Chronic Inflammatory Cardiomyopathy Research Articles

The Role of Rituximab in the Management of Heart Failure

Rituximab is a chimeric monoclonal antibody mice/humans that bind the transmembrane antigen, CD20 specifically. The mechanism of heart failure is mediated by neurohormonal pathways: the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system, and the natriuretic peptide system, thereby triggering activation of the immune system. This literature review will discuss the role of B cell targeted therapy, in this case rituximab in the management of heart failure. Modulation of the immune response holds great promise in the 30% of cases of myocarditis where inflammation does not resolve and progression to chronic inflammatory dilated cardiomyopathy occurs. Pharmacologically, rituximab is a monoclonal immunoglobulin G1 antibody drug that is given intravenously. Rituximab targets the CD20 antigen expressed on the surface of mature B lymphocytes, including memory B cells but not on stem cells or plasma cells. In conclusion, rituximab causes a selective and temporary decrease in the CD20+ B cell subpopulation and represents a more specific and targeted approach to B cell-induced disorders including heart failure.

Cardiac involvement in eosinophilic granulomatosis with polyangiitis: acute eosinophilic myocarditis and chronic inflammatory cardiomyopathy

Abstract Objectives Currently, cardiac involvement is used to describe all eosinophilic granulomatosis with polyangiitis (EGPA) cardiac problems. However, heterogeneity exists among them. We aimed to depict the disease spectrum of EGPA cardiac involvement and identify the high-risk population. Methods We included EGPA patients hospitalized in our centre from 2012 to 2023 and in public databases. Based on the cardiac enzymes, cardiac MRI and endomyocardial biopsy results, the patients were divided into three groups: eosinophilic myocarditis (EGPA-EM), chronic inflammatory cardiomyopathy (EGPA-ICM) and EGPA-Control. Their clinical, laboratory, imaging results and prognoses were collected and compared. Results A total of 193 EGPA patients were included, 118 with cardiac involvement (74 EGPA-EM, 44 EGPA-ICM) and 75 control. Among EGPA-Control, EGPA-ICM and EGPA-EM, eosinophil increased (6.12/8.71/10.42 × 109/l, P < 0.01), ANCA positivity decreased (41.33/31.82/14.86%, P < 0.01) and lung involvement was reduced (73.33/72.73/43.24%, P = 0.02). In EGPA-EM, cardiac troponin was further elevated (0.27 vs 6.00 ng/ml, P < 0.01), ejection fractions decreased (57.79 vs 33.20%, P < 0.01) while more ST-T abnormality was observed (41.89 vs 20.45%, P = 0.02). The prognosis of EGPA-EM was significantly worse, with a 14.86% death rate and 2-year event-free survival rate below 50%. Furthermore, we proposed a LATE-EAST diagnostic score (7 items, 9 points) to discriminate EGPA-EM from EGPA-ICM using 4 points as threshold [area under the receiver operating characteristic curve 0.85 (95% CI 0.78–0.92), sensitivity 0.78, specificity 0.86]. Conclusions We first proposed different subtypes of cardiac involvement in EGPA. Identification and treatment of EGPA-EM needs improvement. LATE-EAST score could recognize the high-risk EGPA-EM effectively. Multi-disciplinary treatment is warranted, immunosuppressive therapy should be given in a timely manner and anti-IL-5 antibodies should be be tested in trials.

Role of genetics in inflammatory cardiomyopathy

Traditional cardiomyopathy paradigms segregate inflammatory etiologies from those caused by genetic variants. An identified or presumed trigger is implicated in acute myocarditis or chronic inflammatory cardiomyopathy but growing evidence suggests a significant proportion of patients have an underlying cardiomyopathy-associated genetic variant often even when a clear inflammatory trigger is identified. Recognizing a possible genetic contribution to inflammatory cardiomyopathy may have major downstream implications for both the patient and family. The presenting features of myocarditis (i.e. chest pain, arrhythmia, and/or heart failure) may provide insight into diagnostic considerations. One example is isolated cardiac sarcoidosis, a distinct inflammatory cardiomyopathy that carries diagnostic challenges and clinical overlap; genetic testing has increasingly reclassified cases of isolated cardiac sarcoidosis as genetic cardiomyopathy, notably altering management. On the other side, inflammatory presentations of genetic cardiomyopathies are likewise underappreciated and a growing area of investigation. Inflammation plays an important role in the pathogenesis of several familial cardiomyopathies, especially arrhythmogenic phenotypes. Given these clinical scenarios, and the implications on clinical decision making such as initiation of immunosuppression, sudden cardiac death prevention, and family screening, it is important to recognize when genetics may be playing a role.

Myocarditis and Chronic Inflammatory Cardiomyopathy, from Acute Inflammation to Chronic Inflammatory Damage: An Update on Pathophysiology and Diagnosis.

