Unveiling the diagnostic enigma of D-dimer testing in cancer patients: Current evidence and areas of application.

BACKGROUND: Cancer is a well-known risk factor for venous thromboembolism (VTE). A combined strategy of D-dimer testing and clinical pre-test probability is usually used to exclude VTE. However, its effectiveness is diminished in cancer patients due to reduced specificity, ultimately leading to a decreased clinical utility. This review article seeks to provide a comprehensive summary of how to interpret D-dimer testing in cancer patients. METHODS: In accordance with PRISMA standards, literature pertaining to the diagnostic and prognostic significance of D-dimer testing in cancer patients was carefully chosen from reputable sources such as PubMed and the Cochrane databases. RESULTS: D-dimers have not only a diagnostic value in ruling out VTE but can also serve as an aid for rule-in if their values exceed 10-times the upper limit of normal. This threshold allows a diagnosis of VTE in cancer patients with a positive predictive value of more than 80%. Moreover, elevated D-dimers carry important prognostic information and are associated with VTE reoccurrence. A gradual increase in risk for all-cause death suggests that VTE is also an indicator of biologically more aggressive cancer types and advanced cancer stages. Considering the lack of standardization for D-dimer assays, it is essential for clinicians to carefully consider the variations in assay performance and the specific test characteristics of their institution. CONCLUSIONS: Standardizing D-dimer assays and developing modified pretest probability models specifically for cancer patients, along with adjusted cut-off values for D-dimer testing, could significantly enhance the accuracy and effectiveness of VTE diagnosis in this population.

Multiparametric Evaluation of Radiomics Features and Dual-Energy CT Iodine Maps for Discrimination and Outcome Prediction of Thymic Masses.

RATIONALE AND OBJECTIVES: To investigate the diagnostic value of radiomics features and dual-source dual-energy CT (DECT) based material decomposition in differentiating low-risk thymomas, high-risk thymomas, and thymic carcinomas. MATERIALS AND METHODS: This retrospective study included 32 patients (16 males, mean age 66 ± 14 years) with pathologically confirmed thymic masses who underwent contrast-enhanced DECT between 10/2014 and 01/2023. Two experienced readers evaluated all patients regarding conventional radiomics features, as well as DECT-based features, including attenuation (HU), iodine density (mg/mL), and fat fraction (%). Data comparisons were performed using analysis of variance and chi-square statistic tests. Receiver operating characteristic curve analysis and Cox-regression tests were used to discriminate between low-risk/high-risk thymomas and thymic carcinomas. RESULTS: Of the 32 thymic tumors, 12 (38%) were low-risk thymomas, 11 (34%) were high-risk thymomas, and 9 (28%) were thymic carcinomas. Values differed significantly between low-risk thymoma, high-risk thymoma, and thymic carcinoma regarding DECT-based features (p ≤ 0.023) and 30 radiomics features (p ≤ 0.037). The area under the curve to differentiate between low-risk/high-risk thymomas and thymic cancer was 0.998 (95% CI, 0.915-1.000; p < 0.001) for the combination of DECT imaging parameters and radiomics features, yielding a sensitivity of 100% and specificity of 96%. During a follow-up of 60 months (IQR, 35-60 months), the multiparametric approach including radiomics features, DECT parameters, and clinical parameters showed an excellent prognostic power to predict all-cause mortality (c-index = 0.978 [95% CI, 0.958-0.998], p = 0.003). CONCLUSION: A multiparametric approach including conventional radiomics features and DECT-based features facilitates accurate, non-invasive discrimination between low-risk/high-risk thymomas and thymic carcinomas.

Cancer patients with venous thromboembolism: Diagnostic and prognostic value of elevated D-dimers.

