SRF: a seriously responsible factor in cardiac development and disease.

The molecular mechanisms that regulate embryogenesis and cardiac development are calibrated by multiple signal transduction pathways within or between different cell lineages via autocrine or paracrine mechanisms of action. The heart is the first functional organ to form during development, which highlights the importance of this organ in later stages of growth. Knowledge of the regulatory mechanisms underlying cardiac development and adult cardiac homeostasis paves the way for discovering therapeutic possibilities for cardiac disease treatment. Serum response factor (SRF) is a major transcription factor that controls both embryonic and adult cardiac development. SRF expression is needed through the duration of development, from the first mesodermal cell in a developing embryo to the last cell damaged by infarction in the myocardium. Precise regulation of SRF expression is critical for mesoderm formation and cardiac crescent formation in the embryo, and altered SRF levels lead to cardiomyopathies in the adult heart, suggesting the vital role played by SRF in cardiac development and disease. This review provides a detailed overview of SRF and its partners in their various functions and discusses the future scope and possible therapeutic potential of SRF in the cardiovascular system.

RhoA: a dubious molecule in cardiac pathophysiology.

The Ras homolog gene family member A (RhoA) is the founding member of Rho GTPase superfamily originally studied in cancer cells where it was found to stimulate cell cycle progression and migration. RhoA acts as a master switch control of actin dynamics essential for maintaining cytoarchitecture of a cell. In the last two decades, however, RhoA has been coined and increasingly investigated as an essential molecule involved in signal transduction and regulation of gene transcription thereby affecting physiological functions such as cell division, survival, proliferation and migration. RhoA has been shown to play an important role in cardiac remodeling and cardiomyopathies; underlying mechanisms are however still poorly understood since the results derived from in vitro and in vivo experiments are still inconclusive. Interestingly its role in the development of cardiomyopathies or heart failure remains largely unclear due to anomalies in the current data available that indicate both cardioprotective and deleterious effects. In this review, we aimed to outline the molecular mechanisms of RhoA activation, to give an overview of its regulators, and the probable mechanisms of signal transduction leading to RhoA activation and induction of downstream effector pathways and corresponding cellular responses in cardiac (patho)physiology. Furthermore, we discuss the existing studies assessing the presented results and shedding light on the often-ambiguous data. Overall, we provide an update of the molecular, physiological and pathological functions of RhoA in the heart and its potential in cardiac therapeutics.

SH3-Binding Glutamic Acid Rich-Deficiency Augments Apoptosis in Neonatal Rat Cardiomyocytes.

Congenital heart disease (CHD) is one of the most common birth defects in humans, present in around 40% of newborns with Down's syndrome (DS). The SH3 domain-binding glutamic acid-rich (SH3BGR) gene, which maps to the DS region, belongs to a gene family encoding a cluster of small thioredoxin-like proteins sharing SH3 domains. Although its expression is confined to the cardiac and skeletal muscle, the physiological role of SH3BGR in the heart is poorly understood. Interestingly, we observed a significant upregulation of SH3BGR in failing hearts of mice and human patients with hypertrophic cardiomyopathy. Along these lines, the overexpression of SH3BGR exhibited a significant increase in the expression of hypertrophic markers (Nppa and Nppb) and increased cell surface area in neonatal rat ventricular cardiomyocytes (NRVCMs), whereas its knockdown attenuated cellular hypertrophy. Mechanistically, using serum response factor (SRF) response element-driven luciferase assays in the presence or the absence of RhoA or its inhibitor, we found that the pro-hypertrophic effects of SH3BGR are mediated via the RhoA-SRF axis. Furthermore, SH3BGR knockdown resulted in the induction of apoptosis and reduced cell viability in NRVCMs via apoptotic Hippo-YAP signaling. Taking these results together, we here show that SH3BGR is vital for maintaining cytoskeletal integrity and cellular viability in NRVCMs through its modulation of the SRF/YAP signaling pathways.

SUMO proteins in the cardiovascular system: friend or foe?

