Current Perspectives of Mitochondria in Sepsis-Induced Cardiomyopathy.

Sepsis-induced cardiomyopathy (SICM) is one of the leading indicators for poor prognosis associated with sepsis. Despite its reversibility, prognosis varies widely among patients. Mitochondria play a key role in cellular energy production by generating adenosine triphosphate (ATP), which is vital for myocardial energy metabolism. Over recent years, mounting evidence suggests that severe sepsis not only triggers mitochondrial structural abnormalities such as apoptosis, incomplete autophagy, and mitophagy in cardiomyocytes but also compromises their function, leading to ATP depletion. This metabolic disruption is recognized as a significant contributor to SICM, yet effective treatment options remain elusive. Sepsis cannot be effectively treated with inotropic drugs in failing myocardium due to excessive inflammatory factors that blunt ß-adrenergic receptors. This review will share the recent knowledge on myocardial cell death in sepsis and its molecular mechanisms, focusing on the role of mitochondria as an important metabolic regulator of SICM, and discuss the potential for developing therapies for sepsis-induced myocardial injury.

Inhibition of Golgi stress alleviates sepsis-induced cardiomyopathy by reducing inflammation and apoptosis.

BACKGROUND: Sepsis is often accompanied by multiple organ dysfunction, in which the incidence of cardiac injury is about 60%, and is closely related to high mortality. Recent studies have shown that Golgi stress is involved in liver injury, kidney injury, and lung injury in sepsis. However, whether it is one of the key mechanisms of sepsis-induced cardiomyopathy (SIC) is still unclear. The aim of this study is to investigate whether Golgi stress mediates SIC and the specific mechanism. METHODS: Sepsis model of male C57BL/6J mice was established by cecal ligation and puncture. To observe the effect of Golgi stress on SIC, mice were injected with Golgi stimulant (Brefeldin A) or Golgi inhibitor (Glutathione), respectively. The 7-day survival rate of mice were recorded, and myocardial injury indicators including cardiac function, myocardial enzymes, myocardial pathological tissue score, myocardial inflammatory factors, and apoptosis were detected. The morphology of Golgi was observed by immunofluorescence, and the Golgi stress indices including GM-130, GOLPH3 and Goligin97 were detected by WB and qPCR. RESULTS: After CLP, the cardiac function of mice was impaired and the levels of myocardial enzymes were significantly increased. Golgi stress was accompanied by increased myocardial inflammation and apoptosis. Moreover, the expressions of morphological proteins GM-130 and Golgin97 were decreased, and the expression of stress protein GOLPH3 was increased. In addition, Brefeldin A increased 7-day mortality and the above indicators in mice. The use of glutathione improves all of the above indicators. CONCLUSION: Golgi stress mediates SIC, and the inhibition of Golgi stress can improve SIC by inhibiting apoptosis and inflammation.

Melatonin: A potential protective multifaceted force for sepsis-induced cardiomyopathy.

Sepsis is a life-threatening condition manifested by organ dysfunction caused by a dysregulated host response to infection. Lung, brain, liver, kidney, and heart are among the affected organs. Sepsis-induced cardiomyopathy is a common cause of death among septic patients. Sepsis-induced cardiomyopathy is characterized by an acute and reversible significant decline in biventricular both systolic and diastolic function. This is accompanied by left ventricular dilatation. The pathogenesis underlying sepsis-induced cardiomyopathy is multifactorial. Hence, targeting an individual pathway may not be effective in halting the extensive dysregulated immune response. Despite major advances in sepsis management strategies, no effective pharmacological strategies have been shown to treat or even reverse sepsis-induced cardiomyopathy. Melatonin, namely, N-acetyl-5-methoxytryptamine, is synthesized in the pineal gland of mammals and can also be produced in many cells and tissues. Melatonin has cardioprotective, neuroprotective, and anti-tumor activity. Several literature reviews have explored the role of melatonin in preventing sepsis-induced organ failure. Melatonin was found to act on different pathways that are involved in the pathogenesis of sepsis-induced cardiomyopathy. Through its antimicrobial, anti-inflammatory, and antioxidant activity, it offers a potential role in sepsis-induced cardiomyopathy. Its antioxidant activity is through free radical scavenging against reactive oxygen and nitrogen species and modulating the expression and activity of antioxidant enzymes. Melatonin anti-inflammatory activities control the overactive immune system and mitigate cytokine storm. Also, it mitigates mitochondrial dysfunction, a major mechanism involved in sepsis-induced cardiomyopathy, and thus controls apoptosis. Therefore, this review discusses melatonin as a promising drug for the management of sepsis-induced cardiomyopathy.

