Outcomes of patients with ST-segment myocardial infarction admitted during the COVID-19 pandemic : A prospective, observational study from a tertiary care center in Germany.

BACKGROUND: Since the beginning of the SARS-CoV­2 outbreak, healthcare professionals reported that patients admitted with ST-segment myocardial infarction (STEMI) were in worse condition compared to STEMI patients admitted before the outbreak. However, data on their outcomes are sparse. METHODS: We conducted a prospective, observational, cohort study of STEMI patients admitted during the COVID-19 pandemic from March 21, 2020 to July 31, 2020 (COVID-19 group). Clinical outcomes, 30-day mortality, and reasons potentially related to a delay in patient presentation were assessed and compared with STEMI patients admitted between November 1, 2019 and March 20, 2020 (pre-COVID-19 group). RESULTS: A total of 124 patients were enrolled, comprising 57 patients in the pre-COVID-19 group and 67 patients in the COVID-19 group. Significantly more patients in the COVID-19 group had a time to first medical contact of greater than 24 h. Additionally, those admitted during the pandemic had a significantly lower left ventricular ejection fraction (LVEF), worse thrombolysis in myocardial infarction (TIMI) flow, received circulatory support significantly more often, and had a significantly higher 30-day mortality. Furthermore, significantly more patients stated that "information by the media" made them hesitate to contact the emergency medical services as soon as possible. CONCLUSION: Here, we show that STEMI patients admitted during the COVID-19 pandemic had significantly prolonged times to first medical contact, were in worse condition at admission, and had an increased 30-day mortality. Additionally, we found that "information by the media" made patients during COVID-19 hesitate to contact the emergency medical services. Consequently, public health strategies have to be developed to avoid potential excess mortality of STEMI patients during the pandemic.

Comparison of transcatheter edge-to-edge and surgical repair in patients with functional mitral regurgitation using a meta-analytic approach.

Background: Evidence regarding favorable treatment of patients with functional mitral regurgitation (FMR) using transcatheter edge-to-edge repair (TEER) is constantly growing. However, there is only few data directly comparing TEER and surgical mitral valve repair (SMVr). Aims: To compare baseline characteristics, short-term and 1-year outcomes in FMR patients undergoing mitral valve (MV) TEER or SMVr using a meta-analytic approach. Methods: Systematic database search identified 1,703 studies reporting on TEER or SMVr for treatment of FMR between January 2010 and December 2020. A meta-analytic approach was used to compare outcomes from single-arm and randomized studies based on measures by means of their corresponding 95% confidence intervals (CI). Statistical significance was assumed if CIs did not overlap. A total of 21 TEER and 37 SMVr studies comprising 4,304 and 3,983 patients were included. Results: Patients in the TEER cohort presented with higher age (72.0 ± 1.7 vs. 64.7 ± 4.7 years, p < 0.001), greater burden of comorbidities like hypertension (p < 0.001), atrial fibrillation (p < 0.001), lung disease (p < 0.001) and chronic renal disease (p = 0.005) as well as poorer left ventricular ejection fraction (30.9 ± 5.7 vs. 36.6 ± 5.3%, p < 0.001). In-hospital mortality was significantly lower with TEER [3% (95%-CI 0.02-0.03) vs. 5% (95%-CI 0.04-0.07)] and 1-year mortality did not differ significantly [18% (95%-CI 0.15-0.21) vs. 11% (0.07-0.18)]. NYHA [1.06 (95%-CI 0.87-1.26) vs. 1.15 (0.74-1.56)] and MR reduction [1.74 (95%-CI 1.52-1.97) vs. 2.08 (1.57-2.59)] were comparable between both cohorts. Conclusion: Despite considerably higher age and comorbidity burden, in-hospital mortality was significantly lower in FMR patients treated with TEER, whereas a tendency toward increased 1-year mortality was observed in this high-risk population. In terms of functional status and MR grade reduction, comparable 1-year results were achieved.

Tiny golden angle stack-of-stars (tygaSoS) free-breathing functional lung imaging.