Post-translational modifications (PTMs) are crucial for the adaptation of various signalling pathways to ensure cellular homeostasis and proper adaptation to stress. PTM is a covalent addition of a small chemical functional group such as a phosphate group (phosphorylation), methyl group (methylation), or acetyl group (acetylation); lipids like hydrophobic isoprene polymers (isoprenylation); sugars such as a glycosyl group (glycosylation); or even small peptides such as ubiquitin (ubiquitination), SUMO (SUMOylation), NEDD8 (neddylation), etc. SUMO modification changes the function and/or fate of the protein especially under stress conditions, and the consequences of this conjugation can be appreciated from development to diverse disease processes. The impact of SUMOylation in disease has not been monotonous, rather SUMO is found playing a role on both sides of the coin either facilitating or impeding disease progression. Several recent studies have implicated SUMO proteins as key regulators in various cardiovascular disorders. The focus of this review is thus to summarize the current knowledge on the role of the SUMO family in the pathophysiology of cardiovascular diseases.

Rho-family GTPase 1 (Rnd1) is a biomechanical stress-sensitive activator of cardiomyocyte hypertrophy.

Cardiac remodeling is induced by mechanical or humoral stress causing pathological changes to the heart. Here, we aimed at identifying the role of differentially regulated genes upon dynamic mechanical stretch. Microarray of dynamic stretch induced neonatal rat ventricular cardiomyocytes (NRVCMs) discovered Rho family GTPase 1 (Rnd1) as one of the significantly upregulated genes, a cardiac role of which is not known yet. Rnd1 was consistently upregulated in NRVCMs after dynamic stretch or phenylephrine (PE) stimulation, and in a mouse model of pressure overload. Overexpression of Rnd1 in NRVCMs activated the fetal gene program (including nppa and nppb) effected into a significant increase in cell surface area in untreated, stretched or PE-treated cells. Furthermore, Rnd1 overexpression showed a positive effect on cell proliferation as detected by significant increase in Ki67, Phosphohistone H3, and EdU positive NRVCMs. Through a Yeast two-hybrid screen and immunoprecipitation analysis, we identified Myozap, an intercalated disc protein, as novel interaction partner of Rnd1. Importantly, functional analysis of this interaction revealed the importance of RND1 in the RhoA and Myozap protein network that activates serum-response factor (SRF) signaling. In summary, we identified Rnd1 as a novel stretch-sensitive gene which influences cell proliferation and cellular hypertrophy via activation of RhoA-mediated SRF dependent and independent signaling pathways.

A cardiac α-actin (ACTC1) p. Gly247Asp mutation inhibits SRF-signaling in vitro in neonatal rat cardiomyocytes.

We recently identified a novel, heterozygous, and non-synonymous ACTC1 mutation (p.Gly247Asp or G247D) in a large, multi-generational family, causing atrial-septal defect followed by late-onset dilated cardiomyopathy (DCM). Molecular dynamics studies revealed possible actin polymerization defects as G247D mutation resides at the juncture of side-chain interaction, which was indeed confirmed by in vitro actin polymerization assays. Since polymerization/de-polymerization is important for the activation of Rho-GTPase-mediated serum response factor (SRF)-signaling, we studied the effect of G247D mutation using luciferase assay. Overexpression of native human ACTC1 in neonatal rat cardiomyocytes (NRVCMs) strongly activated SRF-signaling both in C2C12 cells and NRVCMs, whereas, G247D mutation abolished this activation. Mechanistically, we found reduced GTP-bound Rho-GTPase and increased nuclear localization of globular actin in NRVCMs overexpressing mutant ACTC1 possibly causing inhibition of SRF-signaling activation. In conclusion, our data suggests that human G247D ACTC1 mutation negatively regulates SRF-signaling likely contributing to the late-onset DCM observed in mutation carrier patients.

Myeloid leukemia factor-1 is a novel modulator of neonatal rat cardiomyocyte proliferation.