Acute myocarditis covers a wide spectrum of clinical presentations, from uncomplicated myocarditis to severe forms complicated by hemodynamic instability and ventricular arrhythmias; however, all these forms are characterized by acute myocardial inflammation. The term "chronic inflammatory cardiomyopathy" describes a persistent/chronic inflammatory condition with a clinical phenotype of dilated and/or hypokinetic cardiomyopathy associated with symptoms of heart failure and increased risk for arrhythmias. A continuum can be identified between these two conditions. The importance of early diagnosis has grown markedly in the contemporary era with various diagnostic tools available. While cardiac magnetic resonance (CMR) is valid for diagnosis and follow-up, endomyocardial biopsy (EMB) should be considered as a first-line diagnostic modality in all unexplained acute cardiomyopathies complicated by hemodynamic instability and ventricular arrhythmias, considering the local expertise. Genetic counseling should be recommended in those cases where a genotype-phenotype association is suspected, as this has significant implications for patients' and their family members' prognoses. Recognition of the pathophysiological pathway and clinical "red flags" and an early diagnosis may help us understand mechanisms of progression, tailor long-term preventive and therapeutic strategies for this complex disease, and ultimately improve clinical outcomes.

Biomarkers in Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Updated Review of the Literature.

Myocarditis is a disease caused by cardiac inflammation that can progress to dilated cardiomyopathy, heart failure, and eventually death. Several etiologies, including autoimmune, drug-induced, and infectious, lead to inflammation, which causes damage to the myocardium, followed by remodeling and fibrosis. Although there has been an increasing understanding of pathophysiology, early and accurate diagnosis, and effective treatment remain challenging due to the high heterogeneity. As a result, many patients have poor prognosis, with those surviving at risk of long-term sequelae. Current diagnostic methods, including imaging and endomyocardial biopsy, are, at times, expensive, invasive, and not always performed early enough to affect disease progression. Therefore, the identification of accurate, cost-effective, and prognostically informative biomarkers is critical for screening and treatment. The review then focuses on the biomarkers currently associated with these conditions, which have been extensively studied via blood tests and imaging techniques. The information within this review was retrieved through extensive literature research conducted on major publicly accessible databases and has been collated and revised by an international panel of experts. The biomarkers discussed in the article have shown great promise in clinical research studies and provide clinicians with essential tools for early diagnosis and improved outcomes.

P90 CAMPYLOBACTER JEJUNI–ASSOCIATED MYOCARDITIS: A RARE BACTERIAL TRIGGER OF ACUTE MYOCARDITIS

Abstract Introduction Acute myocarditis is an important cause of chest pain in the young, with potential acute arrhythmic and hemodynamic complications and possible evolution into chronic inflammatory cardiomyopathy. Even though multiple triggers can be recognized, bacterial infections are rarely associated with myocarditis in immunocompetent patients. Case report A 22–year–old Caucasian woman presented to the Emergency Department with stabbing chest pain exacerbated by breathing, for several hours, without fever. She experienced diarrhea and gastroenteric symptoms for 4 days. One year prior she experienced identical pain during an acute myocarditis episode, with no clear trigger. The patient’s father too suffered from myocarditis a few months earlier. She underwent routine blood tests with evidence of elevated troponin HS (peak 8000 ng/L) and PCR (82mg/L). ECG showed sinus rhythm and anterolateral concave ST elevation of a maximum of 2 mm. Echocardiography showed normal bi–ventricular dimensions, thickness, regional motion, and absence of pericardial effusion. MRI exhibited inferolateral subepicardial edema and late gadolinium enhancement (LGE). The previous MRI performed 6 months after the resolution of the previous myocarditis did not show any LGE or edema. We began empirical anti–inflammatory therapy with swift benefit. Due to the persistence of gastroenteric symptoms, fecal film array and coproculture were performed and resulted positive for Campylobacter Jejuni, treated with Azithromycin 500 mg/day for 3 days. Finally, considering the recurrent event and the family history of myocarditis in the father, a genetic test was planned to exclude a “hot phase” in the context of arrhythmogenic cardiomyopathy. Discussion Up to 80% of acute myocarditis has an infectious trigger. The recent 2020 consensus advises against routine serology unless specific pathogens are suspected. In the literature, Campylobacter Jejuni is reported as a trigger of various inflammatory diseases, including acute myocarditis. We suggest investigating the presence of this bacterium in stool in case of active gastroenteric symptoms and adding targeted antibiotic therapy in case of active bacterial infection. Previous case reports excluded viral in myocarditis patients positive for Campylobacter. This may support C. Jejuni’s causal role and not as an innocent bystander.

Prognosis evaluation of chronic inflammatory cardiomyopathy with ring-like late gadolinium enhancement.

