Malat1 deficiency prevents neonatal heart regeneration by inducing cardiomyocyte binucleation.

The adult mammalian heart has limited regenerative capacity, while the neonatal heart fully regenerates during the first week of life. Postnatal regeneration is mainly driven by proliferation of preexisting cardiomyocytes and supported by proregenerative macrophages and angiogenesis. Although the process of regeneration has been well studied in the neonatal mouse, the molecular mechanisms that define the switch between regenerative and nonregenerative cardiomyocytes are not well understood. Here, using in vivo and in vitro approaches, we identified the lncRNA Malat1 as a key player in postnatal cardiac regeneration. Malat1 deletion prevented heart regeneration in mice after myocardial infarction on postnatal day 3 associated with a decline in cardiomyocyte proliferation and reparative angiogenesis. Interestingly, Malat1 deficiency increased cardiomyocyte binucleation even in the absence of cardiac injury. Cardiomyocyte-specific deletion of Malat1 was sufficient to block regeneration, supporting a critical role of Malat1 in regulating cardiomyocyte proliferation and binucleation, a landmark of mature nonregenerative cardiomyocytes. In vitro, Malat1 deficiency induced binucleation and the expression of a maturation gene program. Finally, the loss of hnRNP U, an interaction partner of Malat1, induced similar features in vitro, suggesting that Malat1 regulates cardiomyocyte proliferation and binucleation by hnRNP U to control the regenerative window in the heart.

Post-cardiac injury syndrome triggered by radiofrequency ablation for AVNRT.

BACKGROUND: Post-cardiac injury syndrome (PCIS) is an inflammatory condition following myocardial or pericardial damage. In response to catheter ablation, PCIS most frequently occurs after extensive radiofrequency (RF) ablation of large areas of atrial myocardium. Minor myocardial injury from right septal slow pathway ablation for atrioventricular nodal reentrant tachycardia (AVNRT) is not an established cause of the syndrome. CASE PRESENTATION: A 62-year-old women with a 6-year history of symptomatic narrow-complex tachycardia was referred to perform an electrophysiological study. During the procedure AVNRT was recorded and a total of two RF burns were applied to the region between the coronary sinus and the tricuspid annulus. Pericardial effusion was routinely ruled out by focused cardiac ultrasound. In the following days, the patient developed fever, elevated inflammatory and cardiac markers, new-onset pericardial effusion, characteristic ECG changes, and complained of pleuritic chest pain. An extensive workup for infectious, metabolic, rheumatologic, neoplastic, and toxic causes of pericarditis and myocarditis was unremarkable. Cardiac magnetic resonance imaging showed no signs of ischemia, infiltrative disease or structural abnormalities. The patient was diagnosed with PCIS and initiated on aspirin and low-dose colchicine. At a 1-month follow-up visit the patient was free of symptoms but still had a small pericardial effusion. After three  months of treatment the pericardial effusion had resolved completely. CONCLUSIONS: Inflammatory pericardial reactions can occur after minor myocardial damage from RF ablation without involvement of structures in close proximity to the pericardium.

Constrictive pericarditis in the setting of repeated chest trauma in a mixed martial arts fighter.

