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The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of international experts to discuss new research opportunities for the prevention, detection, and intervention of myocarditis in May 2021. These experts reviewed the current state of science and identified key gaps and opportunities in basic, diagnostic, translational, and therapeutic frontiers to guide future research in myocarditis. In addition to addressing community-acquired myocarditis, the workshop also focused on emerging causes of myocarditis including immune checkpoint inhibitors and SARS-CoV-2 related myocardial injuries and considered the use of systems biology and artificial intelligence methodologies to define workflows to identify novel mechanisms of disease and new therapeutic targets. A new priority is the investigation of the relationship between social determinants of health (SDoH), including race and economic status, and inflammatory response and outcomes in myocarditis. The result is a proposal for the reclassification of myocarditis that integrates the latest knowledge of immunological pathogenesis to refine estimates of prognosis and target pathway-specific treatments. [ABSTRACT FROM AUTHOR]

Background: Currently, the success rate of EVT for treating CTO of the SFA is high; however, EVT is still found to be insufficient in treating CTOs with severely calcified lesions. Even if the guidewire crosses the lesion, the calcifications may still cause difficulties during stent expansion. Main text: A 78-year-old male had been reported to have intermittent claudication with chronic total occlusion (CTO) of the right superficial femoral artery (SFA). Angiography revealed severely calcified plaque (Angiographic calcium score: Group4a [1]) at the ostium of the SFA. Stenting posed a risk of underexpansion, causing the plaque to shift to the deep femoral artery. we decided to remove the calcified plaque using biopsy forceps. After removing the extended calcified plaque, the guidewire could cross easily, and the self-expandable stent was well dilated without causing the plaque to shift to the DFA. Conclusions: Biopsy forceps may be used in some endovascular cases to remove severely calcified lesions. To ensure the safety of the patient, the physician must be adept at performing this technique before attempting it. [ABSTRACT FROM AUTHOR]

Aims: Patients undergoing dialysis, even those without coronary artery disease or valvular abnormalities, sometimes present with reduced heart function, which resembles dilated cardiomyopathy (DCM). This condition is known as uraemic cardiomyopathy (UCM). The mechanisms of UCM development are not fully understood. Previous studies demonstrated that the balance between placental growth factor (PlGF) and fms‐like tyrosine kinase‐1 (Flt‐1) is correlated with renal function, and PlGF/Flt‐1 signalling is involved in the development of cardiovascular diseases in patients with chronic kidney disease. This study was conducted to evaluate the pathogenesis of UCM and clarify the differences in the mechanisms of UCM and DCM by using human endomyocardial biopsy and blood samples. Methods and results: The clinical and pathological features of 30 patients on dialysis with reduced cardiac function [left ventricular ejection fraction (LVEF) ≤50%] (UCM group; mean age: 58.5 ± 9.4 years and LVEF: 39.1 ± 7.2%), 196 DCM patients (DCM group; mean age: 62.7 ± 14.0 years and LVEF: 33.5 ± 8.8%) as controls with reduced cardiac function (LVEF ≤ 45%), and 21 patients as controls with normal cardiac function (control group; mean age: 56.2 ± 19.3 years and LVEF: 67.5 ± 6.7%) were analysed. The percentage of the interstitial fibrosis area in the UCM group was greater than that in the DCM group (P = 0.045). In UCM patients, the percentage of the interstitial fibrosis area was positively correlated with the duration of renal replacement therapy (P < 0.001). The number of infiltrated CD68‐positive macrophages in the myocardium and expression of monocyte chemoattractant protein‐1 (MCP‐1) in cardiomyocytes were significantly greater in the UCM group than in the other groups (P < 0.001, respectively). Furthermore, while the serum level of soluble form of Flt‐1, an endogenous inhibitor of PlGF, in the UCM group was lower compared with that in the DCM group (P < 0.001), the serum levels of PlGF and PlGF/soluble form of Flt‐1 ratio and plasma level of MCP‐1 in the UCM group were higher than those in the DCM group (P < 0.001, respectively). Conclusions: These results suggest that activated PlGF/Flt‐1 signalling and subsequent macrophage‐mediated chronic non‐infectious inflammation via MCP‐1 in the myocardium are involved in the pathogenesis of UCM. [ABSTRACT FROM AUTHOR]

Background Endomyocardial biopsy (EMB) remains the gold standard for cellular rejection surveillance in heart transplant recipients. Coronary artery fistula formation is a rare late and potentially catastrophic complication of repeated endomyocardial biopsies, without contemporary evidence on incidence or management. Case summary A 47-year-old male was found to have a fistula between his right ventricle and his left anterior descending artery on an angiogram that was performed as a part of regular screening of coronary allograft vasculopathy. Given the low shunt fraction, asymptomatic nature, and lack of guidelines on definitive management, the patient is undergoing conservative management with regular surveillance. Discussion Coronary artery fistulas were once thought to be rare complications of repeated EMB, but the true prevalence is likely to be higher than previously believed. Ideal treatment and monitoring is unknown given the relative rarity of the condition. [ABSTRACT FROM AUTHOR]

Background Danon disease is an X-linked dominant disorder with defects in the lysosome-associated membrane protein 2 (LAMP2) gene and is characterized histologically by intracellular autophagic vacuoles in skeletal and cardiac muscles. Cardiac magnetic resonance (CMR) T1 mapping potentially allows to differentiate intracellular and extracellular cardiac abnormalities with a combination of native T1 value and extracellular volume (ECV) fraction. Case summary We assessed CMR T1 mapping in two Danon disease patients (a 22-year-old man and his 48-year-old mother), who had a LAMP2 c.864G>A p. Val288Val mutation, and two blood relatives without Danon disease (his 47-year-old maternal aunt and 49-year-old father). The male patient underwent a left ventricular (LV) assist device implantation at 15 months after the image acquisition because he was inotrope dependent (INTERMACS profile 3) and had no noticeable psychological or musculoskeletal symptoms. His mother was in New York Heart Association Class II with mildly reduced LV ejection fraction (46%). The Danon group showed late gadolinium enhancement (LGE) in the anterior and posterolateral LV walls. In the interventricular wall, where evident LGE was not noted, the Danon group had high native T1 value, compared with the T1 value in the non-Danon group, and normal ECV fraction. Cardiac biopsy from the interventricular wall showed intracytoplasmic autophagic vacuoles, which are characteristics of Danon disease. Discussion This characteristic pattern of high native T1 and normal ECV fraction in the areas without LGE, which may reflect the existence of intracytoplasmic autophagic vacuoles, may support the differential diagnosis of Danon disease from other cardiomyopathies. [ABSTRACT FROM AUTHOR]

The role of immunosuppressive therapy (IT) in paediatric autoimmune/immune‐mediated myocarditis remains poorly defined. To explore its role, we present a series of three consecutive paediatric patients with biopsy‐proven, virus negative, autoimmune/immune‐mediated myocarditis, with distinct clinical and pathological features, who have been successfully treated with IT, a 14‐year‐old boy with Loeffler's fibroblastic parietal endomyocarditis, a 6‐year‐old child with celiac disease with chronic active lymphocytic myocarditis, and a 13‐year‐old boy with long‐standing heart failure and active lymphocytic myocarditis. Patients started IT and entered follow‐up between July 2017 and September 2019; the first patient completed IT. IT was associated with a substantial and sustained recovery of cardiac function in our patients, regardless of their heterogeneous clinical and pathological features. Combination IT was well tolerated and enabled tapering and weaning off steroids. [ABSTRACT FROM AUTHOR]