PURPOSE: MRI of the lung parenchyma is still challenging due to cardiac and respiratory motion, and the low proton density and short T2*. Clinical feasible MRI methods for functional lung assessment are of great interest. It was the objective of this study to evaluate the potential of combining the ultra-short echo-time stack-of-stars approach with tiny golden angle (tyGASoS) profile ordering for self-gated free-breathing lung imaging. METHODS: Free-breathing tyGASoS data were acquired in 10 healthy volunteers (3 smoker (S), 7 non-smoker (NS)). Images in different respiratory phases were reconstructed applying an image-based self-gating technique. Resulting image quality and sharpness, and parenchyma visibility were qualitatively scored by three blinded independent reader, and the signal-to-noise ratio (SNR), proton fraction (fP) and fractional ventilation (FV) quantified. RESULT: The imaging protocol was well tolerated by all volunteers. Image quality was sufficient for subsequent quantitative analysis in all cases with good to excellent inter-reader reliability. Between expiration (EX) and inspiration (IN) significant differences (p < 0.001) were observed in SNR (EX: 3.73 ± 0.89, IN: 3.14 ± 0.74) and fP (EX: 0.27 ± 0.09, IN: 0.25 ± 0.08). A significant (p < 0.05) higher fP (EX/IN: 0.22 ± 0.07/0.21 ± 0.07 (NS), 0.33 ± 0.07/0.30 ± 0.06 (S)) was observed in the smoker group. No significant FV differences resulted between S and NS. CONCLUSION: The study proves the feasibility of free-breathing tyGASoS for multiphase lung imaging. Changes in fP may indicate an initial response in the smoker group and as such proves the sensitivity of the proposed technique. A major limitation in FV quantification rises from the large inter-subject variability of breathing patterns and amplitudes, requiring further consideration.

Influence of permanent pacemaker implantation after transcatheter aortic valve implantation with new-generation devices.

OBJECTIVE: Permanent pacemaker implantation (PPMI) after transcatheter aortic valve implantation (TAVI) is the most common complication after the procedure. PPMI rates remain high with the new-generation TAVI devices despite improved outcomes concerning paravalvular aortic regurgitation and vascular access complications. However, the impact of PPMI on mortality and clinical outcome is still a matter of debate, and data with new-generation devices on this matter are scarce. Therefore, we sought to analyse the influence of PPMI in patients treated with the new-generation devices on one-year outcome. METHODS: We enrolled 612 consecutive patients without prior pacemaker undergoing transfemoral TAVI with the new-generation devices. Patients with or without PPMI were compared with respect to clinical outcome within one year. RESULTS: PPMI was performed in 168 patients (24.4% of the overall study population). There was no significant difference in one-year outcome concerning all-cause mortality (PPMI vs. no-PPMI: 12.2% vs. 12.5%, p = 0.94), rate of major adverse events including cardiac, cerebral or valve-related events and bleeding complications (22.1% vs. 24.5%, p = 0.55) or need for rehospitalisation due to cardiac symptoms (16.1% vs. 18.1%, p = 0.63). In patients with reduced ejection fraction (<45%) there was also no impact of PPMI on one-year mortality (14.3% vs. 15.7%, p = 0.86). Furthermore, multivariate analysis did not reveal PPMI to be independently associated with one-year mortality (odds ratio 0.94, 95% confidence interval 0.50-1.74, p = 0.83). CONCLUSIONS: In this large all-comers TAVI population with new-generation devices the need for postprocedural PPMI did not show a statistical significant impact on survival or combined endpoint of major adverse events within one year.

A zebrafish model for FHL1-opathy reveals loss-of-function effects of human FHL1 mutations.