BACKGROUND: Constrictive pericarditis (CP) is characterized by scarring and loss of elasticity of the pericardium. This case demonstrates that mixed martial arts (MMA) is a previously unrecognized risk factor for CP, diagnosis of which is supported by cardiac imaging, right and left heart catheterization, and histological findings of dense fibrous tissue without chronic inflammation. CASE PRESENTATION: A 47-year-old Caucasian male former mixed martial arts (MMA) fighter from the Western United States presented to liver clinic for elevated liver injury tests (LIT) and a 35-pound weight loss with associated diarrhea, lower extremity edema, dyspnea on exertion, and worsening fatigue over a period of 6 months. Past medical history includes concussion, right bundle branch block, migraine headache, hypertension, chronic pain related to musculoskeletal injuries and fractures secondary to MMA competition. Involvement in MMA was extensive with an 8-year history of professional MMA competition and 13-year history of MMA fighting with recurrent trauma to the chest wall. The patient also reported a 20-year history of performance enhancing drugs including testosterone. Physical exam was notable for elevated jugular venous pressure, hepatomegaly, and trace peripheral edema. An extensive workup was performed including laboratory studies, abdominal computerized tomography, liver biopsy, echocardiogram, and cardiac magnetic resonance imaging. Finally, right and left heart catheterization-the gold standard-confirmed discordance of the right ventricle-left ventricle, consistent with constrictive physiology. Pericardiectomy was performed with histologic evidence of chronic pericarditis. The patient's hospital course was uncomplicated and he returned to NYHA functional class I. CONCLUSIONS: CP can be a sequela of recurrent pericarditis or hemorrhagic effusions and may have a delayed presentation. In cases of recurrent trauma, CP may be managed with pericardiectomy with apparent good outcome. Further studies are warranted to analyze the occurrence of CP in MMA so as to better define the risk in such adults.

Protocol for cryoinjury model in neonatal mice for heart regeneration and repair research.

The variability of animal experimental groups and high maternal cannibalization are two major limitations in cardiac injury models. A cryoinjury model could be an ideal model in heart regeneration and repair research as it can provide reproducible results and the injury size can be scaled. Here, we describe a simple and successful cryoinjury model (rate of mouse survival >90% and rate of maternal cannibalization <5%) for evaluating heart injury in regenerating and non-regenerating mice. For complete details on the use and execution of this protocol, please refer to Zhao et al. (2021).

Transcatheter patent arterial duct closure in premature infants: A new technique to ease access to the patent arterial duct, with particular benefit for the tricuspid valve.

BACKGROUND: Transcatheter patent arterial duct (PAD) closure in premature infants has been shown to be feasible. Since our early transcatheter PAD closure procedures in premature infants at Hôpital Necker Enfants Malades, we have changed our technique several times to advance the guidewire through the right heart to avoid tricuspid valve damage. AIM: To describe the technique we have been using since May 2019, to report our results with a particular focus on tricuspid leaks and to analyse the potential mechanisms of tricuspid lesion development with previous methods. METHODS: All premature infants weighing<2kg who underwent transcatheter PAD closure with this new technique were included. Demographic data, procedural data, outcome and procedural complications were reviewed, with particular attention to the occurrence of tricuspid regurgitation. RESULTS: Between May 2019 and May 2020, 33 patients were included. Median gestational age was 25 weeks. Median birth weight and procedural weight were 690g (range 490-1065g; interquartile range [IQR] 620-785g) and 1160g (range 900-1900g; IQR 1030-1300g), respectively. Median age at procedure was 35 (IQR 30-46) days. PAD anatomy was evaluated on transthoracic echocardiography only. The median duct diameter was 3 (IQR 2.5-3.2) mm at the pulmonary end. Success rate was 100% (defined as successful closure without residual shunt). One patient had a renal vein thrombosis, which fully resolved with low-molecular-weight heparin anticoagulation. No tricuspid regurgitation or stenosis of the left pulmonary artery or the aorta was seen. One patient died of a superior caval vein obstruction with bilateral chylothorax related to a central catheter thrombosis 56 days after the procedure, unrelated to the catheter procedure. CONCLUSION: In this prospective study, we describe a new technique to avoid tricuspid valve damage and facilitate delivery of the PAD device.

Ambient air PM2.5 exposure induces heart injury and cardiac hypertrophy in rats through regulation of miR-208a/b, α/ß-MHC, and GATA4.

Ambient air fine particulate matter (PM2.5) may increase cardiovascular disease risks. In this study, we investigated the miR-208/GATA4/myosin heavy chain (MHC) regulation mechanisms on cardiac injury in rats after PM2.5 exposure via an animal inhalation device. The results showed that PM2.5 exposure for 2 months caused pathological heart injury, reduced nucleus-cytoplasm ratio, and increased the levels of CK-MB and cTnI, showing cardiac hypertrophy. Oxidative stress and inflammatory responses were also observed in rats' hearts exposed to PM2.5. Of note, PM2.5 exposure for 2-month significantly elevated GATA4 and ß-MHC mRNA and protein expression compared with the corresponding controls, along with the high-expression of miR-208b. The ratios of ß-MHC/α-MHC expression induced by PM2.5 were remarkably raised in comparison to their controls. It suggested that the up-regulation of miR-208b/ß-MHC and GATA4 and the conversion from α-MHC to ß-MHC may be the important causes of cardiac hypertrophy in rats incurred by PM2.5.