Long-Term Clinical-Pathologic Results of Enzyme Replacement Therapy in Prehypertrophic Fabry Disease Cardiomyopathy.

BACKGROUND: The limited ability of enzyme replacement therapy (ERT) in removing globotriaosylceramide from cardiomyocytes is recognized for advanced Fabry disease cardiomyopathy (FDCM). Prehypertrophic FDCM is believed to be cured or stabilized by ERT. However, no pathologic confirmation is available. We report here on the long-term clinical-pathologic impact of ERT on prehypertrophic FDCM. METHODS AND RESULTS: Fifteen patients with Fabry disease with left ventricular maximal wall thickness ≤10.5 mm at cardiac magnetic resonance required endomyocardial biopsy because of angina and ventricular arrhythmias. Endomyocardial biopsy showed coronary small-vessel disease in the angina cohort, and vacuoles in smooth muscle cells and cardiomyocytes ≈20% of the cell surface containing myelin bodies at electron microscopy. Patients received α-agalsidase in 8 cases, and ß-agalsidase in 7 cases. Both groups experienced symptom improvement except 1 patients treated with α-agalsidase and 1 treated with ß-agalsidase. After ERT administration ranging from 4 to 20 years, all patients had control cardiac magnetic resonance and left ventricular endomyocardial biopsy because of persistence of symptoms or patient inquiry on disease resolution. In 13 asymptomatic patients with FDCM, left ventricular maximal wall thickness and left ventricular mass, cardiomyocyte diameter, vacuole surface/cell surface ratio, and vessels remained unchanged or minimally increased (left ventricular mass increased by <2%) even after 20 years of observation, and storage material was still present at electron microscopy. In 2 symptomatic patients, FDCM progressed, with larger and more engulfed by globotriaosylceramide myocytes being associated with myocardial virus-negative lymphocytic inflammation. CONCLUSIONS: ERT stabilizes storage deposits and myocyte dimensions in 87% of patients with prehypertrophic FDCM. Globotriaosylceramide is never completely removed even after long-term treatment. Immune-mediated myocardial inflammation can overlap, limiting ERT activity.

Pretreatment with interleukin-15 attenuates inflammation and apoptosis by inhibiting NF-κB signaling in sepsis-induced myocardial dysfunction.

Sepsis-induced myocardial dysfunction (SIMD) is associated with poor prognosis and increased mortality in patients with sepsis. Cytokines are important regulators of both the initiation and progression of sepsis. Interleukin-15 (IL-15), a pro-inflammatory cytokine, has been linked to protective effects against myocardial infarction and myocarditis. However, the role of IL-15 in SIMD remains unclear. We established a mouse model of SIMD via cecal ligation puncture (CLP) surgery and a cell model of myocardial injury via lipopolysaccharide (LPS) stimulation. IL-15 expression was prominently upregulated in septic hearts as well as cardiomyocytes challenged with LPS. IL-15 pretreatment attenuated cardiac inflammation and cell apoptosis and improved cardiac function in the CLP model. Similar cardioprotective effects of IL-15 pretreatment were observed in vitro. As expected, IL-15 knockdown had the opposite effect on LPS-stimulated cardiomyocytes. Mechanistically, we found that IL-15 pretreatment reduced the expression of the pro-apoptotic proteins cleaved caspase-3 and Bax and upregulated the anti-apoptotic protein Bcl-2. RNA sequencing and Western blotting further confirmed that IL-15 pretreatment suppressed the activation of nuclear factor kappa B (NF-κB) signaling in mice with sepsis. Besides, the addition of NF-κB inhibitor can significantly attenuate cardiomyocyte apoptosis compared to the control findings. Our results suggest that IL-15 pretreatment attenuated the cardiac inflammatory responses and reduced cardiomyocyte apoptosis by partially inhibiting NF-κB signaling in vivo and in vitro, thereby improving cardiac function in mice with sepsis. These findings highlight a promising therapeutic strategy for SIMD.

