 195 of cMLC-1 in the regulation of cardiac contractility.

Reliability of noninvasive assessment of systolic pulmonary artery pressure by Doppler echocardiography compared to right heart catheterization: analysis in a large patient population.

Background Pulmonary artery pressure (PAP) is an important marker in cardiovascular disorders, being closely associated with morbidity and mortality. Noninvasive assessment by Doppler echocardiography is recommended by current guidelines. So far, the reliability of this method has been assessed only in small studies with contradictory results. Therefore, the aim of this study was to analyze the reliability of noninvasive PAP assessment by Doppler echocardiography compared to invasive measurements in a large patient population. Methods and Results We retrospectively analyzed data from a large tertiary cardiology department over 6 years in order to compare invasively measured PAP to estimated PAP from echocardiography examinations. N=15 516 patients fulfilled inclusion criteria and n=1695 patients with timely matched examinations (within 5 days) were analyzed. In n=1221 (72%) patients, pulmonary hypertension (PH) was diagnosed invasively (postcapillary PH: n=1122 [66%]; precapillary PH: n=99 [6%]). Systolic pulmonary artery pressure (sPAP) was 45.3±15.5 mm Hg by Doppler echocardiography and 47.4±16.4 mm Hg by right heart catheterization. Pearsons correlation coefficient was r=0.87 (P<0.0001). Mean right atrial pressure (RAP) was 12.0±5.7 mm Hg by right heart catheterization and was estimated to be 12.1±6.6 mm Hg by echocardiography (r=0.82, P<0.0001). Bland–Altman analysis showed a bias of −2.0 mm Hg for sPAP (95% limits of agreement −18.1 to +14.1 mm Hg) and +1.0 mm Hg for RAP (95% limits of agreement +0.1 to +1.9 mm Hg). Noninvasive diagnosis of pulmonary hypertension with Doppler echocardiography had a good sensitivity (87%) and specificity (79%), positive and negative predictive values (91% and 70%), as well as accuracy (85%) for a sPAP cut‐off value of 36 mm Hg (AUC 0.91, P<0.001, CI 0.90 to 0.93). Conclusions In this study, Doppler echocardiography proved to be a reliable method for the assessment of sPAP, being well suited to establish the noninvasive diagnosis of pulmonary hypertension in patients with cardiac diseases.

Successful Implantation of a Coronary Stent Graft in a Peripheral Vessel

Peripheral artery disease (PAD) is a complex, often underdiagnosed illness with rising prevalence in western world countries. During the past decade there has been a rapid advance especially in the field of endovascular treatment of PAD. Here we present for the first time a case reporting on the placement of coronary stent graft in a peripheral vessel for the management of a peripheral side branch perforation. Interventional angiologists or radiologists may consider such an option for complication management after injury of smaller vessels during peripheral percutaneous interventions. Further specialization and novel options of complication management as described in our case may shift the treatment from surgical to even more endovascular treatment procedures in the future.

Exaggerated apical trabeculations mimicking left ventricular thrombus: a 3D TEE perspective

A 67-year-old man was admitted to our hospital with ventricular tachycardia at a heart rate of 180 per minute. Aside from palpitations the patient was asymptomatic. Conversion into sinus rhythm was successful with ajmaline. As troponin T levels were elevated, coronary angiography and left ventriculography was performed. It showed a coronary 1-vessel disease of the circumflex artery without critical stenosis and a severely reduced left ventricular function (Fig. 1a, Movie 1). Thus the primary diagnosis was dilated cardiomyopathy. Because the patient had a history of recurrent ventricular tachycardia, a cardioverter-defibrillator (ICD) implantation was scheduled and an echocardiography performed, showing an echogenic mass in the left ventricular apex, which was first thought to correspond to a thrombus (Fig. 1b, Movie 2). After successful implantation of the ICD, the patient was administered oral anticoagulation therapy and underwent transthoracic echocardiography again 2 months later; a subsequent transesophageal examination was conducted at the same appointment to exclude atrial thrombi previous to ICD testing. The apical structure was still present (Fig. 1c, Movie 3). Deep intertrabecular recessus could be depicted by color doppler (Fig. 1d, Movie 4). 3D imaging finally led to the diagnosis of exaggerated apical trabeculations, which are a hallmark of left ventricular non-compaction cardiomyopathy (LVNC) (Fig. 1e, Movie 5). In retrospective several other hints for LVNC were evident: The left ventriculography shows a ‘‘double wall phenomenon’’ and delayed run-off of the contrast medium as well as preserved basal contractility. In transthoracic echocardiography a ‘‘double layer structure’’ of the endomyocardium is often visible [1, 2]. This feature was not so clearly present in our patient. Still we measured the ratio of compacted to non-compacted myocardium by 0.3. A ratio below 0.5 is another characteristic sign of LVNC. Although the echogenic mass in the apex appeared to be recessus, small apical thrombi are typical in patients with LVNC [3]. Thus, this case highlights the difficulty of diagnosing LVNC which is often misdiagnosed, e.g., as a thrombus or underdiagnosed due to lack of knowledge of the disease [4]. Cardiac MRI, endomyocardial biopsy and genetic or metabolic analysis can exclude other disease entities. As in our case three-dimensional echocardiography is a useful additional diagnostic tool and may provide great help in making the diagnosis.