Evaluation of myocardial injury patterns and ST changes among critical and non-critical patients with coronavirus-19 disease.

Novel coronavirus disease (COVID-19) has led to a major public health crisis globally. Currently, myocardial damage is speculated to be associated with COVID-19, which can be seen as one of the main causes of death of patients with COVID-19. We therefore, aim to investigate the effects of COVID-19 disease on myocardial injury in hospitalized patients who have been tested positive for COVID-19 pneumonia in this study. A prospective study was conducted among 201 patients with COVID-19 in the Pakistan Military Hospital from April 1 to August 31, 2020, including non-critical cases and critical cases. COVID-19 patients were stratified as critical and non-critical according to the signs and symptoms severity; with those requiring intensive care and invasive mechanical ventilation as critical, and those did not requiring invasive mechanical ventilation as non-critical. A total of 201 COVID-19 patients with critical and non-critical categories presented with myocardial injury. All patients with myocardial injury had an elevation in CKMB and Troponin-I levels. Of these patients, 43.7% presented with new electrocardiography (ECG) changes, and ST depression was typically observed in 36.3% patients. In addition, 18.7% patients presented with abnormal echocardiography findings, with right ventricular dilatation and dysfunction commonly seen among critical group patients. Results analyzed by a logistic regression model showing COVID-19 direct contribution to myocardial injury in these patients. COVID-19 disease directly leads to cardiovascular damage among critical and non-critical patients. Myocardial injury is associated not only with abnormal ECG changes but also with myocardial dysfunction on echocardiography and more commonly observed among critical patients.

Association of coagulation dysfunction with cardiac injury among hospitalized patients with COVID-19.

Cardiac injury is a common complication of the coronavirus disease 2019 (COVID-19), and is associated with adverse clinical outcomes. In this study, we aimed to reveal the association of cardiac injury with coagulation dysfunction. We enrolled 181 consecutive patients who were hospitalized with COVID-19, and studied the clinical characteristics and outcome of these patients. Cardiac biomarkers high-sensitivity troponin I (hs-cTnI), myohemoglobin and creatine kinase-myocardial band (CK-MB) were assessed in all patients. The clinical outcomes were defined as hospital discharge or death. The median age of the study cohort was 55 (IQR, 46-65) years, and 102 (56.4%) were males. Forty-two of the 181 patients (23.2%) had cardiac injury. Old age, high leukocyte count, and high levels of aspartate transaminase (AST), D-dimer and serum ferritin were significantly associated with cardiac injury. Multivariate regression analysis revealed old age and elevated D-dimer levels as being strong risk predictors of in-hospital mortality. Interleukin 6 (IL6) levels were comparable in patients with or without cardiac injury. Serial observations of coagulation parameters demonstrated highly synchronous alterations of D-dimer along with progression to cardiac injury. Cardiac injury is a common complication of COVID-19 and is an independent risk factor for in-hospital mortality. Old age, high leukocyte count, and high levels of AST, D-dimer and serum ferritin are significantly associated with cardiac injury, whereas IL6 are not. Therefore, the pathogenesis of cardiac injury in COVID-19 may be primarily due to coagulation dysfunction along with microvascular injury.

Wide QRS Complex and Lateral ST-T Segment Abnormality Are Associated With Worse Clinical Outcomes in COVID-19 Patients.