The present study focuses on the identification of the gene expression profile of neonatal rat cardiomyocytes (NRVCMs) after dynamic mechanical stretch through microarrays of RNA isolated from cells stretched for 2, 6 or 24h. In this analysis, myeloid leukemia factor-1 (MLF1) was found to be significantly downregulated during the course of stretch. We found that MLF1 is highly expressed in the heart, however, its cardiac function is unknown yet. In line with microarray data, MLF1 was profoundly downregulated in in vivo mouse models of cardiomyopathy, and also significantly reduced in the hearts of human patients with dilated cardiomyopathy. Our data indicates that the overexpression of MLF1 in NRVCMs inhibited cell proliferation while augmenting apoptosis. Conversely, knockdown of MLF1 protected NRVCMs from apoptosis and promoted cell proliferation. Moreover, we found that knockdown of MLF1 protected NRVCMs from hypoxia-induced cell death. The observed accelerated apoptosis is attributed to the activation of caspase-3/-7/PARP-dependent apoptotic signaling and upregulation of p53. Most interestingly, MLF1 knockdown significantly upregulated the expression of D cyclins suggesting its possible role in cyclin-dependent cell proliferation. Taken together, we, for the first time, identified an important role for MLF1 in NRVCM proliferation.

TRIM24 protein promotes and TRIM32 protein inhibits cardiomyocyte hypertrophy via regulation of dysbindin protein levels.

We have previously shown that dysbindin is a potent inducer of cardiomyocyte hypertrophy via activation of Rho-dependent serum-response factor (SRF) signaling. We have now performed a yeast two-hybrid screen using dysbindin as bait against a cardiac cDNA library to identify the cardiac dysbindin interactome. Among several putative binding proteins, we identified tripartite motif-containing protein 24 (TRIM24) and confirmed this interaction by co-immunoprecipitation and co-immunostaining. Another tripartite motif (TRIM) family protein, TRIM32, has been reported earlier as an E3 ubiquitin ligase for dysbindin in skeletal muscle. Consistently, we found that TRIM32 also degraded dysbindin in neonatal rat ventricular cardiomyocytes as well. Surprisingly, however, TRIM24 did not promote dysbindin decay but rather protected dysbindin against degradation by TRIM32. Correspondingly, TRIM32 attenuated the activation of SRF signaling and hypertrophy due to dysbindin, whereas TRIM24 promoted these effects in neonatal rat ventricular cardiomyocytes. This study also implies that TRIM32 is a key regulator of cell viability and apoptosis in cardiomyocytes via simultaneous activation of p53 and caspase-3/-7 and inhibition of X-linked inhibitor of apoptosis. In conclusion, we provide here a novel mechanism of post-translational regulation of dysbindin and hypertrophy via TRIM24 and TRIM32 and show the importance of TRIM32 in cardiomyocyte apoptosis in vitro.

Myozap Deficiency Promotes Adverse Cardiac Remodeling via Differential Regulation of Mitogen-activated Protein Kinase/Serum-response Factor and ß-Catenin/GSK-3ß Protein Signaling.

The intercalated disc (ID) is a "hot spot" for heart disease, as several ID proteins have been found mutated in cardiomyopathy. Myozap is a recent addition to the list of ID proteins and has been implicated in serum-response factor signaling. To elucidate the cardiac consequences of targeted deletion of myozap in vivo, we generated myozap-null mutant (Mzp(-/-)) mice. Although Mzp(-/-) mice did not exhibit a baseline phenotype, increased biomechanical stress due to pressure overload led to accelerated cardiac hypertrophy, accompanied by "super"-induction of fetal genes, including natriuretic peptides A and B (Nppa/Nppb). Moreover, Mzp(-/-) mice manifested a severe reduction of contractile function, signs of heart failure, and increased mortality. Expression of other ID proteins like N-cadherin, desmoplakin, connexin-43, and ZO-1 was significantly perturbed upon pressure overload, underscored by disorganization of the IDs in Mzp(-/-) mice. Exploration of the molecular causes of enhanced cardiac hypertrophy revealed significant activation of ß-catenin/GSK-3ß signaling, whereas MAPK and MKL1/serum-response factor pathways were inhibited. In summary, myozap is required for proper adaptation to increased biomechanical stress. In broader terms, our data imply an essential function of the ID in cardiac remodeling beyond a mere structural role and emphasize the need for a better understanding of this molecular structure in the context of heart disease.