BACKGROUND: D-dimer testing is known to have a high sensitivity at simultaneously low specificity, resulting in nonspecific elevations in a variety of conditions. METHODS: This retrospective study sought to assess diagnostic and prognostic features of D-dimers in cancer patients referred to the emergency department for suspected pulmonary embolism (PE) and deep vein thrombosis (DVT). In total, 526 patients with a final adjudicated diagnosis of PE (n = 83) and DVT (n = 69) were enrolled, whereas 374 patients served as the comparative group, in which venous thromboembolism (VTE) has been excluded. RESULTS: For the identification of VTE, D-dimers yielded the highest positive predictive value of 96% (95% confidence interval (CI), 85-99) at concentrations of 9.9 mg/L and a negative predictive value of 100% at .6 mg/L (95% CI, 97-100). At the established rule-out cut-off level of .5 mg/L, D-dimers were found to be very sensitive (100%) at a moderate specificity of nearly 65%. Using an optimised cut-off value of 4.9 mg/L increased the specificity to 95% for the detection of life-threatening VTE at the cost of moderate sensitivities (64%). During a median follow-up of 30 months, D-dimers positively correlated with the reoccurrence of VTE (p = .0299) and mortality in both cancer patients with VTE (p < .0001) and without VTE (p = .0008). CONCLUSIONS: Although D-dimer testing in cancer patients is discouraged by current guidelines, very high concentrations above the 10-fold upper reference limit contain diagnostic and prognostic information and might be helpful in risk assessment, while low concentrations remain useful for ruling out VTE.

Homoarginine in the cardiovascular system: Pathophysiology and recent developments.

Upcoming experimental and epidemiological data have identified the endogenous non-proteinogenic amino acid L-homoarginine (L-hArg) not only as a novel biomarker for cardiovascular disease but also as being directly involved in the pathogenesis of cardiac dysfunction. The association of low L-hArg levels with adverse cardiovascular events and mortality has proposed the idea of nutritional supplementation to rescue pathways inversely associated with cardiovascular health. Subsequent clinical and experimental studies contributed significantly to our knowledge of potential effects on the cardiorenal axis, acting either as a biomarker or a cardiovascular active agent. In this review article, we provide a comprehensive summary of the L-hArg metabolism, pathophysiological aspects, and current developments in the field of experimental and clinical evidence in favor of protective cardiovascular effects. Establishing a reliable biomarker to identify patients at high risk to die of cardiovascular disease represents one of the main goals for tackling this disease and providing individual therapeutic guidance.

Homoarginine treatment of rats improves cardiac function and remodeling in response to pressure overload.

Low serum concentrations of the amino acid homoarginine (HA) are associated with increased cardiovascular mortality by incompletely understood mechanisms. This study sought to assess the influence of HA on cardiac remodeling in rats undergoing either transaortic banding or inhibition of nitric oxide synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). Male Wistar rats (n = 136) underwent sham operation (SH) or aortic banding (AB). Both groups were equally divided into 14 subgroups, receiving different doses of HA alone or in combination with lisinopril, spironolactone, or L-NAME for 4 weeks. HA treatment in AB animals resulted in a dose-dependent improvement of cardiac function up to a concentration of 800 mg·kg-1 ·day-1 . Combining 800 mg·kg-1 ·day-1 HA with spironolactone or lisinopril yielded additional effects, showing a positive correlation with LV ejection fraction (+33%, p = 0.0002) and fractional shortening (+41%, p = 0.0014). An inverse association was observed with collagen area fraction (-41%, p < 0.0001), myocyte cross-sectional area (-22%, p < 0.0001) and the molecular markers atrial natriuretic factor (-74%, p = 0.0091), brain natriuretic peptide (-42%, p = 0.0298), beta-myosin heavy chain (-46%, p = 0.0411), and collagen type V alpha 1 chain (-73%, p = 0.0257) compared to placebo-treated AB animals. Co-administration of HA and L-NAME was found to attenuate cardiac remodeling and prevent NO-deficient hypertension following AB. HA treatment has led to a dose-dependent improvement of myocardial function and marked histological and molecular changes in cardiac remodeling following AB. Combining HA with standard heart failure medication resulted in additional beneficial effects boosting its direct impact on heart failure pathophysiology.

Lung Opacity and Coronary Artery Calcium Score: A Combined Tool for Risk Stratification and Outcome Prediction in COVID-19 Patients.