Ring-like late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging is a special LGE pattern in patients with chronic inflammatory cardiomyopathy (infl-CMP), which is associated with cardiac dysfunction and ventricular remodelling and attributed to viral infection followed by bacterial and parasitic infections. Data on the combination of CMR imaging and clinical parameters that can add long-term prognostic value in patients with infl-CMP are still rare. We aimed to evaluate the prognostic value of CMR in risk stratification in this kind of patients. A total of 319 consecutive patients with clinically suspected myocarditis were retrospectively identified. Forty-seven patients with ring-like LGE on CMR who diagnosed as infl-CMP, and 72 patients with other LGE pattern were eligible for standardized follow-up. The left ventricle (LV) and right ventricle function and mass were analyses by CMR. Myocardial strain of the ventricles was evaluated by feature tracking. Major (cardiac death, resuscitated cardiac arrest, ventricular assist device, transplantation, and appropriate implantable cardioverter-defibrillator shock) and minor (rehospitalization due to heart failure and sustained atrial fibrillation) adverse cardiovascular events were assessed during follow-up since the date of nCMR examination. Cox proportional hazards model was used to investigate which of the prognostic factors identified by univariable analysis were significantly associated with cardiac events. In the ring-like LGE group, adverse cardiac events occurred in 14 (31.11%) patients, including 7 deaths (15.56%), 6 (13.33%) heart-failure hospitalizations, and 1 (2.22%) case of sustained atrial fibrillation during the mean follow-up period of 70.15±45.68months (interquartile range: 32.83-103.71months). No major or minor adverse cardiac event occurred in the other LGE pattern group, except rehospitalization in one patient due to arrhythmia. Further analyses of ring-like LGE group by univariable and Multivariable Cox proportional hazard regression analysis showed that body mass index (BMI) (hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.40-0.73, P=0.000), right ventricle cardiac index (RVCI) (HR: 0.31, 95% CI: 0.14-0.71, P=0.002), LV basal peak circumferential strain (LV-PCSbasal ) (HR: 1.26, 95% CI: 1.11-1.43, P=0.000) were independently associated with the long-term outcome. Receiver operator characteristic curve indicated that the cut-off of LV-PCSBasal was -7.95%, and it has added prognostic value to BMI and RVCI. For infl-CMP patients with ring-like LGE on CMR, low BMI and RVCI were associated with a poor prognosis. LV-PCSBasal with a cut-off of -7.95% can add prognostic value for patients with infl-CMP who have ring-like LGE.

Immunosuppressive therapy in virus-negative inflammatory cardiomyopathy: 20-year follow-up of the TIMIC trial.

AimsLong-term results of the Tailored IMmunosuppression in virus-negative Inflammatory Cardiomyopathy (TIMIC) trial protocol have been evaluated.Methods and resultsEighty-five patients with endomyocardial biopsy-proven virus-negative chronic inflammatory cardiomyopathy were enrolled in the randomized, double-blind, placebo-controlled TIMIC trial and received prednisone and azathioprine (n = 43) vs. placebo (n = 42) for 6 months. Immunosuppressive treatment promoted an improvement in cardiac function in 88% of the cases compared with none of the patients in the placebo group, which were switched to a 6-month immunosuppressive therapy at the end of the 6-month study period. Long-term (up to 20 years) clinical outcomes of the whole cohort of 85 patients originally enrolled in the TIMIC trial (Group A) were compared with those of a 1:2 propensity score-matched control cohort of patients untreated with the TIMIC protocol (Group B) and followed for a comparable period of time. The primary outcome was a composite of cardiovascular death and heart transplantation. At long-term follow-up, the risk of cardiovascular death [hazard ratio (HR) 6.77; 95% confidence interval (CI) 2.36–19.45] and heart transplantation (HR 7.92; 95% CI 1.80–34.88) was significantly higher in Group B patients. Group A showed a persistent improvement in the left ventricular ejection fraction compared with Group B (HR 7.24; 95% CI 3.05–17.18). A higher number of Group B patients underwent implantable cardioverter defibrillator implantation. The incidence of recurrent myocarditis was similar between groups, and patients with evidence of a recurrent cardiac inflammatory process promptly responded to a TIMIC protocol application.ConclusionVirus-negative inflammatory cardiomyopathy benefits from immunosuppressive therapy even after long-term follow-up. Recurrence appears to respond to a new TIMIC protocol application.

State-of-the-Art of Endomyocardial Biopsy on Acute Myocarditis and Chronic Inflammatory Cardiomyopathy.