Diagnosis and Management of Paroxysmal Supraventricular Tachycardia.

Importance: Paroxysmal supraventricular tachycardia (PSVT), defined as tachyarrhythmias that originate from or conduct through the atria or atrioventricular node with abrupt onset, affects 168 to 332 per 100 000 individuals. Untreated PSVT is associated with adverse outcomes including high symptom burden and tachycardia-mediated cardiomyopathy. Observations: Approximately 50% of patients with PSVT are aged 45 to 64 years and 67.5% are female. Most common symptoms include palpitations (86%), chest discomfort (47%), and dyspnea (38%). Patients may rarely develop tachycardia-mediated cardiomyopathy (1%) due to PSVT. Diagnosis is made on electrocardiogram during an arrhythmic event or using ambulatory monitoring. First-line acute therapy for hemodynamically stable patients includes vagal maneuvers such as the modified Valsalva maneuver (43% effective) and intravenous adenosine (91% effective). Emergent cardioversion is recommended for patients who are hemodynamically unstable. Catheter ablation is safe, highly effective, and recommended as first-line therapy to prevent recurrence of PSVT. Meta-analysis of observational studies shows single catheter ablation procedure success rates of 94.3% to 98.5%. Evidence is limited for the effectiveness of long-term pharmacotherapy to prevent PSVT. Nonetheless, guidelines recommend therapies including calcium channel blockers, ß-blockers, and antiarrhythmic agents as management options. Conclusion and Relevance: Paroxysmal SVT affects both adult and pediatric populations and is generally a benign condition. Catheter ablation is the most effective therapy to prevent recurrent PSVT. Pharmacotherapy is an important component of acute and long-term management of PSVT.

Cardiac Resolvin D2 ameliorates sepsis-induced cardiomyopathy via inhibiting Caspase-11/GSDMD dependent pyroptosis.

BACKGROUND: Sepsis-induced cardiomyopathy (SICM) is common complication in septic patients with a high mortality and is characterized by an abnormal inflammation response, which was precisely regulated by endogenous specialized pro-resolving mediators (SPMs). However, the metabolic changes of cardiac SPMs during SICM and the roles of SPMs subset in the development of SICM remain unknown. METHODS: In this work, the SPMs concentration was assessed using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) of SICM mice and SICM patients. The cardiac function was measured by echocardiography after the treatment of a SPMs subset, termed Resolvin D2 (RvD2). Caspase-11-/-, GSDMD-/- and double deficient (Caspase-11-/-GSDMD-/-) mice were used to clarify the mechanisms of RvD2 in SICM. RESULTS: We found that endogenous cardiac SPMs were disorders and RvD2 was decreased significantly and correlated with left ventricular ejection fraction (LVEF) and ß-BNP, cTnT in Lipopolysaccharide/Cecum ligation and puncture (CLP) induced SICM models. Treatment with RvD2 attenuated lethality, cardiac dysfunction and cardiomyocytes death during SICM. Mechanistically, RvD2 alleviated SICM via inhibiting Caspase-11/GSDMD-mediated cardiomyocytes pyroptosis. Finally, the plasma levels of RvD2 were also decreased and significantly correlated with IL-1ß, ß-BNP, cTnT and LVEF in patients with SICM. Of note, plasma RvD2 level is indicator of SICM patients from healthy controls or sepsis patients. CONCLUSION: These findings suggest that decreased cardiac RvD2 may involve in the pathogenesis of SICM. In addition, treatment with RvD2 represents a novel therapeutic strategy for SICM by inhibiting cardiomyocytes pyroptosis.

Presence and utility of electrocardiographic abnormalities in long-term childhood cancer survivors.