BACKGROUND: The information on electrocardiographic features of patients with coronavirus disease 2019 (COVID-19) is limited. Our aim was to determine if baseline electrocardiographic features of hospitalized COVID-19 patients are associated with markers of myocardial injury and clinical outcomes. METHODS: In this retrospective, single center cohort study, we included 223 hospitalized patients with laboratory-confirmed COVID-19. Clinical, electrocardiographic and laboratory data were collected and analyzed. Primary composite endpoint of mortality, need for invasive mechanical ventilation, or admission to the intensive care unit was assessed. RESULTS: Forty patients (17.9%) reached the primary composite endpoint. Patients with the primary composite endpoint were more likely to have wide QRS complex (>120 ms) and lateral ST-T segment abnormality. The multivariable Cox regression showed increasing odds of the primary composite endpoint associated with acute respiratory distress syndrome (odds ratio 7.76, 95% CI 2.67-22.59; p < 0.001), acute cardiac injury (odds ratio 3.14, 95% CI 1.26-7.99; p = 0.016), high flow oxygen therapy (odds ratio 2.43, 95% CI 1.05-5.62; p = 0.037) and QRS duration longer than >120 ms (odds ratio 3.62, 95% CI 1.39-9.380; p = 0.008) Patients with a wide QRS complex (>120 ms) had significantly higher median level of troponin T and pro-BNP than those without it. Patients with abnormality of lateral ST-T segment had significantly higher median level of troponin T and pro-BNP than patients without. CONCLUSIONS: The presence of QRS duration longer than 120 ms and lateral ST-T segment abnormality were associated with worse clinical outcomes and higher levels of myocardial injury biomarkers.

Targeting OCT3 attenuates doxorubicin-induced cardiac injury.

Doxorubicin is a commonly used anticancer agent that can cause debilitating and irreversible cardiac injury. The initiating mechanisms contributing to this side effect remain unknown, and current preventative strategies offer only modest protection. Using stem-cell-derived cardiomyocytes from patients receiving doxorubicin, we probed the transcriptomic landscape of solute carriers and identified organic cation transporter 3 (OCT3) (SLC22A3) as a critical transporter regulating the cardiac accumulation of doxorubicin. Functional validation studies in heterologous overexpression models confirmed that doxorubicin is transported into cardiomyocytes by OCT3 and that deficiency of OCT3 protected mice from acute and chronic doxorubicin-related changes in cardiovascular function and genetic pathways associated with cardiac damage. To provide proof-of-principle and demonstrate translational relevance of this transport mechanism, we identified several pharmacological inhibitors of OCT3, including nilotinib, and found that pharmacological targeting of OCT3 can also preserve cardiovascular function following treatment with doxorubicin without affecting its plasma levels or antitumor effects in multiple models of leukemia and breast cancer. Finally, we identified a previously unrecognized, OCT3-dependent pathway of doxorubicin-induced cardiotoxicity that results in a downstream signaling cascade involving the calcium-binding proteins S100A8 and S100A9. These collective findings not only shed light on the etiology of doxorubicin-induced cardiotoxicity, but also are of potential translational relevance and provide a rationale for the implementation of a targeted intervention strategy to prevent this debilitating side effect.

Zebrafish heart regenerates after chemoptogenetic cardiomyocyte depletion.

BACKGROUND: Zebrafish can regenerate adult cardiac tissue following injuries from ventricular apex amputation, cryoinjury, and cardiomyocyte genetic ablation. Here, we characterize cardiac regeneration from cardiomyocyte chemoptogenetic ablation caused by localized near-infrared excited photosensitizer-mediated reactive oxygen species (ROS) generation. RESULTS: Exposure of transgenic adult zebrafish, Tg(myl7:fapdl5-cerulean), to di-iodinated derivative of the cell- permeable Malachite Green ester fluorogen (MG-2I) and whole-body illumination with 660 nm light resulted in cytotoxic damage to about 30% of cardiac tissue. After chemoptogenetic cardiomyocyte ablation, heart function was compromised, and macrophage infiltration was detected, but epicardial and endocardial activation response was much muted when compared to ventricular amputation. The spared cardiomyocytes underwent proliferation and restored the heart structure and function in 45-60 days after ablation. CONCLUSIONS: This cardiomyocyte ablation system did not appear to activate the epicardium and endocardium as is noted in other cardiac injury models. This approach represents a useful model to study specifically cardiomyocyte injury, proliferation and regeneration in the absence of whole organ activation. Moreover, this system can be adapted to ablate distinct cell populations in any organ system to study their function in regeneration.