Missense mutations in the four and a half LIM domain 1 (FHL1) gene were found to cause X-linked inherited myopathies of both skeletal and heart muscles. However, the mechanisms by which FHL1 mutations impact on FHL1 function and lead to alteration of muscle structure and function have not been deciphered yet. We generated here by Morpholino-modified antisense oligonucleotide-mediated gene knockdown fHL1-deficient zebrafish embryos. Similar to the human situation, fhl1a-morphants zebrafish displayed severe skeletal and heart muscle myopathy. Whereas ectopic expression of wild-type FHL1 (FHL1 wt) suppressed both skeletal and heart muscle myopathy in fhl1a-morphants zebrafish, overexpression of the FHL1-opathy associated human mutations FHL1-H123Y, FHL1-C132F or FHL1-C224W did not rescue skeletal and heart muscle myopathy in fhl1a-morphants. Overexpression of FHL1-H123Y, FHL1-C132F or FHL1-C224W in wild-type zebrafish did not induce myopathy in a dominant-negative mode. Altogether these results indicate that FHL1 mutations found to cause X-linked FHL1-opathies in humans consistently lead to severely impaired FHL1 function.

Antithrombotic therapy in patients with non-valvular atrial fibrillation undergoing percutaneous coronary intervention: should we change our practice after the PIONEER AF-PCI and RE-DUAL PCI trials?

The number of patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) is increasing. Since these patients have a CHA2DS2-VASc score of 1 or higher, they should be treated with oral anticoagulation to prevent stroke. However, combination therapy with oral anticoagulation for prevention of embolic stroke and dual platelet inhibition for prevention of coronary thrombosis significantly increases bleeding complications. The optimal combination, intensity and duration of antithrombotic combination therapy is still not known. In the rather small randomized WOEST trial, the combination of a vitamin K antagonist (VKA) and clopidogrel decreased bleeding compared to the conventional triple therapy with VKA, clopidogrel and aspirin. In the PIONEER AF-PCI trial, two rivaroxaban-based treatment regimens significantly reduced bleeding complications compared to conventional triple therapy without increasing embolic or ischemic complications following PCI. Dual therapy with rivaroxaban and clopidogrel appeared to provide an optimal risk-benefit ratio. In the RE-DUAL PCI trial, dual therapy with dabigatran also reduced bleeding complications compared to conventional triple therapy. With respect to the composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization dabigatran-based dual therapy was non-inferior to VKA-based triple therapy. The upcoming trials AUGUSTUS with apixaban and ENTRUST-PCI with edoxaban will further examine the use of NOACs in this setting. While recent guidelines recommend NOAC-based dual therapy in only a subset of patients (those who are at increased risk of bleeding), the available data now suggest that this should be the preferred choice for the majority of patients. Adding aspirin to this primary choice for up to 4 weeks in patients at especially high ischemic risk would likely prevent atherothrombotic events, but this needs further investigation. Taken together, it is time to adjust our practice and move to dual therapy consisting of a NOAC plus clopidogrel in most patients.

Patient-specific registration of 3D CT angiography (CTA) with X-ray fluoroscopy for image fusion during transcatheter aortic valve implantation (TAVI) increases performance of the procedure.

OBJECTIVES: The aim of this study was to adapt patient-specifically a co-registration procedure for image fusion (IF) of a pre-interventional CT dataset with real-time X-ray (XR) fluoroscopy during transfemoral transcatheter aortic valve implantation (TAVI), enabling improved performance of the procedure. BACKGROUND: The ability to use 3D models of the respective anatomies to complement the anatomic information obtained by XR fluoroscopy and provide a greater degree of real-time anatomical guidance holds great potential for complex cardiac interventions, especially for TAVI procedures with cerebral protection. METHODS: Initial registration of two datasets was performed during the femoral puncture and sheath introduction using routinely acquired arteriographies. On-time refinement of the co-registration was then performed during the on-going procedure avoiding additional angiograms for the co-registration. Performance of the method was evaluated quantitatively in terms of procedural characteristics and clinical events. RESULTS: Significant reduction of the radiation dose [51 (42-55) vs. 64 (49-81) Gy cm2, p = 0.032] and contrast agent (CA) volume [80 (50-95) vs. 100 (80-110) ml, p = 0.010] was achieved with the optimized approach as compared to the control group without IF, with simultaneous decrease of procedural [48 (41-58) vs. 61 (53-67) min, p = 0.002] and fluoroscopy times [14.8 (12.7-18.5) vs. 17.8 (14.3-19.4), p = 0.108]. CONCLUSIONS: In this proof-of-concept study we have demonstrated a novel co-registration approach for IF during TAVI not requiring any additional CA or XR scan. We have evaluated its potential benefit with the strong focus on guiding the femoral puncture, placement of the double-filter cerebral embolic protection device, and deployment of the valve prosthesis. We achieved improved performance and safety of the procedure with the introduced approach.