BACKGROUND: We assessed the prevalence and diagnostic value of ECG abnormalities for cardiomyopathy surveillance in childhood cancer survivors. METHODS: In this cross-sectional study, 1381 survivors (≥5 years) from the Dutch Childhood Cancer Survivor Study part 2 and 272 siblings underwent a long-term follow-up ECG and echocardiography. We compared ECG abnormality prevalences using the Minnesota Code between survivors and siblings, and within biplane left ventricular ejection fraction (LVEF) categories. Among 880 survivors who received anthracycline, mitoxantrone or heart radiotherapy, logistic regression models using least absolute shrinkage and selection operator identified ECG abnormalities associated with three abnormal LVEF categories (<52% in male/<54% in female, <50% and <45%). We assessed the overall contribution of these ECG abnormalities to clinical regression models predicting abnormal LVEF, assuming an absence of systolic dysfunction with a <1% threshold probability. RESULTS: 16% of survivors (52% female, mean age 34.7 years) and 14% of siblings had major ECG abnormalities. ECG abnormalities increased with decreasing LVEF. Integrating selected ECG data into the baseline model significantly improved prediction of sex-specific abnormal LVEF (c-statistic 0.66 vs 0.71), LVEF <50% (0.66 vs 0.76) and LVEF <45% (0.80 vs 0.86). While no survivor met the preset probability threshold in the first two models, the third model used five ECG variables to predict LVEF <45% and was applicable for ruling out (sensitivity 93%, specificity 56%, negative predictive value 99.6%). Calibration and internal validation tests performed well. CONCLUSION: A clinical prediction model with ECG data (left bundle branch block, left atrial enlargement, left heart axis, Cornell's criteria for left ventricular hypertrophy and heart rate) may aid in ruling out LVEF <45%.

Cardiac Amyloidosis Due to Transthyretin Protein: A Review.

Importance: Systemic amyloidosis from transthyretin (ATTR) protein is the most common type of amyloidosis that causes cardiomyopathy. Observations: Transthyretin (TTR) protein transports thyroxine (thyroid hormone) and retinol (vitamin A) and is synthesized predominantly by the liver. When the TTR protein misfolds, it can form amyloid fibrils that deposit in the heart causing heart failure, heart conduction block, or arrhythmia such as atrial fibrillation. The biological processes by which amyloid fibrils form are incompletely understood but are associated with aging and, in some patients, affected by inherited variants in the TTR genetic sequence. ATTR amyloidosis results from misfolded TTR protein deposition. ATTR can occur in association with normal TTR genetic sequence (wild-type ATTR) or with abnormal TTR genetic sequence (variant ATTR). Wild-type ATTR primarily manifests as cardiomyopathy while ATTR due to a genetic variant manifests as cardiomyopathy and/or polyneuropathy. Approximately 50 000 to 150 000 people in the US have heart failure due to ATTR amyloidosis. Without treatment, heart failure due to ATTR amyloidosis is associated with a median survival of approximately 5 years. More than 130 different inherited genetic variants in TTR exist. The most common genetic variant is Val122Ile (pV142I), an allele with an origin in West African countries, that is present in 3.4% of African American individuals in the US or approximately 1.5 million persons. The diagnosis can be made using serum free light chain assay and immunofixation electrophoresis to exclude light chain amyloidosis combined with cardiac nuclear scintigraphy to detect radiotracer uptake in a pattern consistent with amyloidosis. Loop diuretics, such as furosemide, torsemide, and bumetanide, are the primary treatment for fluid overload and symptomatic relief of patients with ATTR heart failure. An ATTR-directed therapy that inhibited misfolding of the TTR protein (tafamidis, a protein stabilizer), compared with placebo, reduced mortality from 42.9% to 29.5%, reduced hospitalizations from 0.7/year to 0.48/year, and was most effective when administered early in disease course. Conclusions and Relevance: ATTR amyloidosis causes cardiomyopathy in up to approximately 150 000 people in the US and tafamidis is the only currently approved therapy. Tafamidis slowed progression of ATTR amyloidosis and improved survival and prevented hospitalization, compared with placebo, in people with ATTR-associated cardiomyopathy.

Supporting Role of Adequate Affected Tissue Biopsy in the Diagnostic Algorithm for Cardiac Amyloidosis.