A biallelic loss-of-function variant in MYZAP is associated with a recessive form of severe dilated cardiomyopathy.

PURPOSE: Dilated cardiomyopathy (DCM) is a primary disorder of the cardiac muscle, characterised by dilatation of the left ventricle and contractile dysfunction. About 50% of DCM cases can be attributed to monogenic causes, whereas the aetiology in the remaining patients remains unexplained. METHODS: We report a family with two brothers affected by severe DCM with onset in the adolescent period. Using exome sequencing, we identified a homozygous premature termination variant in the MYZAP gene in both affected sibs. MYZAP encodes for myocardial zonula adherens protein - a conserved cardiac protein in the intercalated disc structure of cardiomyocytes. RESULTS: The effect of the variant was demonstrated by light and electron microscopy of the heart muscle and immunohistochemical and Western blot analysis of MYZAP protein in the heart tissue of the proband. Functional characterization using patient-derived induced pluripotent stem cell cardiomyocytes revealed significantly lower force and longer time to peak contraction and relaxation consistent with severe contractile dysfunction. CONCLUSION: We provide independent support for the role of biallelic loss-of-function MYZAP variants in dilated cardiomyopathy. This report extends the spectrum of cardiac disease associated with dysfunction of cardiac intercalated disc junction and sheds light on the mechanisms leading to DCM.

C-Reactive Protein to Albumin Ratio in Patients Undergoing Transcatheter Aortic Valve Replacement.

OBJECTIVE: To evaluate whether the serum C-reactive protein to albumin ratio (CAR) could be used for risk stratification of patients undergoing transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS). PATIENTS AND METHODS: Frailty is a predictor of poor outcomes in patients undergoing AS interventions. The CAR reflects key components of frailty (systemic inflammation and nutrition) and could potentially be implemented into assessment and management strategies for patients with AS. From March 1, 2010, through February 29, 2020, 1836 patients were prospectively enrolled in an observational TAVR database. Patients (prospective development cohort, n=763) were grouped into CAR quartiles to compare the upper quartile (CAR Q4) with the lower quartiles (CAR Q1-3). Primary end point was all-cause mortality. Results were verified in an independent retrospective cohort (n=1403). RESULTS: The CAR Q4 had a higher prevalence of impaired left ventricular function, atrial fibrillation, diabetes, and cerebrovascular disease and a higher median logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) vs CAR Q1-3. After median follow-up of 15.0 months, all-cause mortality was significantly higher in CAR Q4 vs CAR Q1-3 (P<.001). In multivariable analyses, risk factors for all-cause mortality were CAR Q4 (>0.1632; hazard ratio, 1.45; 95% confidence interval, 1.05 to 2.00; P=.03), N-terminal pro-B-type natriuretic peptide Q4 (>3230 pg/mL [to convert to ng/L, multiply by 1), high-sensitivity troponin T Q4 (>0.0395 ng/mL [to convert to µg/L, multiply by 1]), above-median logistic EuroSCORE (16.1%), myocardial infarction, Acute Kidney Injury Network stage 3, and life-threatening bleeding. CONCLUSION: Elevated CAR was associated with increased risk of all-cause mortality in patients undergoing transfemoral TAVR. The CAR, a simple, objective tool to assess frailty, could be incorporated into assessing patients with AS being considered for TAVR.

Ignatzschineria indica sp. nov. and Ignatzschineria ureiclastica sp. nov., isolated from adult flesh flies (Diptera: Sarcophagidae).