PURPOSE: To assess and correlate pulmonary involvement and outcome of SARS-CoV-2 pneumonia with the degree of coronary plaque burden based on the CAC-DRS classification (Coronary Artery Calcium Data and Reporting System). METHODS: This retrospective study included 142 patients with confirmed SARS-CoV-2 pneumonia (58 ± 16 years; 57 women) who underwent non-contrast CT between January 2020 and August 2021 and were followed up for 129 ± 72 days. One experienced blinded radiologist analyzed CT series for the presence and extent of calcified plaque burden according to the visual and quantitative HU-based CAC-DRS Score. Pulmonary involvement was automatically evaluated with a dedicated software prototype by another two experienced radiologists and expressed as Opacity Score. RESULTS: CAC-DRS Scores derived from visual and quantitative image evaluation correlated well with the Opacity Score (r=0.81, 95% CI 0.76-0.86, and r=0.83, 95% CI 0.77-0.89, respectively; p<0.0001) with higher correlation in severe than in mild stage SARS-CoV-2 pneumonia (p<0.0001). Combined, CAC-DRS and Opacity Scores revealed great potential to discriminate fatal outcomes from a mild course of disease (AUC 0.938, 95% CI 0.89-0.97), and the need for intensive care treatment (AUC 0.801, 95% CI 0.77-0.83). Visual and quantitative CAC-DRS Scores provided independent prognostic information on all-cause mortality (p=0.0016 and p<0.0001, respectively), both in univariate and multivariate analysis. CONCLUSIONS: Coronary plaque burden is strongly correlated to pulmonary involvement, adverse outcome, and death due to respiratory failure in patients with SARS-CoV-2 pneumonia, offering great potential to identify individuals at high risk.

Diagnostic performance and predictive value of D-dimer testing in patients referred to the emergency department for suspected myocardial infarction.

PURPOSE: The study sought to assess the performance of D-dimer testing for the diagnosis of acute coronary syndrome (ACS) and prediction of outcomes in patients admitted for suspected myocardial infarction (MI). RESULTS: A total of 3,557 patients with suspected ACS presenting to a single center with a broad range of symptoms including atypical chest pain were retrospectively recruited between 02/2012-01/2019. Of the study cohort, 435 patients had unstable angina (UA), 420 non-ST-segment elevation myocardial infarction (NSTEMI), 22 ST-segment elevation myocardial infarction (STEMI), and 2,680 non-coronary chest pain. Plasma D-dimer concentrations in patients with hs-cTnT > 14 ng/L differed significantly from those with hs-cTnT < 14 ng/L (1.5 ± 3.6 mg/L vs. 0.5 ± 0.8 mg/L; p < 0.0001). Positive predictive value for a final diagnosis of ACS increased proportionally to rising D-dimer concentrations. The area under the curve (AUC) to discriminate STEMI from non-coronary chest pain (AUC 0.729, 95% confidence interval [CI] 0.71-0.75) was moderate and differed not significantly to UA (AUC 0.595, 95% CI 0.58-0.61; p = 0.0653). During a median follow-up of 29 months, higher D-dimer was associated with a significantly increased risk of recurrent MI (quartile 4 vs. 1: hazard ratio [HR], 6.9 [95% CI 1.2-39.9]; p < 0.0001) and higher all-cause mortality (HR, 17.4 [95% CI 4.3-69.9]; p < 0.0001). D-dimer was an independent predictor of all-cause mortality (p < 0.0001) and subsequent MI events (p = 0.0333). CONCLUSIONS: D-dimer testing revealed great potential to provide independent prognostic information on recurrent MI and all-cause mortality. However, D-dimers do not improve the diagnostic performance except if values exceed the 95th percentile.

Impact of Homoarginine on Myocardial Function and Remodeling in a Rat Model of Chronic Renal Failure.

PURPOSE: Low plasma concentrations of the amino acid homoarginine (HA) have been shown to correlate with adverse cardiovascular outcome, particularly in patients with chronic kidney disease. The present study sought to investigate the effect of HA treatment on cardiac remodeling in rats undergoing artificially induced renal insufficiency by 5/6 nephrectomy (5/6 Nx). METHODS: A total of 33 male Wistar rats were randomly divided into sham and 5/6 Nx groups, receiving either placebo treatment or 400 mg·kg-1·day-1 HA over a 4-week period. RESULTS: 5/6 Nx per se resulted in adverse myocardial remodeling with aggravated cardiac function and associated cardiac overload as the most obvious alteration (-23% ejection fraction, P < 0.0001), as well as increased myocardial fibrosis (+80%, P = 0.0005) compared to placebo treated sham animals. HA treatment of 5/6 Nx rats has led to an improvement of ejection fraction (+24%, P = 0.0003) and fractional shortening (+21%, P = 0.0126), as well as a decrease of collagen deposition (-32%, P = 0.0041), left ventricular weight (-14%, P = 0.0468), and myocyte cross-sectional area (-12%, P < 0.0001). These changes were accompanied by a downregulation of atrial natriuretic factor (-65% P < 0.0001) and collagen type V alpha 1 chain (-44%, P = 0.0006). Sham animals revealed no significant changes in cardiac function, myocardial fibrosis, or any of the aforementioned molecular changes after drug treatment. CONCLUSION: Dietary HA supplementation appears to have the potential of preventing cardiac remodeling and improving heart function in the setting of chronic kidney disease. Our findings shed new light on HA as a possible new therapeutic agent for patients at high cardiovascular risk.

