A fatal case of fulminant myocarditis after influenza infection with a rapidly progressive course: A case report.

Myocarditis is an inflammation of the heart muscle. The most common cause of myocarditis is viral infections. clinical presentation of acute myocarditis is highly variable and varies from asymptomatic to fulminant heart failure or sudden death. Fulminant myocarditis is a severe form of myocarditis characterized by heart failure, arrhythmia, cardiogenic shock, and sudden cardiac arrest. Early diagnosis and proper treatment are essential for improved survival. We present a case of a 34-year-old woman who presented with viral symptoms for two days and then died suddenly.

Targeting HDAC6 to treat heart failure with preserved ejection fraction in mice.

Heart failure with preserved ejection fraction (HFpEF) poses therapeutic challenges due to the limited treatment options. Building upon our previous research that demonstrates the efficacy of histone deacetylase 6 (HDAC6) inhibition in a genetic cardiomyopathy model, we investigate HDAC6's role in HFpEF due to their shared mechanisms of inflammation and metabolism. Here, we show that inhibiting HDAC6 with TYA-018 effectively reverses established heart failure and its associated symptoms in male HFpEF mouse models. Additionally, in male mice lacking Hdac6 gene, HFpEF progression is delayed and they are resistant to TYA-018's effects. The efficacy of TYA-018 is comparable to a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the combination shows enhanced effects. Mechanistically, TYA-018 restores gene expression related to hypertrophy, fibrosis, and mitochondrial energy production in HFpEF heart tissues. Furthermore, TYA-018 also inhibits activation of human cardiac fibroblasts and enhances mitochondrial respiratory capacity in cardiomyocytes. In this work, our findings show that HDAC6 impacts on heart pathophysiology and is a promising target for HFpEF treatment.

Phenotypic screening with deep learning identifies HDAC6 inhibitors as cardioprotective in a BAG3 mouse model of dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is characterized by reduced cardiac output, as well as thinning and enlargement of left ventricular chambers. These characteristics eventually lead to heart failure. Current standards of care do not target the underlying molecular mechanisms associated with genetic forms of heart failure, driving a need to develop novel therapeutics for DCM. To identify candidate therapeutics, we developed an in vitro DCM model using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) deficient in B-cell lymphoma 2 (BCL2)-associated athanogene 3 (BAG3). With these BAG3-deficient iPSC-CMs, we identified cardioprotective drugs using a phenotypic screen and deep learning. From a library of 5500 bioactive compounds and siRNA validation, we found that inhibiting histone deacetylase 6 (HDAC6) was cardioprotective at the sarcomere level. We translated this finding to a BAG3 cardiomyocyte-knockout (BAG3cKO) mouse model of DCM, showing that inhibiting HDAC6 with two isoform-selective inhibitors (tubastatin A and a novel inhibitor TYA-018) protected heart function. In BAG3cKO and BAG3E455K mice, HDAC6 inhibitors improved left ventricular ejection fraction and reduced left ventricular diameter at diastole and systole. In BAG3cKO mice, TYA-018 protected against sarcomere damage and reduced Nppb expression. Based on integrated transcriptomics and proteomics and mitochondrial function analysis, TYA-018 also enhanced energetics in these mice by increasing expression of targets associated with fatty acid metabolism, protein metabolism, and oxidative phosphorylation. Our results demonstrate the power of combining iPSC-CMs with phenotypic screening and deep learning to accelerate drug discovery, and they support developing novel therapies that address underlying mechanisms associated with heart disease.

A Very Rare Case of Isolated Spontaneous Pneumopericardium Secondary to COVID-19.

Coronavirus disease 2019(COVID-19) is currently a pandemic. In addition to respiratory symptoms, involvement of other organs such as the pericardium is also seen. Pneumomediastinum in COVID-19 patients has rarely been reported. Isolated pneumopericardium without pneumomediastinum is even more uncommon. We described a case of COVID-19 in association with pneumopericardium. To the best of our knowledge, no case with isolated pneumopericardium has been reported thus far.

Type B Interrupted Aortic Arch With a Very Large Right Subclavian Artery Aneurysm in an Adult.

Interruption of the aortic arch and right subclavian artery aneurysm is a rare congenital malformation. Survival in adults depends on the formation of collaterals to supply the descending aorta. The interruption of the aortic arch must be taken into account, particularly in patients with hypertension and weak pulses in the lower extremities. We present a case of aortic arch interruption and a right subclavian artery aneurysm in a woman who survived to adulthood.