Two Gram-negative-staining, aerobic, non-motile, rod-shaped bacteria, designated strains FFA1(T) and FFA3(T), and belonging to the class Gammaproteobacteria were isolated from the gastrointestinal tract of adult flesh flies (Diptera: Sarcophagidae). Phylogenetic analysis of 16S rRNA gene sequence data placed these two strains within the genus Ignatzschineria with similarities of 98.6 % (FFA1(T)) and 99.35 % (FFA3(T)) to Ignatzschineria larvae L1/68(T). The level of gene sequence similarity between strains FFA1(T) and FFA3(T) was 99 %, 97.15 % and 78.1 % based on the 16S rRNA, 23S rRNA and gyrB gene sequences, respectively. Strains FFA1(T) and FFA3(T) shared 24 % DNA-DNA relatedness. DNA-DNA hybridization revealed a very low level of relatedness between the novel strains (22 % for strain FFA1(T) and 44 % for strain FFA3(T)) and I. larvae L1/68(T) genomic DNA. The respiratory quinone was Q-8 in both novel strains. The DNA G+C contents were 41.1 mol% and 40.1 mol% for strains FFA1(T) and FFA3(T), respectively. The cell membrane of both strains consisted of phosphatidylglycerol, phosphatidylethanolamine, phospholipids and aminophospholipid. The major fatty acids for both strains were C(16 : 0), summed feature 8 (C(18 : 1)ω7c and/or C(18 : 1)ω6c), CyC(19 : 0)ω8c and C(14 : 0). The results of DNA-DNA hybridization between the two new strains and I. larvae L1/68(T), in combination with phylogenetic, chemotaxonomic, biochemical and electron microscopic data, demonstrated that strains FFA1(T) and FFA3(T) represented two novel species of the genus Ignatzschineria for which the names Ignatzschineria indica sp. nov. (type strain FFA1(T) = DSM 22309(T) = KCTC 22643(T) = NCIM 5325(T)) and Ignatzschineria ureiclastica sp. nov. (type strain FFA3(T) = DSM 22310(T) = KCTC 22644(T) = NCIM 5326(T)) are proposed.

RhoA Signaling in Immune Cell Response and Cardiac Disease.

Chronic inflammation, the activation of immune cells and their cross-talk with cardiomyocytes in the pathogenesis and progression of heart diseases has long been overlooked. However, with the latest research developments, it is increasingly accepted that a vicious cycle exists where cardiomyocytes release cardiocrine signaling molecules that spiral down to immune cell activation and chronic state of low-level inflammation. For example, cardiocrine molecules released from injured or stressed cardiomyocytes can stimulate macrophages, dendritic cells, neutrophils and even T-cells, which then subsequently increase cardiac inflammation by co-stimulation and positive feedback loops. One of the key proteins involved in stress-mediated cardiomyocyte signal transduction is a small GTPase RhoA. Importantly, the regulation of RhoA activation is critical for effective immune cell response and is being considered as one of the potential therapeutic targets in many immune-cell-mediated inflammatory diseases. In this review we provide an update on the role of RhoA at the juncture of immune cell activation, inflammation and cardiac disease.

Elevated high-sensitivity troponin T levels at 1-year follow-up are associated with increased long-term mortality after TAVR.