Image-guidance for transcatheter aortic valve implantation (TAVI) and cerebral embolic protection.

The study was aimed at evaluation of the feasibility and potential benefit of image fusion (IF) of pre-procedural CT angiography (CTA) and x-ray (XR) fluoroscopy for image-guided navigation in transfemoral transcatheter aortic valve implantation (TAVI) with the strong focus on guiding the double-filter cerebral embolic protection device and valve prosthesis placement. METHODS: In 31 patients undergoing TAVI, image registration of CTA-derived 3D anatomical models of the relevant cardiac anatomy and vasculature, and live XR was performed applying a commercially available navigation tool. The approach was evaluated in terms of the accuracy of the overlay. In 27 TAVI patients with IF receiving double-filter cerebral embolic protection device overall procedure time, fluoroscopy time, radiation dose, and total volume of intra-procedural iodinated contrast agent (CA) were registered and compared to those of a control group of prospectively enrolled during the same period of time N=27 patients receiving the same protection system but without IF. RESULTS AND CONCLUSIONS: Image co-registration and model-based guidance is feasible in TAVI procedures. The overlay facilitates placement of the embolic protection device, placement of the guide wire in the left ventricle and initial alignment of the valve prosthesis prior to final deployment, thus improving the confidence level of the operators during the procedure without compromising CA or XR dose.

Screening for infectious diseases among asylum seekers newly arrived in Germany in 2015: a systematic single-centre analysis.

OBJECTIVES: During the migrant crisis in 2015, Germany was the largest single recipient of new asylum seekers in Europe. The German asylum law requires a screening examination for certain infectious diseases in asylum seekers upon arrival. The aim of this work was to analyse the rate of certain infectious diseases among asylum seekers screened at a reception centre in Southern Germany. STUDY DESIGN: Retrospective medical record review. METHODS: Medical records of 2602 asylum seekers screened by a local public health authority in Germany in 2015 were systematically analysed. RESULTS: The majority of screened subjects came from Afghanistan and Syria. The mean age was 22.1 (±12.0) years. The majority of subjects were male (75.4%). Most individuals were of normal weight or overweight, more subjects were obese than underweight. A total of 78 (3.9%) individuals were infected with hepatitis B and eight (0.4%) with HIV. In 31 cases, chest radiographs suggested active tuberculosis (1.6%), which was confirmed in four cases (0.2%). The physical examination uncovered 44 (1.7%) cases of scabies, nine (0.3%) cases of lice, eight (0.3%) of upper respiratory tract infections, two (0.1%) of varicella and 13 (0.5%) of other skin infections. CONCLUSIONS: In the majority of subjects none of the screened infectious diseases were found. No evidence was found that the overall prevalence of certain infectious diseases screened for in the present analysis was considerably higher than in previous migration studies.

Pulse transit time and blood pressure during cardiopulmonary exercise tests.