Surgical Repair of a Giant Right Atrium Aneurysm That was Incidentally Found in a Boy.

Giant right atrial aneurysms are rare defects with different clinical presentations ranging from lack of symptoms to heart failure. They are diagnosed based on incidental findings. It is commonly found when echocardiography or chest X-ray is performed. Concurrent congenital heart disease and large atrial size are risk factors that may increase the risks of complications such as thromboembolism, fatal arrhythmias, aneurysm rupture, and sudden death. The best treatment has been controversial, with some patients managed surgically and others conservatively. We present a case of a giant right atrium aneurysm that was incidentally detected during a routine examination. The patient underwent successful surgical resection of the right atrial aneurysm.

Incidentally Detected Asymptomatic Cardiac Myxoma in a Patient With COVID-19.

Primary cardiac tumors, such as myxomas, are rare. About 75% of myxomas occur in the left atrium of the heart. Myxomas can have a broad clinical spectrum. The clinical presentation varies from asymptomatic to sudden cardiac death. Sometimes, a diagnosis is difficult. Cardiac myxoma can cause hemodynamic disturbances in the setting of pneumonia and hypercoagulable state in patients with Coronavirus disease 2019(COVID-19) and make treatment decisions difficult. We present a case of unusually huge left atrial mass discovered incidentally in a patient with COVID-19. Upon workup, an echocardiogram revealed an incidental 7 × 5 cm left atrial myxoma. Preoperatively, the patient was monitored closely in the ICU. After stabilization in the ICU, the patient was taken to surgery and the tumor was successfully removed. Pathohistological results after surgical removal of the tumor confirmed the diagnosis of cardiac myxoma. We consider our case extremely rare due to the asymptomatic course despite the large size of the tumor.

Comparing the Effects of Gamification and Teach-Back Training Methods on Adherence to a Therapeutic Regimen in Patients After Coronary Artery Bypass Graft Surgery: Randomized Clinical Trial.

BACKGROUND: Patients undergoing coronary artery bypass graft surgery (CABGS) may fail to adhere to their treatment regimen for many reasons. Among these, one of the most important reasons for nonadherence is the inadequate training of such patients or training using inappropriate methods. OBJECTIVE: This study aimed to compare the effect of gamification and teach-back training methods on adherence to a therapeutic regimen in patients after CABGS. METHODS: This randomized clinical trial was conducted on 123 patients undergoing CABGS in Tehran, Iran, in 2019. Training was provided to the teach-back group individually. In the gamification group, an app developed for the purpose was installed on each patient's smartphone, with training given via this device. The control group received usual care, or routine training. Adherence to the therapeutic regimen was assessed using a questionnaire on adherence to a therapeutic regimen (physical activity and dietary regimen) and an adherence scale as a pretest and a 1-month posttest. RESULTS: One-way analysis of variance (ANOVA) for comparing the mean scores of teach-back and gamification training methods showed that the mean normalized scores for the dietary regimen (P<.001, F=71.80), movement regimen (P<.001, F=124.53), and medication regimen (P<.001, F=9.66) before and after intervention were significantly different between the teach-back, gamification, and control groups. In addition, the results of the Dunnett test showed that the teach-back and gamification groups were significantly different from the control group in all three treatment regimen methods. There was no statistically significant difference in adherence to the therapeutic regimen between the teach-back and control groups. CONCLUSIONS: Based on the results of this study, the use of teach-back and gamification training approaches may be suggested for patients after CABGS to facilitate adherence to the therapeutic regimen. TRIAL REGISTRATION: Iranian Registry of Clinical Trials IRCT20111203008286N8; https://en.irct.ir/trial/41507.

Huge Hydatid Cyst of the Right Ventricular Outflow Tract.

Hydatid disease is a common health problem in sheep-farming countries such as Iran. The liver and lungs are the most common primary sites of hydatid cysts in humans. Cardiac involvement is an uncommon manifestation, and the right ventricle outflow tract (RVOT) is rarely involved. This is a case report of a 34-year-old man who presented to the Heart Clinic, Tehran, Iran, in 2019 with a history of dyspnoea and fatigue. Following an imaging study, the patient was diagnosed with an RVOT hydatid cyst. He underwent surgical resection of the cyst. The post-operative course was uneventful.

Deep learning detects cardiotoxicity in a high-content screen with induced pluripotent stem cell-derived cardiomyocytes.