Purpose of ReviewHistologic evidence of myocardial inflammatory infiltrate not secondary to an ischemic injury is required by current diagnostic criteria to reach a definite diagnosis of myocarditis. Endomyocardial biopsy (EMB) is therefore often indicated for the diagnosis of myocarditis, although it may lack sufficient sensitivity considering the limited possibility of myocardial sampling. Improving the diagnostic yield and utility of EMB is of high priority in the fields of heart failure cardiology and myocarditis in particular. The aim of the present review is to highlight indications, strengths, and shortcomings of current EMB techniques, and discuss innovations currently being tested in ongoing clinical studies, especially in the setting of acute myocarditis and chronic inflammatory cardiomyopathy.Recent FindingsEMB provides unique diagnostic elements and prognostic information which can effectively guide the treatment of myocarditis. Issues affecting the diagnostic performance in the setting of acute myocarditis and chronic inflammatory cardiomyopathies will be discussed in this review in the light of recent expert consensus documents on the management of these conditions and on indication to EMB. Recent innovations using electroanatomic mapping (EAM)-guided EMB and fluoroscopic-guided EMB during temporary mechanical circulatory support have improved the utility of the procedure.SummaryEMB remains an important diagnostic test whose results need to be interpreted in the context of (1) clinical pre-test probability, (2) timing of sampling, (3) quality of sampling (4) site of sampling, (5) histologic type of myocarditis, and (6) analytic methods that are applied. Herein we will review these caveats as well as perspectives and innovations related to the use of this diagnostic tool.

Should We Stay or Should We Go? A Review of Current Management of Non-COVID-19 Acute Myocarditis in a Rural Setting and a Suggested Risk-Based Approach

Acute myocarditis (AM) is uncommon but may be associated with significant acute deterioration, requiring emergency high-level tertiary level care. We therefore sought to examine the contemporary management of myocarditis presenting to a rural referral centre, comparing this to a recently proposed “risk-based approach” [[1]Ammirati E. Frigerio M. Adler E.D. Basso C. Birnie D.H. Brambatti M. et al.Management of acute myocarditis and chronic inflammatory cardiomyopathy: an expert consensus document.Circ Heart Fail. 2020; 13 (e007405)Crossref PubMed Scopus (103) Google Scholar], providing a framework based on risk of deterioration, to help select those requiring transfer for tertiary level care. We conducted a retrospective review of all presentations coded as myocarditis to a rural Australian centre, between May 2019 and June 2021. Twenty-four (24) patients were identified. Five of these were transferred for tertiary level care, all of whom had myocarditis confirmed on cardiac magnetic resonance imaging (CMRI). The estimated AM incidence was 43 per million. Factors associated with transfer were younger age (26 vs 49yrs, p=0.03) and higher troponin I rise (30,986 vs 6,124 ng/L, p=0.01). Reasons for transfer included cardiogenic shock, tachyarrhythmias, concern for potential deterioration, and diagnostic uncertainty. There was one mortality, unrelated to myocarditis. Applying the Ammirati risk-based criteria to transferred patients suggested 1 patient was high risk, 1 was medium risk and 3 were low risk but required CMRI for diagnostic clarity. A risk-based model, based on clinical findings, echocardiography, and cardiac monitoring, safely selects patients requiring tertiary care. However, without routine use of CMRI, there may be the tendency to transfer some patients subsequently found to be low risk, thereby over-utilising resources. Planned wider availability of CMRI in rural settings might be expected to ameliorate this difficulty.

The Oxidative Stress and Chronic Inflammatory Process in Chagas Disease: Role of Exosomes and Contributing Genetic Factors

Chagas disease is a neglected tropical disease caused by the flagellated protozoa Trypanosoma cruzi that affects several million people mainly in Latin American countries. Chagas disease has two phases, which are acute and chronic, both separated by an indeterminate time period in which the infected individual is relatively asymptomatic. The acute phase extends for 40-60 days with atypical and mild symptoms; however, about 30% of the infected patients will develop a symptomatic chronic phase, which is characterized by either cardiac, digestive, neurological, or endocrine problems. Cardiomyopathy is the most important and severe result of Chagas disease, which leads to left ventricular systolic dysfunction, heart failure, and sudden cardiac death. Most deaths are due to heart failure (70%) and sudden death (30%) resulting from cardiomyopathy. During the chronic phase, T. cruzi-infected macrophages respond with the production of proinflammatory cytokines and production of superoxide and nitric oxide by the NADPH oxidase 2 (NOX2) and inducible nitric oxide synthase (iNOS) enzymes, respectively. During the chronic phase, myocardial changes are produced as a result of chronic inflammation, oxidative stress, fibrosis, and cell death. The cellular inflammatory response is mainly the result of activation of the NF-κB-dependent pathway, which activates gene expression of inflammatory cytokines, leading to progressive tissue damage. The persisting production of reactive oxygen species (ROS) is the result of mitochondrial dysfunction in the cardiomyocytes. In this review, we will discuss inflammation and oxidative damage which is produced in the heart during the chronic phase of Chagas disease and recent evidence on the role of macrophages and the production of proinflammatory cytokines during the acute phase and the origin of macrophages/monocytes during the chronic phase of Chagas disease. We will also discuss the contributing factors and mechanisms leading to the chronic inflammation of the cardiac tissue during the chronic phase of the disease as well as the innate and adaptive host immune response. The contribution of genetic factors to the progression of the chronic inflammatory cardiomyopathy of chronic Chagas disease is also discussed. The secreted extracellular vesicles (exosomes) produced for both T. cruzi and infected host cells can play key roles in the host immune response, and those roles are described. Lastly, we describe potential treatments to attenuate the chronic inflammation of the cardiac tissue, designed to improve heart function in chagasic patients.