BACKGROUND: Elevated pre-procedural high-sensitivity troponin T (hs-TnT) levels predict adverse outcomes in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). It is unknown whether elevated troponin levels still provide prognostic information during follow-up after successful TAVR. We evaluated the long-term implications of elevated hs-TnT levels found at 1-year post-TAVR. METHODS AND RESULTS: The study included 349 patients who underwent TAVR for severe AS from 2010-2019 and for whom 1-year hs-TnT levels were available. Any required percutaneous coronary interventions were performed > 1 week before TAVR. The primary endpoint was survival time starting at 1-year post-TAVR. Optimal hs-TnT cutoff for stratifying risk, identified by ROC analysis, was 39.4 pg/mL. 292 patients had hs-TnT < 39.4 pg/mL (median 18.3 pg/mL) and 57 had hs-TnT ≥ 39.4 pg/mL (median 51.2 pg/mL). The high hs-TnT group had a higher median N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, greater left ventricular (LV) mass, higher prevalence of severe diastolic dysfunction, LV ejection fraction < 35%, severe renal dysfunction, and more men compared with the low hs-TnT group. All-cause mortality during follow-up after TAVR was significantly higher among patients who had hs-TnT ≥ 39.4 pg/mL compared with those who did not (mortality rate at 2 years post-TAVR: 12.3% vs. 4.1%, p = 0.010). Multivariate analysis identified 1-year hs-TnT ≥ 39.4 pg/mL (hazard ratio 2.93, 95% CI 1.91-4.49, p < 0.001), NT-proBNP level > 300 pg/mL, male sex, an eGFR < 60 mL/min/1.73 m2 and chronic obstructive pulmonary disease as independent risk factors for long-term mortality after TAVR. CONCLUSIONS: Elevated hs-TnT concentrations at 1-year after TAVR were associated with a higher long-term mortality.

FYCO1 Regulates Cardiomyocyte Autophagy and Prevents Heart Failure Due to Pressure Overload In Vivo.

Autophagy is a cellular degradation process that has been implicated in diverse disease processes. The authors provide evidence that FYCO1, a component of the autophagic machinery, is essential for adaptation to cardiac stress. Although the absence of FYCO1 does not affect basal autophagy in isolated cardiomyocytes, it abolishes induction of autophagy after glucose deprivation. Likewise, Fyco1-deficient mice subjected to starvation or pressure overload are unable to respond with induction of autophagy and develop impaired cardiac function. FYCO1 overexpression leads to induction of autophagy in isolated cardiomyocytes and transgenic mouse hearts, thereby rescuing cardiac dysfunction in response to biomechanical stress.

Dysbindin deficiency Alters Cardiac BLOC-1 Complex and Myozap Levels in Mice.

Dysbindin, a schizophrenia susceptibility marker and an essential constituent of BLOC-1 (biogenesis of lysosome-related organelles complex-1), has recently been associated with cardiomyocyte hypertrophy through the activation of Myozap-RhoA-mediated SRF signaling. We employed sandy mice (Dtnbp1_KO), which completely lack Dysbindin protein because of a spontaneous deletion of introns 5-7 of the Dtnbp1 gene, for pathophysiological characterization of the heart. Unlike in vitro, the loss-of-function of Dysbindin did not attenuate cardiac hypertrophy, either in response to transverse aortic constriction stress or upon phenylephrine treatment. Interestingly, however, the levels of hypertrophy-inducing interaction partner Myozap as well as the BLOC-1 partners of Dysbindin like Muted and Pallidin were dramatically reduced in Dtnbp1_KO mouse hearts. Taken together, our data suggest that Dysbindin's role in cardiomyocyte hypertrophy is redundant in vivo, yet essential to maintain the stability of its direct interaction partners like Myozap, Pallidin and Muted.

Data on the role of cardiac α-actin (ACTC1) gene mutations on SRF-signaling.

We recently reported a novel, heterozygous, and non-synonymous ACTC1 mutation (p.Gly247Asp or G247D) in a large, multi-generational family, causing atrial-septal defect followed by late-onset dilated cardiomyopathy (DCM). We also found that the G247D ACTC1 mutation negatively regulated serum response (SRF)-signaling thereby contributing to the late-onset DCM observed in human patients carrying this mutation ("A cardiac α-actin (ACTC1) p. Gly247Asp mutation inhibits SRF-signaling in vitro in neonatal rat cardiomyocytes" [1]). There are some ACTC1 mutations known to date, majority of which, though, have not been investigated for their functional consequence. We thus aimed at determining the functional impact of various ACTC1 gene mutations on SRF-signaling using SM22-response element driven firefly luciferase activity assays in C2C12 cells.

Prognostic implications of N-terminal pro-B-type natriuretic peptide in patients with normal left ventricular ejection fraction undergoing transcatheter aortic valve implantation.