Amyloidosis is a pathology that occurs as a result of the accumulation of various misfolded proteins in the extracellular space. It is a significant cause of morbidity and mortality due to multi-organ involvement. One of the most important determinants of mortality and morbidity is cardiac involvement. Cardiac amyloidosis (CA) may present with a variety of clinical findings. In this article, we aim to demonstrate the supportive role of cardiac and extra-cardiac tissue in the routine diagnostic pathway for CA.

Case report: Systemic lupus erythematosus combined with myocardial hypertrophy.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a multisystem-involved, highly heterogeneous autoimmune disease with diverse clinical manifestations. We report an extremely rare case of SLE with severe diffuse myocardial hypertrophy. METHODS: The patient's echocardiography and cardiac magnetic resonance imaging (CMR) results indicated diffuse myocardial hypertrophy. After excluding coronary atherosclerosis, hypertensive cardiomyopathy, drug toxicity, and other causes, the patient was diagnosed with SLE-specific cardiomyopathy. Medications such as hormones, antimalarials, immunosuppressants, and biologics were administered. RESULTS: Ancillary test results were as follows: hs-cTnI: 0.054 ng/mL (0-0.016); NTproBNP: 1594.0 pg/mL (<150); A contrast-enhanced CMR revealed the diffuse thickening of the left ventricular wall with multiple abnormal enhancements, reduced left ventricular systolic and diastolic function, and moderate amount of pericardial effusion. Endomyocardial myocardial biopsy was performed, showing cardiomyocyte hypertrophy and degeneration, and no changes in myocarditis or amyloidosis. The pathology viewed by electron microscopy showed increased intracellular glycogen in the myocardium, and no hydroxychloroquine-associated damage in the myocardium. The 24-h ambulatory blood pressure and contrast-enhanced computed tomography of coronary arteries were normal. The diagnosis of SLE-specific cardiomyopathy was clear. The myocardial hypertrophy showed reversible alleviation following treatment with high-dose corticosteroids. CMR results before and after treatment were as follows: interventricular septum, pretreatment (28) versus post-treatment (22) mm; left ventricular inferior wall, pretreatment (18-21) versus post-treatment (12-14) mm; left ventricular lateral wall, pretreatment (17-18) versus post-treatment (10-12) mm; pericardial effusion (left ventricular lateral wall), pretreatment (25) versus post-treatment (12) mm; left ventricular ejection fraction, pretreatment (38.9%) versus post-treatment (66%). CONCLUSION: Myocardial hypertrophy may be an important sign of active and prognostic assessment in SLE diagnosis and management. Similarly, when encountering cases of myocardial hypertrophy, the possibility of autoimmune disease should be considered in addition to common causes.

Prevalence and risk factors for cirrhotic cardiomyopathy: a prospective cross-sectional study.

BACKGROUND: This study aimed to assess cardiac structure and function in patients with cirrhosis, to investigate the prevalence of cirrhotic cardiomyopathy (CCM) in patients with cirrhosis of different etiologies and to analyze the risk factors for the development of CCM. METHODS: This study selected cirrhotic patients aged 18-75 years who were hospitalized in Qilu Hospital of Shandong University. Patients with known heart disease, chronic lung disease, severe renal insufficiency, malignancy, thyroid disease, hypertension, diabetes or pregnancy were excluded. A total of 131 patients with cirrhosis were finally included. Based on the results of echocardiography, patients who met the diagnostic definition of CCM were included in the CCM group, otherwise, they were classified as the non-CCM group. The demographic and clinical data of the two groups were compared, and the clinical characteristics and risk factors of CCM were evaluated. RESULTS: The overall prevalence of CCM was 24.4%, and the occurrence of CCM was not related to the etiology of liver cirrhosis. The prevalence of CCM was significantly higher among cirrhotic patients complicated with ascites (31.4% vs. 16.4%; P  = 0.046) or with portal vein thrombosis (PVT) (42.9% vs. 17.1%; P  = 0.003). Older age [odds ratio (OR) = 1.058; 95% confidence interval (CI), 1.005-1.113; P  = 0.032] and PVT (OR = 2.999; 95% CI, 1.194-7.533; P  = 0.019) were independent risk factors for the development of CCM. CONCLUSION: The prevalence of CCM in cirrhotic patients was 24.4%, and the occurrence of CCM was not related to the etiology of cirrhosis. The prevalence of CCM was higher in cirrhotic patients with ascites or PVT. Older age and PVT are independent risk factors for CCM, but validation in larger sample studies is still needed.