Aims: Limited data are available regarding cardiac expression of molecules involved in heart failure (HF) pathophysiology. The majority of the studies have focused on end‐stage HF with reduced ejection fraction (HFrEF) without comparison with healthy subjects, while no data are available with regard to HF with preserved ejection fraction (HFpEF). HFpEF is a condition whose multiple pathophysiological mechanisms are still not fully defined, with many proposed hypotheses remaining speculative due to limited access to human heart tissue. This study aimed at evaluating cardiac expression levels of key genes of interest in human biopsy samples from patients affected with HFrEF and HFpEF in order to possibly point out distinct phenotypes. Methods and results: Total RNA was extracted from left ventricular cardiac biopsies collected from stable patients with HFrEF (n = 6) and HFpEF (n = 7) and healthy subjects (n = 9) undergoing elective cardiac surgery for valvular replacement, mitral valvuloplasty, aortic surgery, or coronary artery bypass. Real‐time PCR was performed to evaluate the mRNA expression levels of genes involved in somatotropic axis regulation [IGF‐1, IGF‐1 receptor (IGF‐1R), and GH receptor (GHR)], in adrenergic signalling (GRK2, GRK5, ADRB1, and ADRB2), in myocardial calcium handling (SERCA2), and in TNF‐α. Patients with HFrEF and HFpEF showed reduced serum IGF‐1 circulating levels when compared with controls (102 ± 35.6, 138 ± 11.5, and 160 ± 13.2 ng/mL, P < 0.001, respectively). At myocardial level, HFrEF showed significant decreased GHR and increased IGF‐1R expressions when compared with HFpEF and controls (0.54 ± 0.27, 0.94 ± 0.25, and 0.84 ± 0.2, P < 0.05 and 1.52 ± 0.9, 1.06 ± 0.21, and 0.72 ± 0.12, P < 0.05, respectively), while no differences in the local expression of IGF‐1 mRNA were detected among the groups (0.80 ± 0.45, 0.97 ± 0.18, and 0.63 ± 0.23, P = 0.09, respectively). With regard to calcium handling and adrenergic signalling, HFrEF displayed significant decreased levels of SERCA2 (0.19 ± 0.39, 0.82 ± 0.15, and 0.87 ± 0.32, P < 0.01) and increased levels of GRK2 (3.45 ± 2.94, 0.93 ± 0.12, and 0.80 ± 0.14, P < 0.01) and GRK5 (1.32 ± 0.70, 0.71 ± 0.14, and 0.77 ± 0.15, P < 0.05), while no significant difference was found in ADRB1 (0.66 ± 0.4, 0.83 ± 0.3, and 0.86 ± 0.4) and ADRB2 mRNA expression (0.65 ± 0.3, 0.66 ± 0.2, and 0.68 ± 0.1) when compared with HFpEF and controls. Finally, no changes in the local expression of TNF‐α were detected among groups. Conclusions: Heart failure with reduced ejection fraction and HFpEF patients with stable clinical condition display a distinct molecular milieu of genes involved in somatotropic axis regulation, calcium handling, and adrenergic derangement at a myocardial level. The unique opportunity to compare these results with a control group, as reference population, may contribute to better understand HF pathophysiology and to identify novel potential therapeutic targets that could be modulated to improve ventricular function in patients with HF. [ABSTRACT FROM AUTHOR]

Aims: Cardiac scintigraphy, a non‐invasive technique for diagnosing ATTR cardiac amyloidosis, lacks specificity in patients with concomitant monoclonal gammopathy (up to 40% of cases). For these patients, amyloid type is often established by endomyocardial biopsy (EMB), which has clinical risk. This study aimed to investigate the frequency of ATTR in amyloid‐positive tendon/synovium, urinary bladder, and prostate biopsies, sites for which prior biopsy specimens might exist for patients suspected of having cardiac amyloidosis, and, when available, determine the amyloid type concordance rate with other anatomic sites and provide clinical data regarding subsequent development of cardiac amyloidosis. Methods and results: We queried our reference laboratory database of 19,298 amyloid specimens from myriad anatomic sites typed by mass spectrometry‐based proteomics (LC‐MS/MS) to investigate the frequency of ATTR amyloid in tendon/synovium, urinary bladder, and prostate. The amyloid type was ATTR in 104/138 (75.4%) tendon/synovium, 173/453 (38.0%) urinary bladder, and 27/81 (33.3%) prostate samples. Of 62 patients with available clinical data, 12 (19%) had bona fide ATTR cardiac amyloidosis prior to/concomitant with the non‐cardiac site biopsy. Of the remaining 14 with follow‐up, 8 developed bona fide and 2 probable cardiac amyloidosis; at last follow‐up 4 had no evidence of cardiac amyloidosis. Fourteen of 16 patients (87.5%) for whom we typed both non‐cardiac and cardiac sites had concordant amyloid types. There were 2 discordant cases (prostate = ASem1/heart = AL and urinary bladder = AL/heart = ATTR); only the latter is potentially clinically consequential. Conclusions: In patients suspected of having cardiac amyloidosis based on cardiac scintigraphy, LC‐MS/MS typing of Congophilic deposits in pre‐existing biopsy specimens from non‐cardiac sites may help establish the cardiac amyloid type, obviating the need for EMB. However, if the amyloid type identified in the non‐cardiac site is not in keeping with other clinical features, then EMB for typing the cardiac amyloid might be indicated. [ABSTRACT FROM AUTHOR]

Aims: With the present study, we sought to determine the safety of three different endomyocardial biopsy (EMB) access routes in 514 patients admitted for diagnostic workup of heart failure of unknown aetiology. Methods and results: In this retrospective monocentric cohort study, we analysed 514 consecutive patients with heart failure without evidence of significant coronary artery disease or valvular disease undergoing EMB between November 2013 and December 2018, stratified in three access route groups: transradial arterial left ventricular (LV‐)EMB (323 patients), transfemoral LV‐EMB (138 patients), and transfemoral right ventricular (RV‐)EMB (53 patients). Patients undergoing selective transradial LV‐EMB were older compared with patients undergoing selective transfemoral LV‐EMB or RV‐EMB [transradial LV‐EMB: 56.0 (45.0/64.0) vs. transfemoral LV‐EMB: 53 (42.5/64.5), P = 0.455; transradial LV‐EMB: 56 (45.0/64.0) vs. RV‐EMB: 53 (42.5/64), P = 0.695] and presented more often in New York Heart Association‐functional class III and IV. A total of eight major complications including permanent atrioventricular block requiring pacemaker implantation, pericardial tamponade necessitating pericardiocentesis, stroke and transient cerebral ischaemic attack as well as severe valvular damage, vascular access site complications, and ventricular fibrillation were documented with no significant differences between the groups (8/514, 1.5%). Minor complications such as transient chest pain, non‐sustained electrocardiogram abnormalities, and transient atrioventricular block were rare and equally distributed between groups. Conclusions: Transradial LV‐EMB is a safe procedure for experienced radial operators and non‐inferior compared with transfemoral LV‐EMB and RV‐EMB. An accurate peri‐procedural and post‐procedural monitoring and follow‐up care should be recommended for all patients undergoing this procedure in order to identify potential complications. [ABSTRACT FROM AUTHOR]

Background Cardiac amyloidosis, a progressive cardiac disease, results from the accumulation of undegraded proteinaceous substrates in the extracellular matrix of the heart. It may present as acute coronary syndrome (ACS); therefore, a clear distinction remains challenging in clinical practice. We describe a case of cardiac amyloidosis mimicking ACS. Case summary A 72-year-old man experienced chest discomfort for 2 days. He gradually developed dyspnoea during the preceding month. Electrocardiogram (ECG) showed sinus rhythm with right bundle branch block and low voltage. Echocardiography revealed concentric left ventricular thickening, biatrial dilation, and preserved ejection fraction with predominantly left ventricular basal hypokinesis. Serial testing of the cardiac biomarkers showed persistently increased high-sensitive cardiac troponin T levels and normal serum creatine kinase myocardial band levels. He was diagnosed with ACS with haemodynamic stability. However, coronary angiography demonstrated non-obstructive coronary arteries. Furthermore, significant macroglossia and periorbital purpura were noticed. Laboratory investigations revealed elevated serum immunoglobulin free light chain (FLC) kappa and lambda levels with an increased FLC ratio. Histological analysis of the biopsied abdominal skin confirmed amyloidosis. Discussion Cardiac amyloidosis often presents as restrictive cardiomyopathy. The usual symptoms include dyspnoea and peripheral oedema. Chest pain may manifest rarely, leading to misdiagnosis as coronary artery disease. Some findings suggestive of cardiac amyloidosis include clinical signs such as amyloid deposits, dyspnoea, low ECG voltage, and basal-predominant hypokinesis with relative apical sparing in echocardiography. Serum FLC test and abdominal skin biopsy can confirm the diagnosis of amyloidosis when a myocardial biopsy is not feasible. [ABSTRACT FROM AUTHOR]

We designed this study to identify potential key protein interaction networks, genes, and correlated pathways in dilated cardiomyopathy (DCM) via bioinformatics methods. We selected the GSE3586 microarray dataset, consisting of 15 dilated cardiomyopathic heart biopsy samples and 13 nonfailing heart biopsy samples. Initially, the GSE3586 dataset was downloaded and was analyzed with the limma package to identify differentially expressed genes (DEGs). A total of 172 DEGs consisting of 162 upregulated genes and ten downregulated genes in DCM were selected by the criterion of adjusted P values less than 0.01 and the log2-fold change of 0.6 or greater. Gene Ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to view the biological processes, cellular components, molecular function, and KEGG pathways of the DEGs. Next, protein-protein interactions were constructed, and the hub protein modules were identified. Then we selected the key genes DLD, UQCRC2, DLAT, SUCLA2, ATP5A1, PRDX3, FH, SDHD, and NDUFV1, which are involved in a wide range of biological activities, such as the citrate cycle, oxidation-reduction processes and cellular respiration, and energy derivation by oxidation of organic compounds in mitochondria. Finally, we found that currently there are no related gene-targeting drugs after exploring the predicted interactions between key genes and drugs, and transcription factors. In conclusion, our study provides greater understanding of the pathogenesis and underlying molecular mechanisms in DCM. This contributes to the exploration of potential gene therapy targets. [ABSTRACT FROM AUTHOR]