A meta-analysis of the diagnostic accuracy of chest ultrasound for the diagnosis of occult penetrating cardiac injuries in hemodynamically stable patients with penetrating thoracic trauma.

BACKGROUND: We performed a systematic review (SR) and meta-analysis (MA) to determine the diagnostic accuracy of chest ultrasound (US) compared with a pericardial window (PW) for the diagnosis of occult penetrating cardiac injuries in hemodynamically stable patients with penetrating thoracic trauma. METHODS: A literature search in five databases identified relevant articles for inclusion in this SR and MA. Studies were eligible if they evaluated the diagnostic accuracy of chest US, compared with a PW, for the diagnosis of occult penetrating cardiac injuries in hemodynamically stable patients presenting with penetrating thoracic trauma. Two investigators independently assessed articles for inclusion and exclusion criteria and selected studies for final analysis. Methodological quality was evaluated using Quality Assessment of Diagnostic Accuracy Studies-2. We performed a MA of binary diagnostic test accuracy within the bivariate mixed-effects logistic regression modeling framework. RESULTS: We included five studies in our SR and MA. These studies included a total of 556 trauma patients. The MA found that, compared with PW, the US was 79% sensitive and 92% specific for detecting occult penetrating cardiac injuries in hemodynamically stable patients. The presence of a concomitant left hemothorax was frequent in patients with false-negative results. CONCLUSION: This SR and MA found that, compared with PW, US was 79% sensitive and 92% specific for detecting occult penetrating cardiac injuries in hemodynamically stable patients with penetrating thoracic trauma. Caution interpretation of pericardial US results is suggested in the presence of left hemothorax. In these cases, a second diagnostic test should be performed. LEVEL OF EVIDENCE: Systematic Review and Meta-analysis, level II.

Aortic Valve Perforation During Endovascular Repair of an Abdominal Aortic Aneurysm-A Case Report.

Although complications associated with endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms are rarely observed above the diaphragm, they could lead to catastrophic outcomes once they develop. Aortic valve perforation is one of those rare and major adverse events. In this report, we describe a case of an 82-year-old woman who suffered aortic valve perforation during EVAR caused by the wire-push technique. Her hemodynamics became unstable during the procedure and did not improve thereafter. Echocardiography performed 8 days after EVAR revealed aortic valve perforation. Surgical intervention was abandoned because her general condition was poor. The patient died 4 months after EVAR due to heart failure. It should be reminded that inadvertent manipulation of the wire can cause aortic valve perforation even during EVAR.

Volatile versus total intravenous anesthesia for 30-day mortality following non-cardiac surgery in patients with preoperative myocardial injury.

We evaluated whether volatile anesthetics can improve the postoperative outcomes of non-cardiac surgery in patients with preoperative myocardial injury defined by the cardiac troponin elevation. From January 2010 to June 2018, 1254 adult patients with preoperative myocardial injury underwent non-cardiac surgery under general anesthesia and were enrolled in this study. Patients were stratified into following two groups according to anesthetic agents; 115 (9.2%) patients whose anesthesia was induced and maintained with continuous infusion of propofol and remifentanil (TIVA group) and 1139 (90.8%) patients whose anesthesia was maintainted with volatile anesthetics (VOLATILE group). The primary outcome was 30-day mortality. To diminish the remifentanil effect, a further analysis was conducted after excluding the patients who received only volatile anesthetics without remifentanil infusion. In a propensity-score matched analysis, 30-day mortality was higher in the TIVA group than the VOLATILE group (17.0% vs. 9.1%; hazard ratio [HR] 2.60; 95% confidence interval [CI], 1.14-5.93; p = 0.02). In addition, the TIVA group showed higher 30-day mortality than the VOLATILE group, even after eliminating the effect of remifentanil infusion (15.8% vs. 8.3%; HR 4.62; 95% CI, 1.82-11.74; p = 0.001). In our study, the use of volatile anesthetics showed the significant survival improvement after non-cardiac surgery in patients with preoperative myocardial injury, which appears to be irrelevant to the remifentanil use. Further studies are needed to confirm this beneficial effect of volatile anesthetics. Clinical trial number and registry URL: KCT0004349 (www.cris.nih.go.kr).