Recombinant frizzled1 protein attenuated cardiac hypertrophy after myocardial infarction via the canonical Wnt signaling pathway.

Postinfarct cardiac hypertrophy is an independent risk factor for heart failure and sudden death. Regression of cardiac hypertrophy has emerged as a promising strategy in the treatment of myocardial infarction (MI). Here we hypothesized that frizzled1 (FZD1), a receptor of the canonical Wnt signaling pathway, is a novel mediator of ischemia-associated cardiac hypertrophy. MI was induced in mice by left anterior descending (LAD) coronary occlusion. One week after MI, the expression of FZD1 was found to be notably increased in the left ventricles (LVs) of the MI-mice compared to shams. Mouse recombinant FZD1 protein (RFP) was subcutaneously injected in the mice to provoke autoimmunization response. Anti-FZD1 antibody titer was significantly increased in the plasma of RFP-treated mice. RFP significantly mitigated the MI-induced cardiac hypertrophy and improved cardiac function in the MI mouse hearts. Moreover, increased heart and LV weights, myocardial size and the expression of ß-myosin heavy chain in the MI-mice were also found to be attenuated by RFP. FZD1 was found to be significantly up-regulated in hypoxia-treated neonatal rat cardiomyocytes (NRCMs). Silencing FZD1 by siRNA transfection notably repressed the hypoxia-induced myocardial hypertrophy in NRCMs. Mechanistically, activation of canonical Wnt signaling induced by MI, e.g., ß-catenin and glycogen synthase kinase-3ß, was restrained in the LVs of the MI-mice treated by RFP, these inhibition on canonical Wnt signaling was further confirmed in hypoxic NRCMs transfected with FZD1 siRNA. In conclusion, immunization of RFP attenuated cardiac hypertrophy and improved cardiac function in the MI mice via blocking the canonical Wnt signaling pathway.

The cardiac microenvironment uses non-canonical WNT signaling to activate monocytes after myocardial infarction.

A disturbed inflammatory response following myocardial infarction (MI) is associated with poor prognosis and increased tissue damage. Monocytes are key players in healing after MI, but little is known about the role of the cardiac niche in monocyte activation. This study investigated microenvironment-dependent changes in inflammatory monocytes after MI RNA sequencing analysis of murine Ly6Chigh monocytes on day 3 after MI revealed differential regulation depending on location. Notably, the local environment strongly impacted components of the WNT signaling cascade. Analysis of WNT modulators revealed a strong upregulation of WNT Inhibitory Factor 1 (WIF1) in cardiomyocytes-but not fibroblasts or endothelial cells-upon hypoxia. Compared to wild-type (WT) littermates, WIF1 knockout mice showed severe adverse remodeling marked by increased scar size and reduced ejection fraction 4 weeks after MI While FACS analysis on day 1 after MI revealed no differences in neutrophil numbers, the hearts of WIF1 knockouts contained significantly more inflammatory monocytes than hearts from WT animals. Next, we induced AAV-mediated cardiomyocyte-specific WIF1 overexpression, which attenuated the monocyte response and improved cardiac function after MI, as compared to control-AAV-treated animals. Finally, WIF1 overexpression in isolated cardiomyocytes limited the activation of non-canonical WNT signaling and led to reduced IL-1ß and IL-6 expression in monocytes/macrophages. Taken together, we investigated the cardiac microenvironment's interaction with recruited monocytes after MI and identified a novel mechanism of monocyte activation. The local initiation of non-canonical WNT signaling shifts the accumulating myeloid cells toward a pro-inflammatory state and impacts healing after myocardial infarction.

Closure of patent foramen ovale defects using GORE® CARDIOFORM septal occluder: Results from a prospective European multicenter study.