Myocardial fibrosis is observed in various cardiovascular diseases and plays a key role in the impairment of cardiac function. Endomyocardial biopsy, as the gold standard for the diagnosis of myocardial fibrosis, has limitations in terms of clinical application. Therefore, biomarkers have been recommended for noninvasive assessment of myocardial fibrosis. This review discusses the role of biomarkers in myocardial fibrosis from the perspective of collagen. [ABSTRACT FROM AUTHOR]

Background Primary cardiac lymphoma is an extra-nodal non-Hodgkin's lymphoma, which usually responds well to chemotherapy. The disease has high mortality rate unless it is recognized and treated in time. Tissue pathology is crucially the diagnosis gold standard for treatment plan. This is a case report of an elderly female who presented with a huge right-sided cardiac tumour obstructing tricuspid flow. Case summary An 81-year-old Asian female presented with clinical right-sided heart failure. Echocardiogram showed a large mass compressing and obliterating the right atrium. Trans-jugular tissue biopsy was performed. Initial pathology report was consistent with an angiosarcoma, based on an expression of Fli-1 (Friend leukaemia virus integration 1) from immunohistochemical staining. She died shortly after refusal to surgery. Autopsy was performed with diagnosis change to a diffuse large B-cell lymphoma (DLBCL) after tissue pathology. Discussion Primary cardiac lymphoma is extremely rare. Adequate tissue and proper immunohistochemical staining are mandatory for treatment plan. Besides an angiosarcoma, DLBCL should be considered in the differential diagnosis of Fli-1 positive tissue cardiac mass. [ABSTRACT FROM AUTHOR]

Using bone‐avid radiotracers, cardiac transthyretin (TTR) amyloidosis can be diagnosed by scintigraphy, thus obviating endomyocardial biopsy. Radiotracer accumulation, however, may also be due to other causes. A 68‐year‐old male with acute myocardial infarction underwent recanalization of the left anterior descending coronary artery (LAD). Postinterventionally, transthoracic echocardiography showed hypokinesia of the septum and anterior wall and a thickened myocardium with granular sparkling appearance. Cardiac amyloidosis was suspected. A 99mTc‐3,3‐diphosphono‐1,2‐propanodicarboxylic acid whole‐body scan 4 days after LAD recanalization showed Perugini 2 myocardial tracer uptake. Monoclonal gammopathy was excluded, and cardiac TTR amyloidosis was diagnosed. Three months later, 99m‐Tc‐hydroxydiphosphate scan showed no myocardial tracer uptake. Cardiac magnetic resonance imaging revealed late gadolinium enhancement within the LAD supply area. No mutation of the TTR gene was found. Suspicion of amyloidosis should consider not only echocardiography but also history and clinical findings. Myocardial oedema due to reperfusion should be acknowledged as a differential diagnosis for cardiac uptake of bone‐avid radiotracers. [ABSTRACT FROM AUTHOR]

Aims: The alarmin S100A8/S100A9 (S100A8/A9) is released by activated monocytes/macrophages and neutrophils in the setting lymphocytic myocarditis (MC). We recently demonstrated its therapeutic potential in experimental acute MC. Now, we investigated the diagnostic relevance of S100A8/A9 serum levels in patients with suspected acute and chronic MC and in patients with heart failure without cardiac inflammation. Methods and Results: Serum S100A8/A9 levels were analysed in patients with a recent onset of MC [≤ 30 days, n = 32; ejection fraction (EF): 45.4 ± 12.9%], dilated cardiomyopathy patients with inflammation (n = 112; EF: 29.0 ± 11.4%), or without inflammation (n = 58; EF: 26.6 ± 9.3%), and controls (n = 25; EF: 68.5 ± 4.6%), by using specific ELISAs. Blood samples were collected at Time Point 1 (T1), where also endomyocardial biopsies (EMBs) were withdrawn. Patients with a recent onset of MC showed a 4.6‐fold increase in serum S100A8/A9 levels vs. controls (MC: 1948 ± 1670 ng/mL vs. controls: 426 ± 307 ng/mL; P < 0.0001). Serum S100A8/A9 correlated with the disease activity, represented by EMB‐derived counts of inflammatory cells (CD3: r = 0.486, P = 0.0047, lymphocyte function‐associated antigen‐1: r = 0.558, P = 0.0009, macrophage‐1 antigen: r = 0.434, P = 0.013), the EMB mRNA levels of S100A8, S100A9 (r = 0.541, P = 0.002), and left ventricular ejection fraction (LVEF: r = 0.498, P = 0.0043). EMB immunofluorescence co‐stainings display macrophages/monocytes and neutrophils as the main source of S100A8 and S100A9 in recent onset MC. The diagnostic value of serum alarmin levels (cut‐off 583 ng/mL) was characterized by a specificity of 92%, a sensitivity of 90.6%, positive predictive value of 93.5%, negative predictive value of 88.5%, and an accuracy of 0.949 (95% confidence interval [0.89–1]). In a subgroup of MC patients, S100A8/A9 serum levels and EMBs at T1 (n = 12) and a follow‐up visit (T2, n = 12, mean follow‐up 8.5 months) were available. A fall of serum S100A8/A9 (T1: 2208 ± 1843 ng/mL vs. T2: 888.8 ± 513.7 ng/mL; P = 0.00052) was associated with a reduced cardiac inflammation (CD3 T1: 70.02 ± 107.4 cells per square millimetre vs. T2: 59.18 ± 182.5 cells per square millimetre; P = 0.0342, lymphocyte function‐associated antigen‐1 T1: 133.5 ± 187.1 cells per square millimetre vs. T2: 74.12 ± 190.5 cells per square millimetre; P = 0.0186, and macrophage‐1 antigen T1: 132.6 ± 129.5 cells per square millimetre vs. T2: 54.41 ± 65.16 cells per square millimetre; P = 0.0015). Serum S100A8/A9 levels were only slightly increased in patients within the chronic phase of MC and in heart failure patients without inflammation vs. controls. Conclusions: Serum S100A8/A9 might serve as an additional tool in the diagnostic workup of suspected acute MC patients. [ABSTRACT FROM AUTHOR]

Major 5′terminally deleted (5′TD) group-B enterovirus (EV-B) populations were identified in heart biopsies of patients with fulminant myocarditis or dilated cardiomyopathy suggesting that these 5′TD forms are key drivers of host-cell interaction in EV cardiac infections. To date, early emergence of EV-B 5′TD forms and its impact on type 1 IFN response during acute myocarditis remains unknown. Using quantitative RACE-PCR assay, we identified major EV-B 5′TD RNA populations in plasma or heart samples of acute myocarditis cases. Deletions identified within the 5′ non-coding region of EV-B populations only affected secondary-structural elements of genomic RNA domain I and were distinguished in two major groups based on the extent of RNA structural deletions. Proportions of these two respective EV-B 5′TD population groups were positively or negatively correlated with IFN-β levels in plasma samples of myocarditis patients. Transfection of synthetic CVB3/28 RNAs harboring various 5′terminal full-length or deleted sequences into human cultured cardiomyocytes demonstrated that viral genomic RNA domain I possessed essential immunomodulatory secondary-structural elements responsible for IFN-β pathway induction. Overall, our results highlight the early emergence of major EVB-TD populations which deletions affecting secondary–structures of RNA domain I can modulate innate immune sensing mechanisms in cardiomyocytes of patients with acute myocarditis. [ABSTRACT FROM AUTHOR]

Endomyocardial biopsy is a valuable tool in cardiac diagnostics but is limited by low diagnostic yield and significant complication risks. Meanwhile, recent developments in transcriptomic and proteomic technologies promise a wealth of biological data from minimal tissue samples. To take advantage of the minimal tissue amount needed for molecular analyses, we have developed a sub-millimeter endovascular biopsy device, considerably smaller than current clinical equipment, and devised a low-input RNA-sequencing protocol for analyzing small tissue samples. In in vivo evaluation in swine, 81% of biopsy attempts (n = 157) were successful. High quality RNA-sequencing data was generated from 91% of the sequenced cardiac micro-biopsy samples (n = 32). Gene expression signatures of samples taken with the novel device were comparable with a conventional device. No major complications were detected either during procedures or during 7 days' follow-up, despite acquiring a relatively large number of biopsies (median 30) in each animal. In conclusion, the novel device coupled with RNA-sequencing provides a feasible method to obtain molecular data from the myocardium. The method is less traumatic and has a higher flexibility compared to conventional methods, enabling safer and more targeted sampling from different parts of the myocardium. [ABSTRACT FROM AUTHOR]