115 Prognostic significance of iron deficiency status in chronic inflammatory cardiomyopathy

Abstract Aims Iron deficiency (ID) and associated anaemia (IDA) represent major comorbidities in chronic diseases. However, their prevalence and prognostic significance have never been investigated in chronic inflammatory cardiomyopathy (CIC). Methods and results This is a single-centre, prospective study, on consecutive adult patients with CIC (symptom onset > 3 months, endomyocardial biopsy-proven chronic myocarditis) undergoing iron status assessment (enrollment: January 2014–January 2019). ID was defined as either serum ferritin < 100 µg/l or transferrin saturation < 20%. IDA was defined as haemoglobin < 12 g/dl in women, < 13 g/dl in men. The primary endpoint was the occurrence of heart failure events (HFE) and/or arrhythmic events (AE). The study cohort is composed by 219 CIC patients (mean age 46 ± 15 y, 71% males, mean LVEF 50 ± 14%). Diagnosis was furtherly supported by cardiac magnetic resonance in 194 cases (89%). Baseline characteristics of patients with IDA (n = 48), ID (n = 70), and non-ID controls (n = 101) were largely comparable. We found that median in-hospital stay length was 13 days (IQR: 6–20) in IDA patients vs. 8 (IQR: 5–11) in the remaining groups (P = 0.002), and was inversely correlated with haemoglobin values on admission. By 3.9 ± 1.8 year prospective follow-up, events occurred in 86 patients (39%). For the composite endpoint, the only factors associated with events were ID status (HR: 6.3, 95% CI: 2.1–19.5, P = 0.001) and male gender (HR: 5.4, 95% CI: 1.2–24.9, P = 0.030). In detail, HFE occurred in 48 patients (40/118 IDA or ID vs. 8/101 controls, P < 0.001), and AE in 51 (34/118 IDA or ID vs. 17/101 controls, P = 0.039). All cardiac deaths (n = 7) occurred in ID or IDA patients (P = 0.016; n = 1 and 6, respectively). Conclusions ID and IDA are common among CIC patients, and may bare a negative prognostic value. Our findings suggest a careful evaluation of haemoglobin levels and iron status, and call for further investigation on both pathophysiological and prognostic implications of ID and IDA among CIC patients.

Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation in a murine model of early chronic Chagas disease.

Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and is widely distributed worldwide because of migration. In 30% of cases, after years of infection and in the absence of treatment, the disease progresses from an acute asymptomatic phase to a chronic inflammatory cardiomyopathy, leading to heart failure and death. An inadequate balance in the inflammatory response is involved in the progression of chronic Chagas cardiomyopathy. Current therapeutic strategies cannot prevent or reverse the heart damage caused by the parasite. Aspirin-triggered resolvin D1 (AT-RvD1) is a pro-resolving mediator of inflammation that acts through N-formyl peptide receptor 2 (FPR2). AT-RvD1 participates in the modification of cytokine production, inhibition of leukocyte recruitment and efferocytosis, macrophage switching to a nonphlogistic phenotype, and the promotion of healing, thus restoring organ function. In the present study, AT-RvD1 is proposed as a potential therapeutic agent to regulate the pro-inflammatory state during the early chronic phase of Chagas disease. C57BL/6 wild-type and FPR2 knock-out mice chronically infected with T. cruzi were treated for 20 days with 5 μg/kg/day AT-RvD1, 30 mg/kg/day benznidazole, or the combination of 5 μg/kg/day AT-RvD1 and 5 mg/kg/day benznidazole. At the end of treatment, changes in immune response, cardiac tissue damage, and parasite load were evaluated. The administration of AT-RvD1 in the early chronic phase of T. cruzi infection regulated the inflammatory response both at the systemic level and in the cardiac tissue, and it reduced cellular infiltrates, cardiomyocyte hypertrophy, fibrosis, and the parasite load in the heart tissue. AT-RvD1 was shown to be an attractive therapeutic due to its regulatory effect on the inflammatory response at the cardiac level and its ability to reduce the parasite load during early chronic T. cruzi infection, thereby preventing the chronic cardiac damage induced by the parasite.