Pulse transit time (PTT), the interval between ventricular electrical activity and peripheral pulse wave, is assumed to be a surrogate marker for blood pressure (BP) changes. The objective of this study was to analyze PTT and its relation to BP during cardiopulmonary exercise tests (CPET). In 20 patients (mean age 51+/-18.4 years), ECG and finger-photoplethysmography were continuously recorded during routine CPETs. PTT was calculated for each R-wave in the ECG and the steepest slope of the corresponding upstroke in the plethysmogram. For each subject, linear and non-linear regression models were used to assess the relation between PTT and upper-arm oscillometric BP in 9 predefined measuring points including measurements at rest, during exercise and during recovery. Mean systolic BP (sBP) and PTT at rest were 128 mm Hg and 366 ms respectively, 197 mm Hg and 289 ms under maximum exercise, and 128 mm Hg and 371 ms during recovery. Linear regression showed a significant, strong negative correlation between PTT and sBP. The correlation between PTT and diastolic BP was rather weak. Bland-Altman plots of sBP values estimated by the regression functions revealed slightly better limits of agreements for the non-linear model (-10.9 to 10.9 mm Hg) than for the linear model (-13.2 to 13.1 mm Hg). These results indicate that PTT is a good potential surrogate measure for sBP during exercise and could easily be implemented in CPET as an additional parameter of cardiovascular reactivity. A non-linear approach might be more effective in estimating BP than linear regression.

Functional genomics in zebrafish as a tool to identify novel antiarrhythmic targets.

In the face of an aging population and thereby an increasing number of patients suffering from heart rhythm diseases development of therapeutic agents is one of the major challenges in modern biomedical research. Antiarrhythmic drug discovery was mainly hindered by the limited knowledge of the molecular underpinnings of cardiac electrophysiology in health and disease. In recent years, the zebrafish has emerged as an effective model organism to dissect the pathology of human disorders in particular in the area of cardiovascular diseases. Especially, certain aspects of cardiac electrophysiology of the zebrafish such as action potential or heart rate are similar to that of humans. The zebrafish shares many features of human physiology and body plan but it develops extra-uterine and is initially transparent, allowing detailed and comprehensive characterization of cardiac development and function in vivo. Moreover, zebrafish are well amenable to large-scale forward and reverse functional genomics approaches, which has led to the identification of numerous novel genetic key-players and potential targets of cardiac disease. In this context, several zebrafish lines with mutations in defined ion channels have emerged as novel vertebrate models for human arrhythmia disorders such as long or short QT syndrome. In addition, due to its size and the high number of progeny, zebrafish are very suitable for rapid in vivo analysis of the bioactivity of small molecules and their therapeutic potential, especially in the context of cardiovascular diseases such as arrhythmias. In this review we highlight an assortment of established zebrafish models that enable the dissection of human heart rhythm disorders and the potential of this model system for the discovery of novel antiarrhythmic targets and drugs.

GMP-adapted overexpression of CXCR4 in human mesenchymal stem cells for cardiac repair.

BACKGROUND: Human mesenchymal stem cells (MSC) have been utilized for cardiac regeneration after myocardial damage. Their clinical effects are marginal and only a minority of administered cells could make their way into the myocardium. The chemokine receptor CXCR4 has been identified as crucial for migration and homing of stem cells. In this study we overexpressed CXCR4 on human MSC to improve cell trafficking and tissue repair. METHODS: Human MSC were isolated from the spongiosa of tibia and femur as well as from pelvic bone marrow. MSC were characterized by differentiation assays and FACS analysis. CXCR4 was overexpressed by mRNA-nucleofection. Intracellular signaling was analyzed to demonstrate functionality of CXCR4. The modified Boyden chamber, wounding assays and time lapse microscopy were utilized to investigate MSC migration. RESULTS: MSC did not express relevant amounts of CXCR4 spontaneously. CXCR4 could be overexpressed in 93% of MSC with a cell viability of 62%. Functionality of the overexpressed CXCR4 was demonstrated by a significant cytosolic Ca(2+) increase and activation of different MAP kinases followed by SDF-1α stimulation. In contrast no improvement of cell migration could be observed. There was a strong basal MSC chemokinesis independent from CXCR4 expression. CONCLUSIONS: CXCR4 could be effectively overexpressed in human MSC by mRNA-nucleofection. Despite functionality of CXCR4 MSC were characterized by a strong basal chemokinesis that could not be further enhanced by CXCR4 overexpression. As isolation, culture and nucleofection of pelvic bone marrow-derived MSC basically fulfill the GMP-requirements our approach seems suited for an in vivo application in patients.

Myeloperoxidase is associated with incident coronary heart disease independently of traditional risk factors: results from the MONICA/KORA Augsburg study.