Introduction: To determine whether a diet of wheat (Triticum aestivum) germ has a radioprotective effect on albino rat (Rattus rattus var. Albinus) myocardial tissue. Method: Rats between 200 and 250 g were divided into 4 groups of 6 each: Two groups were fed either a wheat diet or regular diet 16 days before and after a single exposure to 18 mSv of X-rays. The other two groups were fed the same diets but not exposed to X-rays. The animals were sacrificed, and heart tissue was submitted to histopathological study. Results: Rats fed a standard diet and exposed to X-rays presented marked hyperemia of blood vessels, necrosis, presence of connective tissue fibrocytes, loss of muscle architecture and radial arrangement. Exposed rats fed a wheat diet presented with only light necrosis and the presence of fibrocytes. Rats not exposed to X-rays had healthy myocardia. Conclusions: Wheat germ diet may have a radioprotective effect on rat myocardium. [ABSTRACT FROM AUTHOR]

Background: Measurement of heart weight is important when investigating cause of death, but there is presently no satisfactory method of heart weight estimation by postmortem computed tomography (PMCT).Method: We investigated 33 consecutive cases that underwent both PMCT and autopsy between February 2008 and June 2014. Heart and left ventricular (LV) weights were calculated by PMCT morphometry. We used a simple method to estimate LV weight: We assumed that LV was an ellipsoid and multiplied its volume on PMCT with myocardial specific gravity. We then compared the various heart and LV weights using linear regression. The calculated and estimated LV weights on PMCT were also compared.Results: It was not possible to predict heart weight at autopsy from PMCT (R2 = 0.53). However, heart weight at autopsy could be accurately predicted from LV weight calculated by PMCT (R2 = 0.77). In addition, there was a strong correlation between the estimated and calculated LV weights by PMCT (R2 = 0.92). Heart weight at autopsy could also be accurately predicted using the PMCT-estimated LV weight (R2 = 0.72).Conclusion: Heart weight at autopsy could be accurately predicted using a simple method in which LV volume was assumed to be an ellipsoid on PMCT. [ABSTRACT FROM AUTHOR]

BACKGROUND Identification of heart transplant (HTx) rejection currently relies on immunohistology and immunohistochemistry. We aimed to identify specific sets of microRNAs (miRNAs) to characterize acute cellular rejection (ACR), antibody-mediated rejection (pAMR), and mixed rejection (MR) in monitoring formalin-fixed paraffin-embedded (FFPE) endomyocardial biopsies (EMBs) in HTx patients. METHODS In this study we selected 33 adult HTx patients. For each, we chose the first positive EMB for study of each type of rejection. The next-generation sequencing (NGS) IonProton technique and reverse transcript quantitative polymerase chain reaction (RT-qPCR) analysis were performed on FFPE EMBs. Using logistic regression analysis we created unique miRNA signatures as predictive models of each rejection. In situ PCR was carried out on the same EMBs. RESULTS We obtained >2,257 mature miRNAs from all the EMBs. The 3 types of rejection showed a different miRNA profile for each group. The logistic regression model formed by miRNAs 208a, 126-5p, and 135a-5p identified MR; that formed by miRNAs 27b-3p, 29b-3p, and 199a-3p identified ACR; and that formed by miRNAs 208a, 29b-3p, 135a-5p, and 144-3p identified pAMR. The expression of miRNAs on tissue, through in situ PCR, showed different expressions of the same miRNA in different rejections. miRNA 126-5p was expressed in endothelial cells in ACR but in cardiomyocytes in pAMR. In ACR, miRNA 29b-3p was significantly overexpressed and detected in fibroblasts, whereas in pAMR it was underexpressed and detected only in cardiomyocytes. CONCLUSIONS miRNA profiling on FFPE EMBs differentiates the 3 types of rejection. Localization of expression of miRNAs on tissue showed different expression of the same miRNA for different cells, suggesting different roles of the same miRNA in different rejections. [ABSTRACT FROM AUTHOR]

Acute viral myocarditis (VM), characterised by leukocyte infiltration and dysfunction of the heart, is an important cause of sudden cardiac death in young adults. Unfortunately, to date, the pathological mechanisms underlying cardiac failure in VM remain incompletely understood. In the current study, we investigated if acute VM leads to cardiac metabolic rewiring and if this process is driven by local inflammation. Transcriptomic analysis of cardiac biopsies from myocarditis patients and a mouse model of VM revealed prominent reductions in the expression of a multitude of genes involved in mitochondrial oxidative energy metabolism. In mice, this coincided with reductions in high-energy phosphate and NAD levels, as determined by Imaging Mass Spectrometry, as well as marked decreases in the activity, protein abundance and mRNA levels of various enzymes and key regulators of cardiac oxidative metabolism. Indicative of fulminant cardiac inflammation, NF-κB signalling and inflammatory cytokine expression were potently induced in the heart during human and mouse VM. In cultured cardiomyocytes, cytokine-mediated NF-κB activation impaired cardiomyocyte oxidative gene expression, likely by interfering with the PGC-1 (peroxisome proliferator-activated receptor (PPAR)-γ co-activator) signalling network, the key regulatory pathway controlling cardiomyocyte oxidative metabolism. In conclusion, we provide evidence that acute VM is associated with extensive cardiac metabolic remodelling and our data support a mechanism whereby cytokines secreted primarily from infiltrating leukocytes activate NF-κB signalling in cardiomyocytes thereby inhibiting the transcriptional activity of the PGC-1 network and consequently modulating myocardial energy metabolism. [ABSTRACT FROM AUTHOR]

Pressure overload of the heart leads to cardiac remodeling that may progress into heart failure, a common, morbid and mortal condition. Increased mechanistic insight into remodeling is instrumental for development of novel heart failure treatment. Cardiac remodeling comprises cardiomyocyte hypertrophic growth, extracellular matrix alterations including fibrosis, and inflammation. Fibromodulin is a small leucine-rich proteoglycan that regulates collagen fibrillogenesis. Fibromodulin is expressed in the cardiac extracellular matrix, however its role in the heart remains largely unknown. We investigated fibromodulin levels in myocardial biopsies from heart failure patients and mice, subjected fibromodulin knock-out (FMOD-KO) mice to pressure overload by aortic banding, and overexpressed fibromodulin in cultured cardiomyocytes and cardiac fibroblasts using adenovirus. Fibromodulin was 3-10-fold upregulated in hearts of heart failure patients and mice. Both cardiomyocytes and cardiac fibroblasts expressed fibromodulin, and its expression was increased by pro-inflammatory stimuli. Without stress, FMOD-KO mice showed no cardiac phenotype. Upon aortic banding, left ventricles of FMOD-KO mice developed mildly exacerbated hypertrophic remodeling compared to wild-type mice, with increased cardiomyocyte size and altered infiltration of leukocytes. There were no differences in mortality, left ventricle dilatation, dysfunction or expression of heart failure markers. Although collagen amount and cross-linking were comparable in FMOD-KO and wild-type, overexpression of fibromodulin in cardiac fibroblasts in vitro decreased their migratory capacity and expression of fibrosis-associated molecules, i.e. the collagen-cross linking enzyme lysyl oxidase, transglutaminase 2 and periostin. In conclusion, despite a robust fibromodulin upregulation in clinical and experimental heart failure, FMOD-KO mice showed a relatively mild hypertrophic phenotype. In cultured cardiac fibroblasts, fibromodulin has anti-fibrotic effects. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) is a form of severe failure of cardiac muscle caused by a long list of etiologies ranging from myocardial infarction, DNA mutations in cardiac genes, to toxics. Systems analysis integrating next‐generation sequencing (NGS)‐based omics approaches, such as the sequencing of DNA, RNA, and chromatin, provide valuable insights into DCM mechanisms. The outcome and interpretation of NGS methods can be affected by the localization of cardiac biopsy, level of tissue degradation, and variable ratios of different cell populations, especially in the presence of fibrosis. Heart tissue composition may even differ between sexes, or siblings carrying the same disease causing mutation. Therefore, before planning any experiments, it is important to fully appreciate the complexities of DCM, and the selection of samples suitable for given research question should be an interdisciplinary effort involving clinicians and biologists. The list of NGS omics datasets in DCM to date is short. More studies have to be performed to contribute to public data repositories and facilitate systems analysis. In addition, proper data integration is a difficult task requiring complex computational approaches. Despite these complications, there are multiple promising implications of systems analysis in DCM. By combining various types of datasets, for example, RNA‐seq, ChIP‐seq, or 4C, deep insights into cardiac biology, and possible biomarkers and treatment targets, can be gained. Systems analysis can also facilitate the annotation of noncoding mutations in cardiac‐specific DNA regulatory regions that play a substantial role in maintaining the tissue‐ and cell‐specific transcriptional programs in the heart. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Laboratory Methods and Technologies > Genetic/Genomic Methods Laboratory Methods and Technologies > RNA Methods [ABSTRACT FROM AUTHOR]

Arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM), despite being two dramatically different entities, have overlapping phenotypes. As it is easy to misdiagnose between ARVC and DCM, there is a need to establish a new differential diagnostic parameter to differentiate the two. We investigated the utility of endomyocardial biopsy (EMB) for the differential diagnosis, and our study had three aims. The first was to verify the EMB high diagnostic efficacy. The second was to investigate the EMB perforation risk at the right ventricle (RV) free wall of end-stage ARVC. The third was to determine the best EMB sampling site in differential diagnosis between ARVC and DCM. Transmural tissues were sampled at six sites on the ventricular free walls and interventricular septum of recipient hearts (35 ARVCs and 35 DCMs). Participants with wall thickness <1.7 mm were included in the subgroup with high perforation risk, and the rest were included in a subgroup with low perforation risk. The best EMB sampling site was determined by the largest area under curve (AUC) among receiver operating characteristic curves. We found significant differences ( P <.01) in percentages of tissue components in transmural sections between ARVC and DCM. In the subgroup with high perforation risk, there were 12 ARVCs and no DCMs, and paper-like RV walls and transmural fat replacement were their features in the cardiac enhancement computed tomography images. In the subgroup with low perforation risk, the largest AUC was on the myocardium at the ARV: AUC=0.839, cutoff=74.76%, sensitivity=73.68%, specificity=97.14%. We conclude that EMB high differential diagnostic efficacy is a meaningful fact regardless of limited sampling range, that EMB perforation risk at the RV free wall of end-stage ARVC cannot be neglected, and that the best EMB sampling site is the ARV. Among participants with low perforation risk, ARV is still recommended as an EMB sampling site with good differential diagnostic efficacy. [ABSTRACT FROM AUTHOR]

Clinical surveillance of acute heart transplantation rejection requires repeated invasive endomyocardial biopsies and noninvasive diagnostic techniques are desperately needed. It is acknowledged that T lymphocyte infiltration is the central process of acute rejection. We hypothesized that ultrasound molecular imaging with T lymphocyte-targeted nanobubbles could be used to detect acute rejection in heart transplantation. In this study, nanobubbles bearing anti-CD3 antibody (NB CD3 ) or isotype antibody (NB con ) were prepared and characterized. There was significant adhesion of NB CD3 to T lymphocytes compared with NB con in vitro . The signal intensity of the adherent NB CD3 was significantly higher than that of the NB con in allograft rats, but not significantly different in isograft rats. Furthermore, the signal intensity of NB CD3 in allograft rats was significantly higher than that in isograft rats, indicating more T lymphocyte infiltration in allograft rats compared with isograft rats. These results were further confirmed by immunohistochemistry examination, and the signal intensity of NB CD3 was positively correlated with the number of T lymphocytes in allograft rats. In summary, ultrasound molecular imaging with T lymphocyte-targeted nanobubbles can detect T lymphocyte infiltration in acute rejection and could be used as a noninvasive method in acute rejection detection after cardiac transplantation. [ABSTRACT FROM AUTHOR]

Restrictive cardiomyopathies are the least common form of heart muscle disease. They are characterized as infiltrative and noninfiltrative, storage diseases, and endomyocardial disorders. Genetic diseases commonly present during childhood or adolescence. However, a growing percentage of elderly patients with heart failure with preserved ejection fraction are being recognized as having forms of restrictive cardiomyopathy, particularly cardiac amyloidosis. Noninvasive evaluation has replaced endomyocardial biopsy in the diagnostic evaluation of most suspected etiologies. The detection of infiltrative cardiomyopathies, particularly primary and secondary forms of iron overload, as well as inflammatory diseases such as sarcoidosis has slowly led to improved outcomes via disease-specific therapies. [ABSTRACT FROM AUTHOR]

Restrictive cardiomyopathies are the least common form of heart muscle disease. They are characterized as infiltrative and noninfiltrative, storage diseases, and endomyocardial disorders. Genetic diseases commonly present during childhood or adolescence. However, a growing percentage of elderly patients with heart failure with preserved ejection fraction are being recognized as having forms of restrictive cardiomyopathy, particularly cardiac amyloidosis. Noninvasive evaluation has replaced endomyocardial biopsy in the diagnostic evaluation of most suspected etiologies. The detection of infiltrative cardiomyopathies, including lysosomal and glycogen storage disorders, iron overload, and amyloidosis (both light chain amyloidosis and transthyretin amyloidosis variants), as well as inflammatory diseases such as sarcoidosis has slowly led to improved outcomes via disease-specific therapies. [ABSTRACT FROM AUTHOR]

Background Cardiac allograft vasculopathy (CAV) has been associated with graft-infiltrating B cells, although their characteristics are still unclear. In this study we examined the frequency, localization and reactivity profile of graft-infiltrating B cells to determine their contribution to the pathophysiology of CAV. Methods B cells, plasma cells and macrophages were examined by immunohistochemistry in 56 allografts with CAV, 49 native failed hearts and 25 autopsy specimens. A total of 102 B-cell clones were immortalized directly from the infiltrates of 3 fresh cardiac samples with CAV. Their secreted antibodies were assessed using enzyme-linked immunoassay and flow cytometry. Results B-cell infiltration was observed around coronary arteries in 93% of allograft explants with CAV. Comparatively, intragraft B cells were less frequent and less dense in the intraventricular myocardium from where routine biopsies are obtained. Plasma cells and macrophages were also detected in 85% and 95% of explants, respectively. Remarkably, B-cell infiltrates were not associated with circulating donor-specific antibodies (DSA) or prior episodes of antibody-mediated rejection (AMR). Among all B-cell clones generated from 3 explants with CAV, a majority secreted natural antibodies reactive to multiple autoantigens and apoptotic cells, a characteristic of innate B cells. Conclusions Our study reveals a high frequency of infiltrating B cells around the coronary arteries of allografts with CAV, independent of DSA or AMR. These cells are enriched for innate B cells with a polyreactive profile. The findings shift the focus from conventional DSA-producing B cells to the potentially pathogenic polyreactive B cells in the development of clinical CAV. [ABSTRACT FROM AUTHOR]

Aims Giant-cell myocarditis (GCM) is a rare and often fatal form of myocarditis. Only a few reports have focused on fulminant forms. We describe the clinical characteristics, management and outcomes of GCM patients rescued by mechanical circulatory support (MCS). Methods and results The clinical features, diagnoses, treatments and outcomes of MCS-treated patients in refractory cardiogenic shock secondary to fulminant GCM admitted to eight French intensive care units (2002–2016) were analysed. We also conducted a systematic review of this topic. Thirteen patients (median age 44 [range 21–76] years, Simplified Acute Physiology Score II 55 [40–79]) in severe cardiogenic shock (median [range] left ventricular ejection fraction 15% [15–35%] and blood lactate 4 mmol/L) were placed on MCS 4 [0–28] days after hospital admission. Severe arrhythmic disturbances were frequent (77%), with six (46%) patients experiencing an electrical storm prior to MCS. Venoarterial extracorporeal membrane oxygenation was the first MCS option for 11 (85%) patients. GCM was diagnosed in five (38%) patients before transplant or death and treated with immunosuppressants; infections were the main complication (80%). Four patients died on MCS and no patient presented long-term survival free from heart transplant (nine patients, 69%). All transplanted patients were alive 1 year later and no GCM recurrence was reported after median follow-up of 42 [12–145] months. Conclusion Outcomes of fulminant GCMs may differ from those of milder forms. In this context, heart transplant might likely be the only long-term survival option. [ABSTRACT FROM AUTHOR]