Staged therapeutic surgery for progressive pulmonary regurgitation and pacemaker induced cardiomyopathy after the tetralogy of fallot repair.

BACKGROUND: Recently, improvements in the repair of tetralogy of Fallot have increased the need for reoperation in adulthood, and it's not rare that these reoperation candidates suffer from biventricular failure. However, there are no firm treatment guidelines, and each country, and even each facility, treats each case individually. CASE PRESENTATION: We report the successful staged treatment of pulmonary regurgitation and pacemaker-induced cardiomyopathy with biventricular failure in adulthood in a case of complete atrioventricular block after tetralogy of Fallot repair in childhood. We planned a staged therapeutic strategy with preoperative left ventricular volume reduction with medication, following surgical pulmonary valve replacement concomitant epicardial lead implantation on the lateral basal wall, placed just beneath the generator pocket through 3rd intercostal space. in addition to postoperative intervention with a defibrillator to adjust cardiac resynchronization therapy, resulted in improvement of symptoms. CONCLUSION: In a patient with biventricular failure after TOF repair, a staged treatment strategy involving medication, PVR, and CRT with a combination of epicardial and intravenous leads could be a useful treatment worth trying before heart transplantation.

[Incidence and causes of hospitalization in patients with transthyretin (ATTR-CA) and light chain (AL-CA) cardiac amyloidosis]. / Incidencia y causas de hospitalización en pacientes con amiloidosis cardiaca por transtiretina (AC-ATTR) y por cadenas ligeras (AC-AL).

INTRODUCTION AND OBJETIVES: Cardiac amyloidosis (CA) is a disorder associated with high number of hospital admissions. Given the scarce information available, we propose an analysis of the incidence and causes of hospitalization in this disease. MATERIAL AND METHODS: One hundred and forty-three patients [128 by transthyretin (ATTR-CA) and 15 by light chains (AL-CA)] included in Registro de Amiloidosis Cardiaca de Galicia (AMIGAL) were evaluated, including all hospitalizations. RESULTS: During a median follow-up of 959 days there were 179 unscheduled hospitalizations [incidence rate (IR) 512.6 admissions per 1000 patients-year], most common due to cardiovascular reasons (n=109, IR 312.2). Most frequent individual cause of hospitalization was heart failure (n=87, TI 249.2). AL-CA was associated with a higher IR of unscheduled hospitalizations than ATTR-CA (IR 781 vs. 483.2; HR 1.62; p=0,029) due to non-cardiovascular admissions (IR 376 vs. 181.2; HR 2.07; p=0.027). Unscheduled admission-free survival at 1 and 3 years in AL-CA was inferior than in ATTR-CA (46.7% and 20.0% vs. 73.4% and 35.2%, respectively; p=0.021). CONCLUSIONS: CA was associated with high incidence of hospitalizations, being heart failure the most frequent individual cause; unscheduled admission-free survival in AL-CA was lower than in ATTR-CA due mostly to non-cardiovascular admissions.

Cardiac events in newly diagnosed acute myeloid leukaemia during treatment with venetoclax + hypomethylating agents.

Among 301 newly diagnosed patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent, 23 (7.6%) experienced major cardiac complications: 15 cardiomyopathy, 5 non-ST elevation myocardial infarction and/or 7 pericarditis/effusions. Four patients had more than one cardiac complication. Baseline characteristics included median age ± interquartile range; 73 ± 5 years; 87% males; 96% with cardiovascular risk factors; and 90% with preserved baseline ejection fraction. In multivariate analysis, males were more likely (p = 0.02) and DNMT3A-mutated cases less likely (p < 0.01) to be affected. Treatment-emergent cardiac events were associated with a trend towards lower composite remission rates (43% vs. 62%; p = 0.09) and shorter survival (median 7.7 vs. 13.2 months; p < 0.01). These observations were retrospectively retrieved and warrant further prospective examination.