Postoperative myocardial injury in a patient with left ureteric stone and asymptomatic COVID-19 disease.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first identified on 8thDecember 2019 in Wuhan, Hubei, China, and has since spread globally to become an emergency of international concern. Patients infected with SARS-CoV-2 may be asymptomatic or present with symptoms ranging from mild clinical manifestations: such as fever, cough, and sore throat to moderate and severe form of the disease such as pneumonia and acute respiratory distress syndrome (ARDS). In some patients, SARS-CoV-2 can affect the heart and cause myocardial injury which is evidenced either by electrocardiographic (ECG) changes or by a rise in serum troponin level. Patients with myocardial involvement are generally at risk of developing severe illness and tend to have a poor outcome. We hereby present a case of a hypertensive male patient with undiagnosed, asymptomatic COVID-19, who underwent an emergency urologic procedure for ureteric calculi. He eventually sustained a postoperative myocardial injury resulting in his demise. This case highlights the importance of detailed preoperative assessment and anticipation of complications during this global pandemic.

Delayed cardiac tamponade following catheter ablation of frequent premature ventricular complexes: a case report.

BACKGROUND: Cardiac tamponade is a potentially fatal complication after catheter ablation of ventricular arrhythmias. It often happens during or shortly after the procedure and needs urgent treatment. Here, we present a very incredible case about delayed cardiac tamponade after ablation of premature ventricular complexes. CASE PRESENTATION: A 66-year-old woman who underwent successful catheter ablation of right ventricular outflow tract origin premature ventricular complexes. Nineteen days after ablation, the patient experienced sudden syncope. Upon arriving at our hospital, she was "confused and shock". Transthoracic echocardiography revealed hemorrhagic cardiac tamponade, which was considered due to a delayed tiny perforation in the heart induced by the previous ablation. Following an emergent pericardiocentesis to drain a 200 mL hemorrhagic effusion, the patient's hemodynamics improved significantly. The patient was discharged after a 2-week hospitalization for investigating other probable causes with negative results. No signs of pericardial effusion recurred in a follow-up time of 12 months. CONCLUSION: This case report demonstrated, for the first time, that very late post-procedural cardiac tamponade might occur after catheter ablation of ventricular arrhythmias, even without antithrombotic treatment.

SAPIEN S3 valve deployment in the pulmonary position using the gore DrySeal sheath to protect the tricuspid valve.

BACKGROUND: Tricuspid valve injury can occur during implantation of a SAPIEN valve in the pulmonary position. We describe our experience using a long Gore DrySeal (GDS) sheath to protect the tricuspid valve during advancement of the Commander delivery system. METHODS: Retrospective single center review of all patients who underwent placement of a SAPIEN valve in the right ventricular outflow tract between January 2016 and April 2020. Patients were divided into two groups: delivery of the valve using standard technique (Group I), and with the use of a GDS (Group II), for comparison. RESULTS: There were 48 patients in total: 25 in Group I and 23 in Group II. In Group II, the first 10 patients had a 29 mm S3 placed through a 26 French (Fr), 65 cm GDS. We then performed additional crimping of the S3 onto the balloon after the balloon catheter was withdrawn to position the valve on the balloon outside the body. Subsequently, seven had a 29 mm S3 placed through a 24 Fr GDS, and four had a 26 mm S3 placed through a 22 Fr GDS including one weighing 16 kg. Two had a 23 mm S3 placed through a 22Fr GDS as the 20Fr GDS was not available in our lab. Severe tricuspid valve injury occurred in 2/25 (8%) of Group I patients and 0/23 of Group II patients. CONCLUSION: Use of a long GDS may protect the tricuspid valve from injury during implantation of the S3 valve in the pulmonary position, and is technically feasible in smaller patients.