Prediction of follow-up shock is crucial to stratify patients with dilated cardiomyopathy (DCM) requiring implantable cardioverter defibrillator (ICD). The objective of the article is to assess the predictive value of endo-myocardial biopsy (EMB) towards ICD shock and follow-up mortality. A series of patients with DCM scheduled for ICD implantation underwent EMB to further determine the genesis of DCM. Presence of fibrosis and inflammation was documented and related to outcomes. A total of 240 patients were referred for ICD as primary (56%) and secondary (44%) prophylaxis. EMB showed myocardial fibrosis in 55.4%, inflammation in 55.7%, and viral genomic material in 60%. Median follow-up was 39 months (1-209). Appropriate and inappropriate shocks occurred in 29.2 and 20.4%. At logistic regression, determinants of appropriate shock were ICD indication for secondary prophylaxis (direct relationship: p = 0.009, OR 3.4, CI 1.3-8.8) and presence of inflammation at EMB (inverse relationship: p = 0.04, OR 0.4, CI 0.1-0.9). Moreover, the sole determinant of inappropriate shock was age at implant (inverse relationship: p = 0.003, OR = 0.9, CI 0.90-0.98). Overall mean estimated survival was 168 months and 5-year survival was 83%. Degree of improvement in LVEF% was the sole determinant of follow-up mortality (inverse relationship p = 0.02; HR = 0.9; CI 0.88-0.99). Present selection criteria for ICDs implant rely mainly on LVEF% that lacks sensitivity and specificity. EMB can identify the substrate of increased or reduced life-threatening arrhythmias. Presence of inflammation is a positive prognostic factor for reduced arrhythmogenic risk, independently by the ICD implantation indication. [ABSTRACT FROM AUTHOR]

Non-coding RNAs play major roles in cardiac pathophysiology. Recent studies reported that long non-coding RNAs (lncRNAs) are dysregulated in the failing heart, but how they contribute to heart failure development is unclear. In this study, we aimed to identify heart-enriched lncRNAs and investigate their regulation and function in the failing heart. Results Analysis of a RNA-seq dataset of 15 Caucasian tissues allowed the identification of 415 heart-enriched lncRNAs. Fifty-three lncRNAs were located on the genome in close vicinity to protein-coding genes associated with cardiac function and disease. Analysis of a second RNA-seq dataset of 16 failing human hearts highlighted one lncRNA which we arbitrarily named TRDN-AS due to its localisation in the antisense position of the gene encoding triadin (TRDN). Expression of TRDN-AS and cardiac TRDN was up-regulated in biopsies from failing human hearts compared to control hearts. In failing hearts, TRDN-AS was positively correlated with a cardiac isoform of TRDN and negatively correlated with a skeletal muscle isoform of TRDN. A murine homolog of human TRDN-AS was identified and found to be enriched in the heart and localised in the nuclear compartment of cardiomyocytes. Trdn-AS expression as well as the ratio between cardiac and skeletal muscle isoforms were down-regulated after experimental myocardial infarction. In murine cardiomyocytes, activation of Trdn-AS transcription with the CRISPR/dCas9-VPR system enhanced the ratio between cardiac and skeletal isoforms of Trdn. Conclusion The lncRNA TRDN-AS regulates the balance between cardiac and skeletal isoforms of triadin. This finding may have implications for the treatment of heart failure. [ABSTRACT FROM AUTHOR]

Objectives: Our objectives involved identifying whether repeated averaging in basal and mid left ventricular myocardial levels improves precision and correlation with collagen volume fraction for 11 heartbeat MOLLI T1 mapping versus assessment at a single ventricular level.Materials and methods: For assessment of T1 mapping precision, a cohort of 15 healthy volunteers underwent two CMR scans on separate days using an 11 heartbeat MOLLI with a 5(3)3 beat scheme to measure native T1 and a 4(1)3(1)2 beat post-contrast scheme to measure post-contrast T1, allowing calculation of partition coefficient and ECV. To assess correlation of T1 mapping with collagen volume fraction, a separate cohort of ten aortic stenosis patients scheduled to undergo surgery underwent one CMR scan with this 11 heartbeat MOLLI scheme, followed by intraoperative tru-cut myocardial biopsy. Six models of myocardial diffuse fibrosis assessment were established with incremental inclusion of imaging by averaging of the basal and mid-myocardial left ventricular levels, and each model was assessed for precision and correlation with collagen volume fraction.Results: A model using 11 heart beat MOLLI imaging of two basal and two mid ventricular level averaged T1 maps provided improved precision (Intraclass correlation 0.93 vs 0.84) and correlation with histology (R2 = 0.83 vs 0.36) for diffuse fibrosis compared to a single mid-ventricular level alone. ECV was more precise and correlated better than native T1 mapping.Conclusion: T1 mapping sequences with repeated averaging could be considered for applications of 11 heartbeat MOLLI, especially when small changes in native T1/ECV might affect clinical management. [ABSTRACT FROM AUTHOR]

Introduction. Extracorporeal cardiopulmonary resuscitation (ECPR) is a challenging approach for treating refractory out-of-hospital cardiac arrest (OHCA). Case Presentation. The authors describe a case of a 40-year-old Caucasian female who suffered from refractory OHCA, was admitted to a hospital while receiving ongoing cardiopulmonary resuscitation, and was connected to venoarterial extracorporeal membrane oxygenation 73 minutes after collapse. Ventricular tachyarrhythmias alternating with pulseless electrical activity resolved after eight hours. Following complete cardiac and neurological recovery, only adenoviral genome was found in myocardial biopsy. After 11 months, another episode of identical arrhythmias was rescued by an implantable cardioverter-defibrillator. Conclusion. Adequate prehospital and early hospital logistics is a prerequisite for successfully implementing extracorporeal cardiopulmonary resuscitation for refractory OHCA. [ABSTRACT FROM AUTHOR]

Empagliflozin (EMPA), a drug approved for type 2 diabetes management, reduced cardiovascular death but is unknown if it reduces myocardial infarction. We sought to investigate: (i) the effect of EMPA on myocardial function and infarct size after ischemia/reperfusion in mice fed with western diet (WD), (ii) the underlying signaling pathways, (iii) its effects on cell survival in rat embryonic-heart-derived cardiomyoblasts (H9C2) and endothelial cells (ECs). To facilitate the aforementioned aims, mice were initially randomized in Control and EMPA groups and were subjected to 30min ischemia and 2 h reperfusion. EMPA reduced body weight, blood glucose levels, and mean arterial pressure. Cholesterol, triglyceride, and AGEs remained unchanged. Left ventricular fractional shortening was improved (43.97 ± 0.92 vs. 40.75 ± 0.61%) and infarct size reduced (33.2 ± 0.01 vs. 17.6 ± 0.02%). In a second series of experiments, mice were subjected to the above interventions up to the 10th min of reperfusion and myocardial biopsies were obtained for assessment of the signaling cascade. STAT3 was increased in parallel with reduced levels of malondialdehyde (MDA) and reduced expression of myocardial iNOS and interleukin-6. Cell viability and ATP content were increased in H9C2 and in ECs. While, STAT3 phosphorylation is known to bestow infarct sparing properties through interaction with mitochondria, we observed that EMPA did not directly alter the mitochondrial calcium retention capacity (CRC); therefore, its effect in reducing myocardial infarction is STAT3 dependent. In conclusion, EMPA improves myocardial function and reduces infarct size as well as improves redox regulation by decreasing iNOS expression and subsequently lipid peroxidation as shown by its surrogate marker MDA. The mechanisms of action implicate the activation of STAT3 anti-oxidant and anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

Key points Autologous cardiac progenitor cell (CPC) therapy is a promising approach for treatment of heart failure (HF). There is an unmet need to identify inherent deficits in aged/diseased human CPCs (hCPCs) derived from HF patients in the attempts to augment their regenerative capacity prior to use in the clinical setting., Here we report significant functional correlations between phenotypic properties of hCPCs isolated from cardiac biopsies of HF patients, clinical parameters of patients and expression of the P2Y14 purinergic receptor (P2Y14R), a crucial detector for extracellular UDP-sugars released during injury/stress., P2Y14R is downregulated in hCPCs derived from HF patients with lower ejection fraction or diagnosed with diabetes., Augmenting P2Y14R expression levels in aged/diseased hCPCs antagonizes senescence and improves functional responses., This study introduces purinergic signalling modulation as a potential strategy to rejuvenate and improve phenotypic characteristics of aged/functionally compromised hCPCs prior to transplantation in HF patients., Abstract Autologous cardiac progenitor cell therapy is a promising alternative approach to current inefficient therapies for heart failure (HF). However, ex vivo expansion and pharmacological/genetic modification of human cardiac progenitor cells (hCPCs) are necessary interventions to rejuvenate aged/diseased cells and improve their regenerative capacities. This study was designed to assess the potential of improving hCPC functional capacity by targeting the P2Y14 purinergic receptor (P2Y14R), which has been previously reported to induce regenerative and anti-senescence responses in a variety of experimental models. c-Kit+ hCPCs were isolated from cardiac biopsies of multiple HF patients undergoing left ventricular assist device implantation surgery. Significant correlations existed between the expression of P2Y14R in hCPCs and clinical parameters of HF patients. P2Y14R was downregulated in hCPCs derived from patients with a relatively lower ejection fraction and patients diagnosed with diabetes. hCPC lines with lower P2Y14R expression did not respond to P2Y14R agonist UDP-glucose (UDP-Glu) while hCPCs with higher P2Y14R expression showed enhanced proliferation in response to UDP-Glu stimulation. Mechanistically, UDP-Glu stimulation enhanced the activation of canonical growth signalling pathways ERK1/2 and AKT. Restoring P2Y14R expression levels in functionally compromised hCPCs via lentiviral-mediated overexpression improved proliferation, migration and survival under stress stimuli. Additionally, P2Y14R overexpression reversed senescence-associated morphology and reduced levels of molecular markers of senescence p16INK4a, p53, p21 and mitochondrial reactive oxygen species. Findings from this study unveil novel biological roles of the UDP-sugar receptor P2Y14 in hCPCs and suggest purinergic signalling modulation as a promising strategy to improve phenotypic properties of functionally impaired hCPCs. [ABSTRACT FROM AUTHOR]