AIMS: The GORE® CARDIOFORM Septal Occluder (GSO) is a novel device designed for rapid and effective closure of patent foramen ovale (PFO) which has distinctive features making it suitable for a broad spectrum of anatomical variations. We report the procedural and 6 months follow-up results of the first prospective, multicenter study using GSO. METHODS AND RESULTS: This single-arm study included 150 subjects undergoing closure of PFO in 10 European centers. In 149 out of 150 patients implantation of a GSO device was successful. One patient had a different PFO-closure device implanted. Periprocedural complications were few including one patient with suspected transient ischemic attack, two access site bleedings, and one patient with AV-fistula. No device embolization occurred. During the 6-month follow-up period one patient had a transient asymptomatic thrombus on the device and four patients (2.6%) were diagnosed new onset paroxysmal atrial fibrillation, which were successfully treated. No thrombembolic events occurred. Closure was successful in 94.2% of subjects at discharge evaluation and 96.9% at 6 months follow-up. CONCLUSION: This prospective, multicenter study adds to previous published data and suggests that GSO is a versatile device for PFO closure with high procedural and closure success rates and low complication rates through mid-term follow-up. © 2017 Wiley Periodicals, Inc.

Cardiac Effects of Attenuating Gsα - Dependent Signaling.

AIMS: Inhibition of ß-adrenergic signalling plays a key role in treatment of heart failure. Gsα is essential for ß-adrenergic signal transduction. In order to reduce side-effects of beta-adrenergic inhibition diminishing ß-adrenergic signalling in the heart at the level of Gsα is a promising option. METHODS AND RESULTS: We analyzed the influence of Gsα on regulation of myocardial function and development of cardiac hypertrophy, using a transgenic mouse model (C57BL6/J mice) overexpressing a dominant negative Gsα-mutant under control of the α-MHC-promotor. Cardiac phenotype was characterized in vivo and in vitro and under acute and chronic ß-adrenergic stimulation. At rest, Gsα-DN-mice showed bradycardia (602 ± 13 vs. 660 ± 17 bpm, p<0.05) and decreased dp/dtmax (5037 ± 546- vs. 6835 ± 505 mmHg/s, p = 0.02). No significant differences were found regarding ejection fraction, heart weight and cardiomyocyte size. ß-blockade by propranolol revealed no baseline differences of hemodynamic parameters between wildtype and Gsα-DN-mice. Acute adrenergic stimulation resulted in decreased ß-adrenergic responsiveness in Gsα-DN-mice. Under chronic adrenergic stimulation, wildtype mice developed myocardial hypertrophy associated with increase of LV/BW-ratio by 23% (4.4 ± 0.2 vs. 3.5 ± 0.1 mg/g, p<0.01) and cardiac myocyte size by 24% (14927 ± 442 px vs. 12013 ± 583 px, p<0.001). In contrast, both parameters were unchanged in Gsα-DN-mice after chronic isoproterenol stimulation. CONCLUSION: Overexpression of a dominant negative mutant of Gsα leads to decreased ß-adrenergic responsiveness and is protective against isoproterenol-induced hypertrophy. Thus, Gsα-DN-mice provide novel insights into ß-adrenergic signal transduction and its modulation in myocardial overload and failure.

Anterior Aortic Plane Systolic Excursion: A Novel Indicator of Transplant-Free Survival in Systemic Light-Chain Amyloidosis.

BACKGROUND: Anterior aortic plane systolic excursion (AAPSE) was evaluated in the present pilot study as a novel echocardiographic indicator of transplant-free survival in patients with systemic light-chain amyloidosis. METHODS: Eighty-nine patients with light-chain amyloidosis were included in the post-hoc analysis. A subgroup of 54 patients with biopsy-proven cardiac amyloid infiltration were compared with 41 healthy individuals to evaluate the discriminative ability of echocardiographic findings. AAPSE is defined as the systolic excursion of the anterior aortic margin. To quantify AAPSE, the M-mode cursor was placed on the aortic valve plane in parasternal long-axis view at end-diastole. Index echocardiography had been performed before chemotherapy. Median follow-up duration was 2.4 years. The primary combined end point was heart transplantation or overall death. RESULTS: Mean AAPSE was 14 ± 2 mm in healthy individuals (mean age=57 ± 10 years; 56% men; BMI=25 ± 4 kg/m2). AAPSE < 11 mm separated patients from age-, gender-, and BMI-matched control subjects with 93% sensitivity and 97% specificity. Median transplant-free survival of patients with AAPSE < 5 mm was 0.7 versus 4.8 years (P = .0001). AAPSE was an independent indicator of transplant-free survival in multivariate Cox regression (echocardiographic model: hazard ratio=0.72 [P = .03]; biomarker model: hazard ratio=0.62 [P = .0001]). Sequential regression analysis suggested incremental power of AAPSE as a marker of transplant-free survival. An ejection fraction-based model with an overall χ2 value of 22.8 was improved by the addition of log NT-proBNP (χ2 = 32.6, P < .005), troponin-T (χ2 = 39.6, P < .01), and AAPSE (χ2 = 54.0, P < .0001). CONCLUSIONS: AAPSE is suggested as an indicator of transplant-free survival in patients with systemic light-chain amyloidosis. AAPSE provided significant incremental value to established staging models.