Successful treatment of cardiac manifestation of eosinophilic leukemia

A 37-year-old male patient presented to the stroke unit of our neurology department with weakness and paresthesia of the right arm and slight anomia. Physical examination revealed distal palsy of both arms, predominantly on the right side. No other pathologic findings were observed. Cranial MRI revealed bilateral territorial infarction in the supply territories of the middle and posterior cerebral arteries. A 12-lead electrocardiography showed incomplete right bundle branch block, negative T waves and ST depression in II, III, aVF and V4–V6 (Fig. 1a). Transesophageal and transthoracic echocardiography revealed normal dimensions of both ventricles with regular systolic and diastolic function. No intracardiac thrombi and no patent foramen ovale could be detected at that time. HolterECG did not show paroxysmal atrial fibrillation. Carotid artery stenosis was ruled out by duplex ultrasound. Blood examination showed increased creatinine (1.59 mg/dL) and urea (60 mg/dL). The white cell count was 13.2 9 10/L, with 6.9 9 10/L eosinophils (52%). A screening for vasculitis was unremarkable aside from an ANA titer of 1:320. Stool analysis and serologic tests were unsuspicious for parasitic helminth infection and there was no apparent primary allergic disorder. Because of the drastically increased eosinophils, we suspected a myeloproliferative disorder. A bone marrow biopsy was done, showing increased myelopoiesis and megakaryopoiesis as well as massive eosinophilia. These findings led us to the diagnosis of hypereosinophilic syndrome (HES). The firstline therapy for HES is steroids [3]; so, we started treatment with prednisone. Antiplatelet therapy with aspirin was administered because of the stroke. As it may have influence on the treatment, it is necessary to further classify the disease by cytogenetic and molecular genetic analysis. During these diagnostic procedures, a chromosomal deletion on 4q12 leading to creation of the FIP1L1–PDGFRA fusion gene was detected. This gene encodes a protein displaying constitutive tyrosine kinase activity. Thus, the final diagnosis was F/P ? chronic eosinophilic leukemia (CEL) [7] and the tyrosine kinase inhibitor imatinib, which is regarded as first line therapy for this special disease subgroup [3, 7], was administered at a dose of 100 mg/day. A control echocardiography was performed 2 months later, revealing an elastic echogenic mass filling the left ventricular apex (Fig. 1b; Movie 1) and right ventricular involvement. These findings could be confirmed in further follow-up studies. Cardiac magnetic resonance (CMR) also confirmed the presence of thrombotic formations in the left and right ventricular apex (Fig. 1d). Strikingly, leukocyte count was normalized to 9.1 9 10/L with 0.5% eosinophils at this point of time. No FIP1L1–PDGFRA transcripts were detectable, so a complete molecular genetic remission was achieved. The patient remained clinically stable without symptoms. Echocardiography follow-up was continued and after 1 year of therapy with imatinib, a clear regression of cardiac involvement could be assessed, since the left and right ventricular echogenic masses could not be detected any longer (Fig. 1c; Movie 2). Chronic eosinophilic leukemia is part of the heterogenous group of HESs. As these are very rare, there are no published Electronic supplementary material The online version of this article (doi:10.1007/s00392-010-0143-9) contains supplementary material, which is available to authorized users.