AIMS: Oxidative stress plays a critical role in the initiation and progression of atherosclerosis. Myeloperoxidase (MPO) is a marker of oxidative stress. We prospectively investigated whether an increased serum concentration of MPO is associated with an increased risk of incident coronary heart disease (CHD). METHODS: We conducted a population-based case-cohort study in middle-aged, healthy men and women within the MONICA/KORA Augsburg studies. Serum levels of MPO were measured in 333 subjects with (cases) and 1727 without (noncases) incident CHD. Mean follow-up time was 10.8 ± 4.6 years. RESULTS: Baseline concentrations of MPO were higher in cases compared with noncases (P ≤ 0.001 in men; P=0.131 in women). After adjustment for major cardiovascular risk factors, the hazard ratio (HR) with 95% confidence interval (CI) comparing the top with the two lower tertiles was 1.70 (95% CI, 1.25-2.30). After additional adjustment for markers of inflammation and endothelial dysfunction, the association was attenuated (HR 1.50; 95% CI, 1.08-2.09). There were no significant interactions of MPO with sex or increased weight on CHD risk. CONCLUSIONS: Elevated concentrations of the oxidative stress marker MPO were independently associated with increased risk of incident CHD. This finding deserves detailed evaluation in further studies.

[The role of cardiovascular magnetic resonance imaging in the diagnosis and prognosis of patients with heart failure]. / Die Rolle der Kardio-MRT bei Diagnose und Prognosebeurteilung der Herzinsuffizienz.

Cardiovascular magnetic resonance (CMR) imaging is a tomographic technique, which allows three-dimensional slice orientation without limitations from acoustic windows inherent to echocardiography. Further advantages of CMR are its high temporal and spatial resolution, its excellent soft tissue resolution and its high blood-to-tissue contrast. Cardiovascular magnetic resonance is currently the only imaging technique, which provides a comprehensive study of both structure and function of the heart as well as myocardial perfusion and viability. Moreover, post-processing of CMR images does not require any geometric assumptions as in echocardiography to determine ventricular dimensions. This is particularly important when evaluating ventricles of patients with chronic heart failure with severely altered morphology that may have regional variations in wall thickness and contractility at least in ischemic cardiomyopathy. The highly reproducible results of CMR imaging have turned this technique into a reference standard for the non-invasive assessment of ventricular dimensions, mass and function. In cases with indeterminate results of clinical, electrocardiographic and particularly echocardiographic findings CMR should be used early in the process of diagnosis of patients with heart failure. Not only can altered structure and degree of ventricular and valvular dysfunctions be accurately assessed but also regional perfusion deficits and/or myocardial scars are easily detected. For therapeutic and prognostic reasons a simple differentiation between ischemic and non-ischemic cardiomyopathy should be achieved as the first diagnostic step. In addition, the type and localization of the late gadolinium enhancement (LGE) phenomenon may aid in non-invasively differentiating the etiology of non-ischemic cardiomyopathy. CMR may also improve the assessment and extent of interventricular and intraventricular dyssynchrony in patients to be selected for cardiac resynchronization therapy (CRT). Lastly, the LGE phenomenon may provide independent prognostic information in patients with a CRT system implanted, as well as in patients with ischemic and non-ischemic cardiomyopathy. Thus, CMR imaging should be implemented early in the diagnostic process of patients with heart failure to significantly improve the speed and accuracy of diagnostic procedures, to control the effect of therapeutic measures, and to select patients with a limited prognosis by assessing the degree of ventricular dysfunction and the extent of myocardial scarring.

[Patients with coronary artery stents: when and how should operations be carried out?]. / Der Patient mit Koronarstent : Wann und wie sollte operiert werden?