Using the GORE® Septal Occluder (GSO) in challenging patent foramen ovale (PFO) anatomies.

OBJECTIVES: We assessed efficacy and safety of the Gore(®) Septal Occluder (GSO) for patent foramen ovale (PFO) closure focusing on patients with challenging septal anatomies. BACKGROUND: In times of controversial discussion whether percutaneous PFO closure is superior to medical therapy for the prevention of recurrent embolic events after cryptogenic stroke, patient selection should mainly focus on individuals with an increased likelihood that the ischaemic event is related to the PFO. In this context, specific septal anatomies-such as the presence of an atrial septal aneurysm as well as long PFO tunnel anatomy-have been associated with a higher rate of cerebrovascular accidents. METHODS: The GSO was used for PFO closure in 41 patients presenting with either atrial septal aneurysm (ASA; 27/41; 65.9%) or long PFO tunnel (> 10 mm; 32/41; 78%). Seven of these patients even presented with a tunnel length ≥ 20 mm (7/41; 17.1%). Eighteen patients had both, long-tunnel anatomy and ASA (18/41; 43.9%). RESULTS: The GSO was successfully implanted in all cases. No procedural complications occurred and all patients were discharged the day after the procedure. Short-term follow-up, including TEE examination, in all patients was performed 37.6 ± 9.0 days after the procedure. Mid-term follow-up was performed after 192.7 ± 45.3 days. Later complications occurred in 7.3% (2 new onset atrial fibrillation, 1 device thrombus). Only 3 patients (7.3%) had more than trace residual shunts at 6-weeks follow-up. At 6-months follow-up, the complete closure rate was 95.1% (39/41). CONCLUSIONS: The Gore(®) Septal Occluder is an efficient device for patent foramen ovale closure in challenging anatomies, including long-tunnel PFOs and atrial septal aneurysms.

Calcium/calmodulin-dependent protein kinase II couples Wnt signaling with histone deacetylase 4 and mediates dishevelled-induced cardiomyopathy.

Activation of Wnt signaling results in maladaptive cardiac remodeling and cardiomyopathy. Recently, calcium/calmodulin-dependent protein kinase II (CaMKII) was reported to be a pivotal participant in myocardial remodeling. Because CaMKII was suggested as a downstream target of noncanonical Wnt signaling, we aimed to elucidate the role of CaMKII in dishevelled-1-induced cardiomyopathy and the mechanisms underlying its function. Dishevelled-1-induced cardiomyopathy was reversed by deletion of neither CaMKIIδ nor CaMKIIγ. Therefore, dishevelled-1-transgenic mice were crossed with CaMKIIδγ double-knockout mice. These mice displayed a normal cardiac phenotype without cardiac hypertrophy, fibrosis, apoptosis, or left ventricular dysfunction. Further mechanistic analyses unveiled that CaMKIIδγ couples noncanonical Wnt signaling to histone deacetylase 4 and myosin enhancer factor 2. Therefore, our findings indicate that the axis, consisting of dishevelled-1, CaMKII, histone deacetylase 4, and myosin enhancer factor 2, is an attractive therapeutic target for prevention of cardiac remodeling and its progression to left ventricular dysfunction.

Prognostic significance of semiautomatic quantification of left ventricular long axis shortening in systemic light-chain amyloidosis.