Transthyretin-derived amyloid (ATTR) and sarcoidosis: Does ATTR deposition cause a granulomatous inflammatory response in older adults with sarcoidosis?

This study aimed to assess the frequency and association between transthyretin-derived (ATTR) amyloidosis and sarcoidosis in a large autopsy cohort including many cases of sudden cardiac death (SCD). We identified 73 sporadic ATTR amyloidosis cases and 11 sarcoidosis cases, among which we found two cases with concomitant ATTR amyloidosis and sarcoidosis (2.4% of all cases; 2.7% within the sporadic ATTR group). The first case involved a 92-year-old man who experienced SCD. In this patient's heart, we observed ATTR deposition and noncaseating epithelioid granulomas consistent with sarcoidosis. Focally, ATTR deposits and granulomas co-localized, with histiocyte phagocytosis of transthyretin-immunoreactive fragments. However, in most lesions, they were distributed independently. The second case was that of an 86-year-old woman who also experienced SCD. In this patient, we detected ATTR deposition in the heart and lung, while noncaseating epithelioid granulomas were only observed in the lung, liver, kidney, and thyroid. Furthermore, no co-localization of the two lesions was observed. Based on these findings, we concluded that the coexistence of ATTR amyloidosis and sarcoidosis was likely coincidental. Nevertheless, despite the rarity of the combination of these two diseases, it should be recognized as a potential cause of SCD, especially among elderly people.

Hematopoietic Prostaglandin D Synthase Is Increased in Mast Cells and Pericytes in Autopsy Myocardial Specimens from Patients with Duchenne Muscular Dystrophy.

The leading cause of death for patients with Duchenne muscular dystrophy (DMD), a progressive muscle disease, is heart failure. Prostaglandin (PG) D2, a physiologically active fatty acid, is synthesized from the precursor PGH2 by hematopoietic prostaglandin D synthase (HPGDS). Using a DMD animal model (mdx mice), we previously found that HPGDS expression is increased not only in injured muscle but also in the heart. Moreover, HPGDS inhibitors can slow the progression of muscle injury and cardiomyopathy. However, the location of HPGDS in the heart is still unknown. Thus, this study investigated HPGDS expression in autopsy myocardial samples from DMD patients. We confirmed the presence of fibrosis, a characteristic phenotype of DMD, in the autopsy myocardial sections. Additionally, HPGDS was expressed in mast cells, pericytes, and myeloid cells of the myocardial specimens but not in the myocardium. Compared with the non-DMD group, the DMD group showed increased HPGDS expression in mast cells and pericytes. Our findings confirm the possibility of using HPGDS inhibitor therapy to suppress PGD2 production to treat skeletal muscle disorders and cardiomyopathy. It thus provides significant insights for developing therapeutic drugs for DMD.

Breakthrough advances enhancing care in ATTR amyloid cardiomyopathy.

Transthyretin amyloid cardiomyopathy (ATTR-CM) has been traditionally considered a rare and inexorably fatal condition. ATTR-CM now is an increasingly recognized cause of heart failure (HF) and mortality worldwide with effective pharmacological treatments. Advances in non-invasive diagnosis, coupled with the development of effective treatments, have transformed the diagnosis of ATTR-CM, which is now possible without recourse to endomyocardial biopsy in ≈70 % of cases. Many patients are now diagnosed at an earlier stage. Echocardiography and cardiac magnetic resonance have enabled identification of patients with possible ATTR-CM and more accurate prognostic stratification. Although radionuclide scintigraphy with 'bone' tracers has an established diagnostic value, the diagnostic performance of the bone tracers validated for non-invasive confirmation of ATTR-CM may not be equal. Characterising the wider clinical phenotype of patients with ATTR-CM has enabled identification of features with potential for earlier diagnosis such as carpal tunnel syndrome. Therapies able to slow or halt ATTR-CM progression and increase survival are now available and there is also evidence that patients may benefit from specific conventional HF medications. Cutting-edge research in the field of antibody-mediated removal of ATTR deposits compellingly suggest that ATTR-CM is a truly reversible disorder, bringing hope for patients even with advanced disease. A wide horizon of possibilities is unfolding and awaits discovery.