Cardiovascular consequences of viral infections: from COVID to other viral diseases.

Infection of the heart muscle with cardiotropic viruses is one of the major aetiologies of myocarditis and acute and chronic inflammatory cardiomyopathy (DCMi). However, viral myocarditis and subsequent dilated cardiomyopathy is still a challenging disease to diagnose and to treat and is therefore a significant public health issue globally. Advances in clinical examination and thorough molecular genetic analysis of intramyocardial viruses and their activation status have incrementally improved our understanding of molecular pathogenesis and pathophysiology of viral infections of the heart muscle. To date, several cardiotropic viruses have been implicated as causes of myocarditis and DCMi. These include, among others, classical cardiotropic enteroviruses (Coxsackieviruses B), the most commonly detected parvovirus B19, and human herpes virus 6. A newcomer is the respiratory virus that has triggered the worst pandemic in a century, SARS-CoV-2, whose involvement and impact in viral cardiovascular disease is under scrutiny. Despite extensive research into the pathomechanisms of viral infections of the cardiovascular system, our knowledge regarding their treatment and management is still incomplete. Accordingly, in this review, we aim to explore and summarize the current knowledge and available evidence on viral infections of the heart. We focus on diagnostics, clinical relevance and cardiovascular consequences, pathophysiology, and current and novel treatment strategies.

February 2021 at a glance: focus on amyloidosis, myocarditis and cardiomyopathy

Cardiac amyloidosis (CA) is emerging as a major cause of heart failure (HF).1-3 Castiglione et al.4 reviewed the role of circulating biomarkers as tools to guide diagnosis, prognostic stratification, and therapy in CA. The independent prognostic role of cardiopulmonary exercise testing in patients with light chain or transthyretin CA (TTR-CA) was shown by Nicol et al.5 in a multicentre study. Both peak oxygen consumption (VO2) ≤13 mL/kg/min and N-terminal pro B-type natriuretic peptide (NT-proBNP) ≥1800 ng/L had independent prognostic value with a hazard ratio (HR) of 2.7 [95% confidence interval (CI) 1.6–4.8] and 2.2 (95% CI 1.1–4.3), respectively. No events occurred in patients with peak VO2 >13 mL/kg/min and NT-proBNP <1800 ng/L during a median follow-up of 20 months, despite overall 25% mortality and 29% hospitalization rates. Amyloidosis may be present in patients with severe aortic stenosis.2, 6 TTR-CA was detected in 13% of patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. It had no impact on mortality but was associated with a higher HF hospitalization rate during a 3-year follow-up.3 Tafamidis has emerged as an effective treatment option to improve prognosis in patients with TTR-CA.7, 8 A single-centre study in 648 real-world patients with TTR-CA matching the inclusion criteria of the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) showed a significant benefit of tafamidis on major cardiovascular outcomes (HR after propensity score matching 0.546, P = 0.0132).9 In an analysis of the long-term extension of ATTR-ACT, both tafamidis 80 mg and 20 mg reduced all-cause mortality and cardiovascular hospitalizations at 30 months compared with placebo, with the higher dose associated with better outcomes without safety issues in the long-term extension.10 Sinagra et al.11 reviewed data about the role of viral detection for immunomodulation in acute lymphocytic myocarditis, highlighting current limitations of this approach and providing a framework for future dedicated studies. The Authors pointed out that the value of viral presence to guide immunosuppressive treatment in lymphocytic myocarditis requires more evidence and remains a subject of debate. As a further support, intravenous immunoglobulin did not improve cardiac systolic function or functional status in patients with chronic inflammatory cardiomyopathy, namely idiopathic dilated cardiomyopathy with parvovirus B19 persistence, in a randomized controlled trial.12 Over the last years, improvement in survival was observed in patients with dilated cardiomyopathy, with many patients with new-onset cardiomyopathy who may show reverse remodelling.13, 14 In TRED-HF, withdrawal of pharmacological treatment for HF in patients with recovered dilated cardiomyopathy was associated with relapses in 44% of patients.15 In a further analysis by cardiac magnetic resonance, treatment withdrawal resulted in early ventricular remodelling with an increase in myocardial mass and a reduction in global longitudinal strain. Interestingly, these changes may also occur in patients who do not show clinical deterioration.16 Shorter left ventricular systolic ejection time has been identified as a marker of worse prognosis among patients with HF with reduced ejection fraction (HFrEF).17 Alhakak et al.18 confirmed the prognostic impact of left ventricular systolic ejection time on mortality in a large HFrEF population (per 10 ms decrease: adjusted HR 1.06, 95% CI 1.01–1.11, P = 0.030), hence supporting its use to stratify patients' risk and to guide therapeutic response. Heightened chemosensitivity has a major role in the excessive ventilatory response to exercise and sleep breathing abnormalities in patients with HF. Buspirone, a 5HT1A receptor agonist that inhibits serotonergic chemoreceptor neuron firing, reduced carbon dioxide chemosensitivity and improved central apnoeas in patients with HF.19 A relatively large number of patients with advanced HF may benefit from long-term mechanical circulatory support.20 This indication might be further expanded if this device therapy may cause regression of myocardial fibrosis. Unfortunately, such hypothesis was not proven in a recent study in 125 patients.21