AIMS: To assess left ventricular long axis shortening (LAS) in patients with AL amyloidosis as a potential predictor for outcome. METHODS AND RESULTS: We performed a de novo echocardiographic analysis of LAS in 120 patients with biopsy-proven AL amyloidosis evaluated at first presentation before specific treatment. Additionally, 47 control subjects were analyzed retrospectivly. LAS was measured using a semiautomatic tissue motion annular displacement software algorithm (TMAD). LAS was significantly better than ejection fraction (EF) (p < 0.0001) and M-mode-derived mitral annular plane systolic excursion (MAPSE) (p < 0.05) discriminating AL patients from control subjects, while being non-inferior compared to tissue Doppler-derived peak systolic mitral annular velocity. One year outcome analysis in patients with AL amyloidosis showed that LAS remained the only significant echocardiographic parameter (HR:0.76; p < 0.005) in a multivariable Cox regression model of echocardiographic values. In a comprehensive clinical model, LAS (HR:0.72, p < 0.0001), cardiac troponin-T (HR:2.86, p < 0.01) and free light chain difference (HR:1.00; p < 0.05) were independently associated with the outcome. Assessment of LAS led to a significant integrated discrimination improvement and offered incremental information compared to EF and biomarkers. The cut-off value for LAS discriminating the endpoint was 5.8%. CONCLUSION: LAS was an independent predictor of survival within the first year and offers incremental information in patients with AL amyloidosis evaluated prior to specific treatment.

Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling.

In preclinical studies, endothelin receptor A (ETA) antagonists (ETAi) attenuated the progression of heart failure (HF). However, clinical HF trials failed to demonstrate beneficial effects of ETAi. These conflicting data may be explained by the possibility that established HF drugs such as adrenergic receptor blockers interfered with the mechanism of ETAi action in clinical trials. Here we report that mice lacking ETA only in sympathetic neurons (SN-KO) showed less adverse structural remodeling and cardiac dysfunction in response to pathological pressure overload induced by transverse aortic constriction (TAC). In contrast, mice lacking ETA only in cardiomyocytes (CM-KO) were not protected. TAC led to a disturbed sympathetic nerve function as measured by cardiac norepinephrine (NE) tissue levels and [(124)I]-metaiodobenzylguanidine-PET, which was prevented in SN-KO. In a rat model of HF, ETAi improved cardiac and sympathetic nerve function. In cocultures of cardiomyocytes (CMs) and sympathetic neurons (SNs), endothelin-1 (ET1) led to a massive NE release and exaggerated CM hypertrophy compared with CM monocultures. ETA-deficient CMs gained a hypertrophic response through wild-type SNs, but ETA-deficient SNs failed to mediate exaggerated CM hypertrophy. Furthermore, ET1 mediated its effects indirectly via NE in CM-SN cocultures through adrenergic receptors and histone deacetylases, resulting in activation of the prohypertrophic transcription factor myocyte enhancer factor 2. In conclusion, sympathetic ETA amplifies ET1 effects on CMs through adrenergic signaling pathways. Thus, antiadrenergic therapies may blunt potentially beneficial effects of ETAi. Taken together, this may indicate that patients with ß blocker intolerance or disturbed sympathetic nerve function could be evaluated for a potential benefit from ETAi.

Dapper-1 is essential for Wnt5a induced cardiomyocyte hypertrophy by regulating the Wnt/PCP pathway.

The Wnt signaling pathway was identified as crucial mediator of cardiomyocyte hypertrophy. In this study we found that activation of non-canonical Wnt signaling by Wnt5a stimulates protein synthesis and enlargement of cardiomyocyte surface area. These hypertrophic features were inhibited in Dapper-1 (Dpr1) depleted cells. On the molecular level, we observed inhibition of the non-canonical Wnt/planar-cell-polarity (PCP) pathway denoted by reduction of c-jun-n-terminal-kinase (JNK) phosphorylation. Upstream of JNK, increased protein levels of the Wnt/PCP trans-membrane receptor van-Gogh-like-2 (Vangl2) were observed along with an enrichment of Vangl2 in perinuclear located vesicles. The findings suggest that Dpr1 is essential for execution of the Wnt/PCP pathway and regulation of the Vangl2/JNK axis. Depletion of Dpr1 inhibits non-canonical Wnt signaling induced cardiomyocyte hypertrophy by blocking Wnt/PCP signaling.

Quantitative analysis of left ventricular strain using cardiac computed tomography.