Nowadays stents are implanted in over 90% of percutaneous coronary interventions. Depending on the type of stent implanted, dual antiplatelet therapy combining a cyclooxygenase inhibitor such as acetylsalicylic acid and an adenosine diphosphate receptor antagonist (thienopyridine) such as clopidogrel is required for 1-12 months. Premature termination of antiplatelet therapy during non-cardiac surgery significantly increases the risk of stent thrombosis and consequently myocardial infarction, whereas continuation of dual antiplatelet therapy during surgery increases the risk of severe bleeding. Accordingly, treatment recommendations have to be based on the individual relative risk. In cases with a high risk for major bleeding during surgery, interruption of antiplatelet therapy may be required, whereas in cases of a high risk of stent thrombosis, both antiplatelet drugs should be continued throughout surgery. Patients on dual antiplatelet therapy should be counseled by a team of anesthesiologists, surgeons and cardiologists, to devise the right point in time for the operation, the best perioperative antiplatelet therapy and the appropriate perioperative monitoring.

Growth and function of the embryonic heart depend upon the cardiac-specific L-type calcium channel alpha1 subunit.

The heart must function from the moment of its embryonic assembly, but the molecular underpinnings of the first heart beat are not known, nor whether function determines form at this early stage. Here, we find by positional cloning that the embryonic lethal island beat (isl) mutation in zebrafish disrupts the alpha1 C L-type calcium channel subunit (C-LTCC). The isl atrium is relatively normal in size, and individual cells contract chaotically, in a pattern resembling atrial fibrillation. The ventricle is completely silent. Unlike another mutation with a silent ventricle, isl fails to acquire the normal number of myocytes. Thus, calcium signaling via C-LTCC can regulate heart growth independently of contraction, and plays distinctive roles in fashioning both form and function of the two developing chambers.

Novel splice donor site mutation in the cardiac myosin-binding protein-C gene in familial hypertrophic cardiomyopathy. Characterization Of cardiac transcript and protein.

Familial hypertrophic cardiomyopathy is a disease generally believed to be caused by mutations in sarcomeric proteins. In a family with hypertrophic cardiomyopathy linked to polymorphic markers on chromosome 11, we found a new mutation of a splice donor site of the cardiac myosin-binding protein-C gene. This mutation causes the skipping of the associated exon in mRNA from lymphocytes and myocardium. Skipping of the exon with a consecutive reading frame shift leads to premature termination of translation and is thus expected to produce a truncated cardiac myosin-binding protein-C with loss of the myosin- and titin-binding COOH terminus. However, Western blot analysis of endomyocardial biopsies from histologically affected left ventricular myocardium failed to show the expected truncated protein. These data show for the first time that a splice donor site mutation in the myosin-binding protein-C gene is transcribed to cardiac mRNA. Truncated cardiac myosin-binding protein-C does not act as a "poison polypeptide," since it seems not to be incorporated into the sarcomere in significant amounts. The absence of mutant protein and of significantly reduced amounts of wild-type protein in the presence of the mutated mRNA argues against the "poison protein" and the "null allele" hypotheses and suggests yet unknown mechanisms relevant to the genesis of chromosome-11- associated familial hypertrophic cardiomyopathy.

Troponin T: a diagnostic marker for myocardial infarction and minor cardiac cell damage.

The diagnosis of acute myocardial infarction is straightforward when anginal pain is accompanied by typical ECG changes and in these patients measurements of cardiac markers are unnecessary in deciding whether thrombolytic therapy is appropriate. Cardiac markers in patients with acute ischaemic coronary syndromes, however, may serve to identify a high risk subgroup of patients with small acute infarctions or minor myocardial damage. In many patients with chest pain a valid diagnosis of myocardial cell injury depends on the result of biochemical assays. In 30% of patients with unstable angina, troponin T is elevated although myocardial infarction was ruled out by cardiac enzymes and ECG recordings. The outcome of these patients at 4 weeks and 6 months follow-up is not different from that of patients with definite myocardial infarction. To guide therapeutic decisions on these patients a troponin T test result needs to be available rapidly. The rapid troponin T test strip assay, which allows the determination of troponin T levels in whole blood at the patient's bedside, can be performed conveniently in the emergency room or in laboratories with less sophisticated equipment and has the potential to aid in the triage of chest pain patients and the selection of therapeutic strategies.