The objective of this study was to compare radiation doses and imaging quality using Philips AlluraClarity (Philips Healthcare, Best, The Netherlands) X-ray system and an older generation reference system. AlluraClarity is a new generation fluoroscopy system designed to reduce radiation without compromising image quality, but reports of its use in pediatric patients are limited. Dose area products (DAP, mGy cm) and DAP/kg were compared in patients catheterized using Allura Xper and AlluraClarity systems over a year of use for each. Randomly selected studies from each system were assessed for image quality. The 430 patients imaged with Clarity were larger than the 332 imaged with Xper (median BSA: 0.74 vs. 0.64 m, p = 0.06), and median total fluoroscopic times (TFT) were similar (15.8 vs. 16.1 min, p = 0.37). Median DAPs were 8661 mGy cm (IQR: 18,300 mGy cm) and 4523 mGy cm (IQR: 11,596 mGy cm) with Xper and Clarity, respectively ( p < 0.001). There was a reduction in median DAP in all procedure categories. After adjustment for BSA, TFT, and procedure type, using Clarity was associated with a 57.5% (95% CI 51.5-62.8%, p < 0.001) reduction in DAP for all procedures. Reductions did not significantly differ by weight (<10 kg, 10-40 kg, ≥ 40 kg). There was an adjusted percent reduction in DAP for each procedure category ranging from 39.0% (95% CI 25.6-50.1%, p < 0.001) for cardiac biopsies with or without coronary angiography to 67.6% (95% CI 61.2-72.8%, p < 0.001) for device occlusions. Mean overall imaging quality scores (4.3 ± 0.8 with Clarity vs. 4.4 ± 0.6 with Xper, p = 0.62) and scores based on specific quality parameters were similar in the two groups. Use of AlluraClarity substantially reduced radiation doses compared to the older generation reference system without compromising imaging quality in a pediatric cardiac catheterization lab. [ABSTRACT FROM AUTHOR]

Background: Diagnosing myocarditis is challenged by nonspecific clinical signs and symptoms and low accuracy of endomyocardial biopsy. Cardiac magnetic resonance imaging (CMR) provides both cardiac anatomy and tissue characterization in this setting, but the prognostic value of this method as a primary assessment tool in patients with suspected myocarditis remains limited.Objectives: This study sought to determine cardiac event-free survival of a consecutive cohort with suspected myocarditis with regard to CMR findings.Methods: Six hundred seventy patients with suspected myocarditis underwent CMR including late gadolinium enhancement (LGE) parameters between 2002 and 2015 and were included and followed. We performed multivariable model for major adverse cardiovascular events (MACE) and determined the continuous net reclassification improvement by LGE markers.Results: At a median follow-up of 4.7 years (interquartile range [IQR]: 2.3 to 7.3 years), 98 patients experienced a MACE. Two hundred ninety-four (44%) patients showed LGE presence, which was associated with a more than doubling risk of MACE (hazard ratio [HR]: 2.22; 95% confidence interval [CI]: 1.47 to 3.35; p < 0.001). Annualized MACE rates were 4.8% and 2.1% corresponding to LGE presence and absence, respectively (p < 0.001). In the multivariable model, LGE presence maintained significant association with MACE (HR: 1.72; 95% CI: 1.08 to 2.76; p = 0.023). The computed continuous net reclassification improvement was 0.39 (95% CI: 0.10 to 0.67) when LGE presence was added to the multivariable model for MACE. Regarding location and pattern, septal and midwall LGE showed strongest associations with MACE (HR: 2.55; 95% CI: 1.77 to 3.83 and HR: 2.39; 95% CI: 1.54 to 3.69, respectively; both p < 0.001). A patchy distribution portended to a near 3-fold increased hazard to MACE (HR: 2.93; 95% CI: 1.79 to 4.80; p < 0.001). LGE extent (per 10% increase) corresponded to a 79% increase in risk of MACE (HR: 1.79; 95% CI: 1.25 to 2.57; p = 0.002). A normal CMR study corresponded to low annual MACE and death rates of 0.8% and 0.3%, respectively.Conclusions: CMR tissue characterization provides effective risk stratification in patients with suspected myocarditis. [ABSTRACT FROM AUTHOR]

Background Up to one third of patients with chronic myocarditis (MC) have preserved left ventricular (LV) ejection fraction (MCpEF). The purpose of this study was to evaluate the role of adding 2D speckle-tracking echocardiography (STE) to cardiac magnetic resonance imaging (cMRI) in the diagnosis of patients with MCpEF. Methods and results We analyzed 67 patients with suspected MCpEF who underwent endomyocardial biopsy (EMB). Thirty-two patients with confirmed chronic myocardial inflammation by EMB served as study group (MCpEF) and the remaining patients ( n = 35) served as control group. In all patients, 2D STE and cMRI were performed within 48 h before EMB. Patients with MCpEF had significantly lower LV global longitudinal systolic strain (GLS) than controls (GLS: − 17.01 ± 2.42% vs. − 19.39 ± 3.81%, p < 0.001; respectively). In line, an abnormal GLS had adequate diagnostic performance to detect MCpEF (sensitivity, specificity, and accuracy of 82%, 70%, and 76%, respectively), which was superior to cMRI based on the Lake-Louise criteria (sensitivity, specificity, and accuracy 54%, 71%, and 67%, respectively). In addition, adding GLS to the Lake-Louise criteria improved significantly the diagnostic performance of cMRI to detect MCpEF (sensitivity, specificity, and accuracy 96%, 55%, and 75%, respectively). Conclusion The findings of this study suggest that GLS using 2D STE could play an important role in the diagnostic evaluation of patients with suspected chronic myocarditis with preserved LV ejection fraction (MCpEF). [ABSTRACT FROM AUTHOR]

Objectives: Urinary Proteomics in Predicting Heart Transplantation Outcomes (uPROPHET; NCT03152422) aims: (i) to construct new multidimensional urinary proteomic (UP) classifiers that after heart transplantation (HTx) help in detecting graft vasculopathy, monitoring immune system activity and graft performance, and in adjusting immunosuppression; (ii) to sequence UP peptide fragments and to identify key proteins mediating HTx-related complications; (iii) to validate UP classifiers by demonstrating analogy between UP profiles and tissue proteomic signatures (TP) in diseased explanted hearts, to be compared with normal donor hearts; (iv) and to identify new drug targets. This article describes the uPROPHET database construction, follow-up strategies and baseline characteristics of the HTx patients. Methods: HTx patients enrolled at the University Hospital Gasthuisberg (Leuven) collected mid-morning urine samples. Cardiac biopsies were obtained at HTx. UP and TP methods and the statistical work flow in pursuit of the research objectives are described in detail in the Data supplement. Results: Of 352 participants in the UP study (24.4% women), 38.9%, 40.3%, 5.7% and 15.1% had ischemic, dilated, hypertrophic or other cardiomyopathy. The median interval between HTx and first UP assessment (baseline) was 7.8 years. At baseline, mean values were 56.5 years for age, 25.2 kg/m2 for body mass index, 142.3/84.8 mm Hg and 124.2/79.8 mm Hg for office and 24-h ambulatory systolic/diastolic pressure, and 58.6 mL/min/1.73 m2 for the estimated glomerular filtration rate. Of all patients, 37.2% and 6.5% had a history of mild (grade = 1B) or severe (grade ≥ 2) cellular rejection. Anti-body mediated rejection had occurred in 6.2% patients. The number of follow-up urine samples available for future analyses totals over 950. The TP study currently includes biopsies from 7 healthy donors and 15, 14, and 3 patients with ischemic, dilated, and hypertrophic cardiomyopathy. Conclusions: uPROPHET constitutes a solid resources for UP and TP research in the field of HTx and has the ambition to lay the foundation for the clinical application of UP in risk stratification in HTx patients. [ABSTRACT FROM AUTHOR]