OBJECTIVES: To investigate whether cardiac computed tomography (CCT) can determine left ventricular (LV) radial, circumferential and longitudinal myocardial deformation in comparison to two-dimensional echocardiography in patients with congestive heart failure. BACKGROUND: Echocardiography allows for accurate assessment of strain with high temporal resolution. A reduced strain is associated with a poor prognosis in cardiomyopathies. However, strain imaging is limited in patients with poor echogenic windows, so that, in selected cases, tomographic imaging techniques may be preferable for the evaluation of myocardial deformation. METHODS: Consecutive patients (n=27) with congestive heart failure who underwent a clinically indicated ECG-gated contrast-enhanced 64-slice dual-source CCT for the evaluation of the cardiac veins prior to cardiac resynchronization therapy (CRT) were included. All patients underwent additional echocardiography. LV radial, circumferential and longitudinal strain and strain rates were analyzed in identical midventricular short axis, 4-, 2- and 3-chamber views for both modalities using the same prototype software algorithm (feature tracking). Time for analysis was assessed for both modalities. RESULTS: Close correlations were observed for both techniques regarding global strain (r=0.93, r=0.87 and r=0.84 for radial, circumferential and longitudinal strain, respectively, p<0.001 for all). Similar trends were observed for regional radial, longitudinal and circumferential strain (r=0.88, r=0.84 and r=0.94, respectively, p<0.001 for all). The number of non-diagnostic myocardial segments was significantly higher with echocardiography than with CCT (9.6% versus 1.9%, p<0.001). In addition, the required time for complete quantitative strain analysis was significantly shorter for CCT compared to echocardiography (877±119 s per patient versus 1105±258 s per patient, p<0.001). CONCLUSION: Quantitative assessment of LV strain is feasible using CCT. This technique may represent a valuable alternative for the assessment of myocardial deformation in selected patients with poor echogenic windows and general contraindications for magnetic resonance imaging.

DYRK2 negatively regulates cardiomyocyte growth by mediating repressor function of GSK-3ß on eIF2Bε.

BACKGROUND: A prerequisite of hypertrophic response of the myocardium is an increase in protein synthesis. A central regulator of translation initiation is Eukaryotic initiation factor 2B (eIF2B). Here we assessed the hypothesis that regulation of protein synthesis via eIF2Bε is essential to cardiac hypertrophic response in vivo. METHODS: Two transgenic mouse lines were generated with cardiac restricted overexpression of eIF2Bε or its mutant eIF2Bε-eIFS(535)A, which cannot be inactivated by phosphorylation through GSK-3ß. RESULTS: (1) Under baseline conditions eIF2Bε transgenic mice showed no difference in cardiac phenotype compared to wild type, whereas in the mutant eIF2Bε-S(535)A an increase in LV/tibia length (7.5 ± 0.4 mg/mm vs. 6.2 ± 0.2 mg/mm, p<0.001) and cardiomyocyte cross sectional area (13004 ± 570 vs. 10843 ± 347 RU, p<0.01) was observed. (2) Cardiac overexpression of eIF2Bε did not change the response of the heart to pathologic stress induced by chronic isoproterenol treatment. (3) Cardiac overexpression of the eIF2Bε transgene was followed by overexpression of DYRK2 which is known to prime the inhibitory action of GSK-3ß on eIF2Bε, while DYRK1A and GSK-3ß itself were not increased. (4) In C57BL/6 mice after 48 h of isoproterenol-stimulation or aortic banding, eIF2Bε was increased and DYRK2 was concomitantly decreased. (5) In line with these in vivo findings, siRNA knockdown of DYRK2 in cultured cardiomyocytes resulted in decreased levels of p(S535)- eIF2Bε, (6) whereas adenoviral induced overexpression of DYRK2 was accompanied by clearly increased phosphorylation of eIF2Bε, indicating a coordinated response pattern (7) Adenoviral induced overexpression of DYRK2 leads to significantly reduced cardiomyocyte size and diminishes hypertrophic response to adrenergic stimulation. CONCLUSIONS: The interaction of GSK-3ß and its priming kinase DYRK2 regulate the activity of eIF2Bε in cardiac myocytes. DYRK2 is a novel negative regulator of cardiomyocyte growth. DYRK2 could serve as a therapeutic option to regulate myocardial growth.