Drug-induced cardiotoxicity and hepatotoxicity are major causes of drug attrition. To decrease late-stage drug attrition, pharmaceutical and biotechnology industries need to establish biologically relevant models that use phenotypic screening to detect drug-induced toxicity in vitro. In this study, we sought to rapidly detect patterns of cardiotoxicity using high-content image analysis with deep learning and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We screened a library of 1280 bioactive compounds and identified those with potential cardiotoxic liabilities in iPSC-CMs using a single-parameter score based on deep learning. Compounds demonstrating cardiotoxicity in iPSC-CMs included DNA intercalators, ion channel blockers, epidermal growth factor receptor, cyclin-dependent kinase, and multi-kinase inhibitors. We also screened a diverse library of molecules with unknown targets and identified chemical frameworks that show cardiotoxic signal in iPSC-CMs. By using this screening approach during target discovery and lead optimization, we can de-risk early-stage drug discovery. We show that the broad applicability of combining deep learning with iPSC technology is an effective way to interrogate cellular phenotypes and identify drugs that may protect against diseased phenotypes and deleterious mutations.

A novel mutation in PRKAR1A gene in a patient with Carney complex presenting with pituitary macroadenoma, acromegaly, Cushing's syndrome and recurrent atrial myxoma

SUMMARY Carney complex (CNC) is a rare syndrome of multiple endocrine and non-endocrine tumors. In this paper we present a 23-year-old Iranian woman with CNC who harbored a novel mutation (c.642dupT) in PRKAR1A gene. This patient presented with pituitary macroadenoma, acromegaly, recurrent atrial myxoma, Cushing's syndrome secondary to primary pigmented nodular adrenocortical disease and pigmented schwanoma of the skin. PRKAR1A gene was PCR amplified using genomic DNA and analyzed for sequence variants which revealed the novel mutation resulting in substitution of amino acid cysteine instead of the naturally occurring valine in the peptide chain and a premature stop codon at position 18 (V215CfsX18). This change leads to development of tumors in different organs due to lack of tumor suppressive activity secondary to failure of synthesis of the related protein.

A novel mutation in PRKAR1A gene in a patient with Carney complex presenting with pituitary macroadenoma, acromegaly, Cushing's syndrome and recurrent atrial myxoma.

Carney complex (CNC) is a rare syndrome of multiple endocrine and non-endocrine tumors. In this paper we present a 23-year-old Iranian woman with CNC who harbored a novel mutation (c.642dupT) in PRKAR1A gene. This patient presented with pituitary macroadenoma, acromegaly, recurrent atrial myxoma, Cushing's syndrome secondary to primary pigmented nodular adrenocortical disease and pigmented schwanoma of the skin. PRKAR1A gene was PCR amplified using genomic DNA and analyzed for sequence variants which revealed the novel mutation resulting in substitution of amino acid cysteine instead of the naturally occurring valine in the peptide chain and a premature stop codon at position 18 (V215CfsX18). This change leads to development of tumors in different organs due to lack of tumor suppressive activity secondary to failure of synthesis of the related protein.

Iranian Society of Cardiac Surgeons COVID-19 task force version II, restarting elective surgeries.

Given the nature of heart disease and the importance of continuing heart surgery during the pandemic and its aftermath and in order to provide adequate safety for the surgical team and achieve the desired result for patients, as well as the optimal use of ICU beds, the medical team, blood, blood products, and personal protective equipment, it is essential to change the usual approach during the pandemic. There are still a lot of evidences and experiences needed to produce the perfect protocol. Some centers may have a special program for their centers during this period of epidemics that can be respected and performed. Generally, in pandemic conditions, the use of non-surgical approaches is preferred if similar outcomes can be obtained.

Quantifying drug-induced structural toxicity in hepatocytes and cardiomyocytes derived from hiPSCs using a deep learning method.