Vacuolar degeneration of cardiomyocytes is a histological finding commonly encountered during routine light microscopic examination of human endomyocardial biopsy specimens. The vacuoles appear as intracellular clear areas lacking myofibers. By itself, this finding has little diagnostic value, but may have important clinical implications when the vacuolar contents are of etiological significance (e.g., accumulation of abnormal metabolites), and the clinical importance is increased when the disease is treatable. Thanks to its great resolving power, electron microscopy can often reveal the contents of the vacuoles and lead to a correct diagnosis. It can be used to differentially diagnose lysosomal storage diseases such as Fabry, Danon, and Pompe disease, doxorubicin cardiomyopathy, mitochondrial cardiomyopathy, autophagic degeneration, and accumulation of subcellular organelles (mitochondria, lipofuscin, glycogen granules, endoplasmic reticulum, etc.) as a nonspecific finding in failing cardiomyocytes. Nonetheless, undiagnosed cases certainly remain. It is strongly recommended that small pieces of tissue samples be fixed for electron microscopy at every endomyocardial biopsy procedure, and electron microscopic examination should be performed when a marked vacuolar degeneration is found. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Combined coronary artery bypass grafting and valve surgery requires a prolonged period of cardioplegic arrest (CA) predisposing to myocardial injury and postoperative cardiac-specific complications. The aim of this trial was to reduce the CA time in patients undergoing combined coronary artery bypass grafting and valve surgery and assess if this was associated with less myocardial injury and related complications. METHODS: Participants were randomized to (i) coronary artery bypass grafting performed on the beating heart with cardiopulmonary bypass support followed by CA for the valve procedure (hybrid) or (ii) both procedures under CA (conventional). To assess complications related to myocardial injury, we used the composite of death, myocardial infarction, arrhythmia, need for pacing or inotropes for >12 h. To assess myocardial injury, we used serial plasma troponin T and markers of metabolic stress in myocardial biopsies. RESULTS: Hundred and sixty patients (80 hybrid and 80 conventional) were randomized. Mean age was 66.5 years and 74% were male. Valve procedures included aortic (61.8%) and mitral (33.1%) alone or in combination (5.1%). CA time was 16% lower in the hybrid group [median 98 vs 89 min, geometric mean ratio (GMR) 0.84, 95% confidence interval (CI) 0.77–0.93, P = 0.0004]. Complications related to myocardial injury occurred in 131/160 patients (64/80 conventional, 67/80 hybrid), odds ratio 1.24, 95% CI 0.54–2.86, P = 0.61. Release of troponin T was similar between groups (GMR 1.04, 95% CI 0.87–1.24, P = 0.68). Adenosine monophosphate was 28% lower in the hybrid group (GMR 0.72, 95% CI 0.51–1.02, P = 0.056). CONCLUSIONS: The hybrid procedure reduced the CA time but myocardial injury outcomes were not superior to conventional approach. [ABSTRACT FROM AUTHOR]

Introduction:During the past years, endomyocardial biopsy (EMB) has gradually spread into clinical practice. However, the role of EMB in the diagnosis and treatment of cardiovascular diseases remains a controversial issue, especially in the setting of unexplained ventricular arrhythmias. Areas covered:This review describes the methodology of EMB guided by combined use of three-dimensional electroanatomical mapping systems and intracardiac echo and summarizes the classical, fluoroscopy-guided EMB technique. Finally, the personal experience acquired with the ‘electrophysiologist-made’ integration methodology has been reported. Expert commentary:Since EMB has been considered in the setting of arrhythmogenic cardiomyopathy, myocarditis, cardiac sarcoidosis, drug toxicity, and/or other diseases causing malignant ventricular arrhythmias, the electrophysiologists have started to perform firsthand biopsy. The electrophysiologists introduced the use of electroanatomical mapping systems and intracardiac echo. This new methodology improved significantly biopsy diagnostic yield and allowed to reduce complications. [ABSTRACT FROM PUBLISHER]

Aims: We sought to determine whether myocardial expression of Toll-like receptor 4 (TLR4) may predict the response to immunosuppression.Methods and Results: Endomyocardial biopsies from 237 patients with virus-negative inflammatory cardiomyopathy treated with immunosuppression were retrospectively examined for the expression of TLR4, differentiating those patients responding to immunosuppression (n = 193) from non-responder patients (n = 44). A semiquantitative evaluation of the immunoreactivity (grading from 0 to 4) for TLR4 and human leucocyte antigen (HLA)-DR was performed together with real-time PCR and western blot for TLR4. Cardiomyocyte apoptosis and necrosis was evaluated by in situ ligation with hairpin probes. A focal intense positive cytoplasmic immunostaining for TLR4 was observed in cardiomyocytes of all responders (P < 0.001 vs. non-responders). A grading 2 or above (2+) at baseline showed a sensitivity of 100% and 90.9% specificity with a positive predictive value of 98% as a predictor of an immunosuppression-positive response. Real-time PCR and western blot analysis for TLR4 were 4.3-fold and 4.6-fold higher, respectively, in responders vs. non-responders. Correlation between TLR4 grading and TLR4 mRNA molecular and protein expression was highly significant. HLA-DR did not discriminate between the two groups. Cardiomyocyte death by apoptosis was 3.7-fold higher in responders vs. non-responders and significantly correlated with TLR4 expression, while necrosis was comparable. Intensity of baseline TLR4 expression correlated with the variation in ejection fraction after 6 months of immunosuppression.Conclusion: TLR4 is highly expressed in human myocarditis responding to immunosuppression. It can be considered as a new sensitive marker in patient selection predicting a good response to immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Background Heart transplantation is a valuable therapeutic option for Chagas disease patients with severe cardiomyopathy. During patient follow-up, the differential diagnosis between cardiac transplant rejection and Chagas disease infection reactivation remains a challenging task, which hinders rapid implementation of the appropriate treatment. Herein we investigate whether polymerase chain reaction (PCR) strategies could facilitate early detection of Trypanosoma cruzi ( T cruzi ) in transplanted endomyocardial biopsies (EMBs). Methods In this study we analyzed 500 EMB specimens obtained from 58 chagasic cardiac transplant patients, using PCR approaches targeted to nuclear (rDNA 24Sα) and kinetoplastid (kDNA) markers, and compared the efficiency of these approaches with that of other tests routinely used. Results T cruzi DNA was detected in 112 EMB specimens derived from 39 patients (67.2%). The first positive result occurred at a median 1.0 month post-transplant. Conventional histopathologic, blood smear and hemoculture analyses showed lower sensitivity and higher median time to the first positive result. Patient follow-up revealed that 31 of 39 PCR-positive cases presented clinical reactivation of Chagas disease at different time-points after transplantation. PCR techniques showed considerable sensitivity (0.82) and specificity (0.60), with area under the receiver operating characteristic (ROC) curves of 0.708 ( p = 0.001). Moreover, PCR techniques anticipated the clinical signs of Chagas disease reactivation by up to 36 months, with a median time of 6 months and an average of 9.1 months. Conclusions We found a good association between the PCR diagnosis and the clinical signs of the disease, indicating that the PCR approaches used herein are suitable for early diagnosis of Chagas disease reactivation, with high potential to assist physicians in treatment decisions. For this purpose, an algorithm is proposed for surveillance based on the molecular tests. [ABSTRACT FROM AUTHOR]

Routine endomyocardial biopsy ( EMB) to detect acute cellular rejection ( ACR) late (>1 year) after heart transplantation ( HT) remains debated. To gain knowledge on late ACR and thereby approach this issue, we studied the incidence, predictors, and outcome of late ACR. 815 late EMBs from 183 patients transplanted 1988-2010 were retrospectively reviewed until June 30, 2012. Only 4.4% of the routine and 17.6% of the additional clinically indicated late EMBs showed ACR ≥ grade 2. With time post- HT, there was a clear trend toward fewer ACRs, a lower incidence of ACR per patient per year, and a deceleration in the decrease in the proportion of patients free from ACR. Sex-mismatching and first-year ACR were associated with an increased risk of late ACR, which also was associated with worse outcome. Although rare, when compared to our previous study on first-year EMBs, it appears as if late more often than early ACR remains undetected and that also late and not only early ACR influences outcome. Extended EMB surveillance >1 year post- HT therefore still seems reasonable in 'high-risk' patients, as also suggested in the International Society for Heart and Lung Transplantation guidelines. These should include, but not be limited to, the two risk groups above. [ABSTRACT FROM AUTHOR]