ANMCO/SIC Consensus document on the management of myocarditis

Myocarditis is an inflammatory heart disease that can occur acutely, as in acute myocarditis, or persistently, as in chronic myocarditis or chronic inflammatory cardiomyopathy. Different agents can induce myocarditis, with viruses being the most common triggers. Generally, acute myocarditis affects relatively young people and men more than women. Myocarditis has a broad spectrum of clinical presentations and evolution trajectories, although most cases resolve spontaneously. Patients with reduced left ventricular ejection fraction, heart failure symptoms, advanced atrioventricular block, sustained ventricular arrhythmias or cardiogenic shock (the latter known as fulminant myocarditis) are at increased risk for death and heart transplantation. The presentation of chronic inflammatory cardiomyopathy may be more subtle, with progressive symptoms of heart failure or appearance of rhythm disturbance, not rarely preceded by an infective episode. Autoimmune disorder or systemic inflammatory conditions can be another significant predisposing substrate of myocarditis, especially in women. Emerging causes of myocarditis are drug-related like the new anticancer therapies, the immune checkpoint inhibitors. In this Italian Association of Hospital Cardiologists (ANMCO) and Italian Society of Cardiology (SIC) expert consensus document on myocarditis, we propose diagnostic strategies for identifying possible causes of the disease and factors associated with increased risk. Finally, we propose potential treatments and when referring patients to tertiary centers, especially for high-risk patients. Even if endomyocardial biopsy is the invasive diagnostic tool for making definitive diagnosis and differentiation of histological subtypes (i.e., lymphocytic vs eosinophilic vs giant cell myocarditis), it is not always readily available in all centers. Thus, we propose when this exam is mandatory or when it can be postponed or substituted by cardiac magnetic resonance imaging. This document reflects the Italian perspective on managing patients with myocarditis and their follow-up, considering also current US and European scientific position statements.

Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document.

Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month). In contrast, chronic inflammatory cardiomyopathy indicates myocardial inflammation with established dilated cardiomyopathy or hypokinetic nondilated phenotype, which in the advanced stages evolves into fibrosis without detectable inflammation. Suggested diagnostic and treatment recommendations for AM and chronic inflammatory cardiomyopathy are mainly based on expert opinion given the lack of well-designed contemporary clinical studies in the field. We will provide a shared and practical approach to patient diagnosis and management, underlying differences between the European and US scientific statements on this topic. We explain the role of histology that defines subtypes of myocarditis and its prognostic and therapeutic implications.

Treatment of virus negative chronic myocarditis: long term follow-up of TIMIC trial

Abstract Background The TIMIC trial demonstrated the short term efficacy of immunosuppression (IMS) in virus-negative inflammatory cardiomyopathy. However long term outcome of patients responsive to this treatment is still unclear. Purpose To assess the long term outcome of patients enrolled in the TIMIC trial. Methods The 85 (51 M, 34 F, 42.7±14.7 years) patients with endomyocardial biopsy proven virus-negative chronic inflammatory cardiomyopathy, enrolled in the TIMIC trial and treated either with prednisone and azathioprine (prednisone 1mg kg–1 day–1 for 4 weeks followed by 0.33 mg kg–1 day–1 for 5 months and azathioprine 2 mg kg–1 day–1 for 6 months) or placebo for 6 months, were evaluated in a long-term follow-up of up to 18 years (mean 15.2±2.0 SD, range 12–18 ys). Patients treated with placebo at the end of the 6-month enrollment because of the lack of improvement received IMS for further 6 months. Results At 6 months' follow-up 89% patients showed a significant improvement of left ventricular ejection fraction compared to baseline (LVEF rising from 27.0±5.7 to 46.2±6.4, % p&amp;lt;0.001). This improvement was maintained in the long term follow-up (LVEF 51.1±6.4%, p&amp;lt;0.001). Importantly, the 42 patients initially on placebo showed an improvement comparable to the branch on IMS either on short (EF from 27.7% to 46.8±6.2%) and on long term follow up (LVEF from 27.7% to 50.6±5.6%, p&amp;lt;0.001). Nine patients (11%) did not show a significant improvement of LVEF either at short and long term follow-up and among them 4 died and 2 had a cardiac transplantation. Five patients (5.8%) had a relapse of the cardiac inflammatory process that promptly responded to a new TIMIC dose treatment. Four of them (4F, 41.2±9.4 ys age) had concomitant autoimmune diseases and the relapse was within the first 2 years after IMS discontinuation. One patient (M, 56 ys) had a relapse after 10 years following a flu-like syndrome. Conclusion Immunosuppressive therapy of virus negative inflammatory cardiomyopathy warrants in susceptible patients a long term recovery of heart function with very low incidence of recurrences, that respond to a new TIMIC protocol dose treatment. Long term efficacy of TIMIC-IMS therapy Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): AIFA