Cardiac and hepatic toxicity result from induced disruption of the functioning of cardiomyocytes and hepatocytes, respectively, which is tightly related to the organization of their subcellular structures. Cellular structure can be analyzed from microscopy imaging data. However, subtle or complex structural changes that are not easily perceived may be missed by conventional image-analysis techniques. Here we report the evaluation of PhenoTox, an image-based deep-learning method of quantifying drug-induced structural changes using human hepatocytes and cardiomyocytes derived from human induced pluripotent stem cells. We assessed the ability of the deep learning method to detect variations in the organization of cellular structures from images of fixed or live cells. We also evaluated the power and sensitivity of the method for detecting toxic effects of drugs by conducting a set of experiments using known toxicants and other methods of screening for cytotoxic effects. Moreover, we used PhenoTox to characterize the effects of tamoxifen and doxorubicin-which cause liver toxicity-on hepatocytes. PhenoTox revealed differences related to loss of cytochrome P450 3A4 activity, for which it showed greater sensitivity than a caspase 3/7 assay. Finally, PhenoTox detected structural toxicity in cardiomyocytes, which was correlated with contractility defects induced by doxorubicin, erlotinib, and sorafenib. Taken together, the results demonstrated that PhenoTox can capture the subtle morphological changes that are early signs of toxicity in both hepatocytes and cardiomyocytes.

Advancing physiological maturation in human induced pluripotent stem cell-derived cardiac muscle by gene editing an inducible adult troponin isoform switch.

Advancing maturation of stem cell-derived cardiac muscle represents a major barrier to progress in cardiac regenerative medicine. Cardiac muscle maturation involves a myriad of gene, protein, and cell-based transitions, spanning across all aspects of cardiac muscle form and function. We focused here on a key developmentally controlled transition in the cardiac sarcomere, the functional unit of the heart. Using a gene-editing platform, human induced pluripotent stem cell (hiPSCs) were engineered with a drug-inducible expression cassette driving the adult cardiac troponin I (cTnI) regulatory isoform, a transition shown to be a rate-limiting step in advancing sarcomeric maturation of hiPSC cardiac muscle (hiPSC-CM) toward the adult state. Findings show that induction of the adult cTnI isoform resulted in the physiological acquisition of adult-like cardiac contractile function in hiPSC-CMs in vitro. Specifically, cTnI induction accelerated relaxation kinetics at baseline conditions, a result independent of alterations in the kinetics of the intracellular Ca2+ transient. In comparison, isogenic unedited hiPSC-CMs had no cTnI induction and no change in relaxation function. Temporal control of adult cTnI isoform induction did not alter other developmentally regulated sarcomere transitions, including myosin heavy chain isoform expression, nor did it affect expression of SERCA2a or phospholamban. Taken together, precision genetic targeting of sarcomere maturation via inducible TnI isoform switching enables physiologically relevant adult myocardium-like contractile adaptations that are essential for beat-to-beat modulation of adult human heart performance. These findings have relevance to hiPSC-CM structure-function and drug-discovery studies in vitro, as well as for potential future clinical applications of physiologically optimized hiPSC-CM in cardiac regeneration/repair.

Huge Mediastinal Thymic Cyst in the Elderly Patient.

Mediastinal thymic cysts are uncommon lesions. Thymic cysts are usually diagnosed incidentally, and their origin could be congenital or acquired. Herein we present the case of a patient who presented with dyspnea. Chest computerized scan showed a large cystic mass. Surgical excision was performed. Pathology findings were consistent with congenital thymic cyst.

Right Atrial Diverticulum in an Adult Woman with Left Bundle Branch Block.

Right atrial diverticulum is a very rare anomaly. It is an outpouching arising from the right atrial free wall. Clinical presentations vary widely but some cases are associated with supraventricular tachycardia and atrial flutter/fibrillation. The incidence/prevalence of this anomaly is not available because only a few cases have been reported. We report a 38-year-old female patient who presented to the Heart Clinic, Tehran, Iran in 2019 with a history of dyspnea and chest pain. Electrocardiography revealed left bundle branch block. Following a magnetic resonance imaging study, the patient was diagnosed with a right atrial diverticulum. She underwent surgical resection of the diverticulum. The post-operative course was uneventful and no recurrence of the arrhythmia was detected during the six months of follow-up. To the best of the authors' knowledge, this combination has not been described in the literature.

Mitral valve-in-valve replacement supported by a transapically snared guidewire via septostomy.

We describe a 72-year-old woman, a known case of rheumatic heart disease with a history of mitral and aortic valve replacement 8 years previously, who underwent mitral valve-in-valve replacement supported by a transapically snared guidewire through septostomy.

Single-session double valve replacement: TAVI+tricuspid valve-in-valve procedures.

We describe a 70-year-old lady with rheumatic heart disease and a history of the mitral valve and tricuspid valve replacement, who underwent transcatheter aortic valve implantation and the tricuspid valve-in-valve procedure in a single session.