BACKGROUND: Biomarkers may significantly improve risk stratification algorithms for patients undergoing transcatheter aortic valve implantation (TAVI). While N-terminal pro-B-type natriuretic peptide (NT-proBNP) is established as a biomarker in the context of heart failure, its prognostic implications in patients with normal left ventricular ejection fraction (LVEF) undergoing TAVI are unclear. METHODS: A total of 504 TAVI patients with normal LVEF were analyzed. Based on preprocedural NT-proBNP levels, patients were stratified into two groups comparing the upper quartile ("Q4", n = 126) with the lower three quartiles ("Q1-3", n = 378). The primary outcome of our study was survival. RESULTS: The "Q4" group included more men (46.8% vs. 34.9%, p = 0.017), had higher rates of atrial fibrillation (55.6% vs. 28.3%, p < 0.001) and showed features of more advanced aortic stenosis (mean pressure gradient 49 mmHg vs. 40 mmHg, aortic valve area 0.6 cm2 vs. 0.7 cm2; p < 0.001, respectively). The "Q4" group was also characterized by more extensive cardiac remodeling including severe diastolic dysfunction (18.1% vs. 6.5%, p < 0.001) and left atrial dilation (26.8% vs. 10.8%, p < 0.001). Kaplan-Meier analysis demonstrated superior survival of the "Q1-3" group (median follow-up 22.1 months, log-rank test p < 0.001). In a multivariable analysis, preprocedural NT-proBNP emerged as a significant risk factor for all-cause mortality after TAVI (HR 1.87, CI 1.31-2.65, p < 0.001). CONCLUSIONS: NT-proBNP is associated with survival in TAVI patients with normal LVEF. In this patient group, preprocedural NT-proBNP levels do not only correlate with aortic stenosis, but reflect advanced cardiovascular dysfunction, including HFpEF, that might not be completely reversible after TAVI.

The E3 ubiquitin ligase HectD3 attenuates cardiac hypertrophy and inflammation in mice.

Myocardial inflammation has recently been recognized as a distinct feature of cardiac hypertrophy and heart failure. HectD3, a HECT domain containing E3 ubiquitin ligase has previously been investigated in the host defense against infections as well as neuroinflammation; its cardiac function however is still unknown. Here we show that HectD3 simultaneously attenuates Calcineurin-NFAT driven cardiomyocyte hypertrophy and the pro-inflammatory actions of LPS/interferon-γ via its cardiac substrates SUMO2 and Stat1, respectively. AAV9-mediated overexpression of HectD3 in mice in vivo not only reduced cardiac SUMO2/Stat1 levels and pathological hypertrophy but also largely abolished macrophage infiltration and fibrosis induced by pressure overload. Taken together, we describe a novel cardioprotective mechanism involving the ubiquitin ligase HectD3, which links anti-hypertrophic and anti-inflammatory effects via dual regulation of SUMO2 and Stat1. In a broader perspective, these findings support the notion that cardiomyocyte growth and inflammation are more intertwined than previously anticipated.

Cardiac transcriptional and metabolic changes following thoracotomy.

Non-cardiac surgery is associated with significant cardiovascular complications. Reported mortality rate ranges from 1.9% to 4% in unselected patients. A postoperative surge in pro-inflammatory cytokines is a well-known feature and putative contributor to these complications. Despite much clinical research, little is known about the biomolecular changes in cardiac tissue following non-cardiac surgery. In order to increase our understanding, we analyzed whole-transcriptional and metabolic profiling data sets from hearts of mice harvested two, four, and six weeks following isolated thoracotomy. Hearts from healthy litter-mates served as controls. Functional network enrichment analyses showed a distinct impact on cardiac transcription two weeks after surgery characterized by a downregulation of mitochondrial pathways in the absence of significant metabolic alterations. Transcriptional changes were not detectable four and six weeks following surgery. Our study shows distinct and reversible transcriptional changes within the first two weeks following isolated thoracotomy. This coincides with a time period, in which most cardiovascular events happen.