P340Inflammatory cardiomyopathy in Fabry disease

Abstract Background Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in α-galactosidase A. Cardiovascular magnetic resonance (CMR) has helped unveil the pathogenesis of Fabry cardiomyopathy: sphingolipid storage (low T1 mapping values), left ventricular hypertrophy (LVH) and myocardial fibrosis with late gadolinium enhancement (LGE) characteristically present in the basal inferolateral (BIFL) wall. Recent evidence has suggested that the LGE may be inflammation and oedema as part of this pathogenic process. Purpose To assess the presence of inflammation in patients with FD using T2 mapping (for oedema/inflammation) supported by blood troponin levels (showing myocyte death and by inference inflammation). Methods A multi-centre international study in gene positive FD patients using CMR and blood biomarkers. All participants underwent CMR at 1.5 T. Native T1 and T2 mapping were performed. The T1 mapping sequence was MOLLI with sampling scheme in seconds. LGE used a phase sensitive inversion recovery sequence. Global longitudinal 2D strain (GLS) values were obtained using feature tracking analysis. Blood high-sensitivity troponin T (hsTnT) was measured on the same day. Results 100 FD patients (age 43.8±1.3 years, 42% male) were included. 45% had LVH, 35% LGE. Low T1 mapping (normal &lt;943ms) was found in 49% and 33% had high hsTnT values (normal &lt;15ng/L). Mean T2 mapping values were 52.6±0.6ms in the BIFL wall and 49.5±0.3ms in the remote myocardium/septum (p&lt;0.001, normal &lt;53ms). T2 values in the BIFL wall were significantly higher among patients with LGE (58.2±6.1ms vs 49.2±3.1ms, p&lt;0.001, Figure 1). In a per-segment analysis of 1600 segments, higher T2 values correlated positively with percentage of LGE per segment (r=0,262, p&lt;0.001), T1 values (r=0,205, p&lt;0.001), maximum wall thickness (r=0,253, p&lt;0.001) and GLS values (r=0,212, p&lt;0.001). HsTnT values were higher among patients with LGE (median of 31 vs 3ng/L in patients without LGE, p&lt;0.001). There was a strong positive correlation between T2 values in the BIFL wall and ln(hsTnT) (r=0.776, p&lt;0.001, Figure 2). The strongest predictor of increased hsTnT in multivariate analysis (age, sex, LVH, septum T1, T2 in the BIFL, GLS, LGE) was T2 in the BIFL wall (β=0.4, p=0.001). Conclusions Cardiac involvement in FD goes beyond storage (low T1 values). When LGE is present, this is almost always associated with a high T2 and troponin elevation supporting FD as a chronic inflammatory cardiomyopathy. Initial reports of LGE being fibrosis are too simplistic – LGE in FD appears to have a significant chronic inflammation/oedema component.

O18-2 - Inflammatory Cardiomyopathy Associated with Rheumatoid Arthritis Treated with Left Ventricular Assist Device

Cardiovascular involvement is common in patients with rheumatoid arthritis (RA), however, advanced heart failure is rare. We report a case of severe heart failure who required the placement of left ventricular assist device (LVAD). A 34-year old woman, who had been diagnosed as RA 8 years before and treated with predonisolone and methotrexate, was admitted to the local hospital due to short of breath. She had severe left ventricular (LV) dysfunction with an ejection fraction (EF) of 15%. Twenty days after the recovery by intensive treatment, she was re-hospitalized due to cardiogenic shock requiring intravenous administration of inotropes and intraaortic balloon pump (IABP). She was referred to our institution as a candidate of heart transplantation because she required the continuous infusions of high-dose inotropes. Fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) revealed increased uptake in LV. Histologic examination from right ventricle showed infiltration of CD3-T lymphocytes and diffuse interstitial or replacement myocardial fibrosis. Based on these finding, she was diagnosed as chronic inflammatory cardiomyopathy with little chance of LV recovery. On the other hand, RA was in a state of remission. She was judged as an indication for heart transplantation and underwent a successful placement of LVAD.