Recent highlights on myocarditis and cardiomyopathies from the International Journal of Cardiology and International Journal of Cardiology: Heart & Vasculature

Acute myocarditis (AM) is an inflammatory disease of the myocardium caused by a wide spectrum of infectious or toxic agents or immune system-mediated responses [1]. Although endomyocardial biopsy (EMB) remains the gold standard for AM diagnosis, it is generally reserved for most severe cases [2]. A noninvasive diagnosis of AM is also achievable using cardiac magnetic resonance (CMR), as the diagnostic Lake Louise Criteria have been validated against EMB [3]. The noninvasive diagnostic work-up of relatively rare forms of myocarditis like cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) is still challenging, but is clinically relevant, as GCM is characterized by a rapid progression and a poor prognosis [4].

Bobbio et al. [5] reanalyzed the initial echocardiographic findings of histologically proven cases of GCM and CS versus CMR-verified cases of AM. For both GCM and CS, echocardiography revealed indices of left and right ventricular dysfunction more frequently than in controls, but without further differentiation between the two forms. The same group [6] tried to phenotype GCM versus CS using CMR, but the CMR appearance of both entities was very similar. Thus, the echocardiographic and CMR-based differentiation between GCM and CS remains difficult. Interestingly, a retrospective analysis of outcomes of hospitalized CS patients showed that age and arrhythmic burden were associated with a higher risk for in-hospital mortality, while concomitant heart failure (HF) was not an independent predictor of in-hospital mortality or length of stay [7]. Cancer therapeutics often cause cardiac damage. Although checkpoint inhibitors (ICIs)-related AM is an infrequent complication, it can be life-threatening [8]. Thus, accurate surveillance of ICI-treated patients and use of cardiac biomarkers to diagnose, screen, and monitor patients at risk for ICI-related AM are recommended [9].

AM may occur in patients affected by inflammatory bowel diseases (IBD), and the term cardio-intestinal inflammatory syndrome is often used to describe this clinical entity. AM in this setting may result from infections or immune diseases, and could be due to 5-aminosalicylic acid toxicity [10]. A retrospective analysis [11] of IBD patients showed that AM develops mostly in young males within an acute phase of the IBD and has an overall benign clinical course, even if in some cases it may have a worse prognosis, especially in cases of GCM histology that can occasionally occur. Systemic sclerosis (SSc) is an autoimmune disease with potential cardiac involvement that can affect morbidity and mortality in such patients. CMR can help the diagnosis of myocarditis in patients with SSc. Meloni et al. [12] analyzed CMR findings in a cohort of 55 SSc patients and detected myocardial inflammation in 62% of all cases. They reported the relevance of T1- and T2-mapping to detect early cardiac involvement in asymptomatic patients, which allows risk re-stratification and adoption of early tailored therapies. Pheochromocytoma can induce active catecholaminergic myocarditis that can also lead to cardiogenic shock. A multicenter retrospective trial showed [13] that cardiogenic shock can be reversible in this setting with a good mid-term prognosis.

Cardiovascular complications often accompany COVID-19 infections [14]. The CoV-COR registry [15] showed that myocardial injury including COVID-19 associated myocarditis is relatively common associated with an increased 90-day mortality. A case-report documented the late occurrence of AM after COVID-19 infection [16]. COVID-19 vaccines have been related to rare cases of AM, occurring approximately between 1 in 10,000 and 1 in 100,000 individuals in large registries [17], [18]. Incidence of COVID-19 vaccine-associated myocarditis varies with age, sex, and type of vaccine [19]. Most patients with COVID-19 vaccine-related myocarditis have a benign course [20], with a small incidence of complicated forms. Seitz et al. [21] compared CMR findings in patients referred for suspected mRNA-vaccination-associated myocarditis to myocarditis findings in a pre-COVID period. They demonstrated a lower prevalence of LGE, but a higher prevalence of abnormal T1/T2 mapping in patients with myocarditis following COVID-19 vaccination compared with patients with myocarditis not related to a vaccine. A relatively small amount of LGE in vaccine-related AM has also been observed in another multinational registry [22]. Finally, Ishisaka et al. [23] compared the outcomes of patients with COVID-19 infection vs. mRNA COVID-19 vaccine-associated AM vs. those with AM in a pre-COVID-19 period. They found more favorable outcomes in patients with COVID-19 mRNA vaccination, while incidence rate and mortality were higher in the COVID-19 infection group.

Cardiomyopathies are a heterogeneous group of disorders characterized by structural and functional alterations of the heart muscle not explained by coronary artery disease, hypertension, valvular disease, or congenital heart disease. These entities have been elaborated in one of the latest 2023 guidelines of the European Society of Cardiology [24] and in many articles published recently in our journals. The non-invasive diagnosis of cardiomyopathies often relies on imaging, and many parameters derived from different imaging techniques have clear prognostic value.

Hypertrophic cardiomyopathy (HCM) is the most prevalent genetic heart disease [25]. HCM can present left ventricular (LV) outflow-tract obstruction (LVOTO), which can cause disabling symptoms on exertion. LVOTO can be affected by LV preload. The HCM-Vein study assessed venous function in HCM patients using venous air plethysmography and upper member arterial Doppler echography. They found a 30 % prevalence of venous dysfunction in symptomatic obstructive HCM patients, which tended to be associated with endothelial dysfunction [26]. Further studies are required to assess if LVOTO obstruction could be reversed by improving venous return. A case-control study found a significant association between HCM with or without LVOTO and dilated sinus of Valsalva (SV) on echocardiography regardless of height, weight, and aortic valve disease [27]. The fact that HCM patients have a 9-fold higher prevalence of SV dilatation should prompt regular evaluation of the ascending aorta in clinical practice. The slow progression of the disease can then lead to LV adverse remodeling and progressive dysfunction, termed as the dilative phase of HCM (dHCM) or end-stage HCM, which is associated with a poor prognosis. To timely identify patients at risk for dHCM, a Japanese analysis found that a single-lead digital electrocardiogram (ECG) is a readily available and cost-effective method that can be a valid alternative to eight-lead ECG for mass screening [28]. Also peak systolic-global longitudinal myocardial strain rate on CMR showed a good predictive value to identify patients at risk of cardiovascular events beyond LGE and LV mass [29]. Reduced left atrial reservoir function on CMR was associated with risk of HF at 2-year follow-up [30]. Computational fluid dynamics on cardiac computed tomography might be used to optimize surgical planning in septal myectomy [31]; and LGE entropy reflecting variability and extent of LGE was associated with worse prognosis in patients with HCM [32].

Amyloid cardiomyopathy (CA) is a progressive infiltrative disease characterized by left ventricular hypertrophy (LVH) caused by amyloid depositions within cardiac tissue and is associated with a poor prognosis. The impact of various disease-specific therapies that have been recently introduced in the clinical practice is often limited to patients with advanced-stage disease. Hence, early diagnosis and differentiation of the hypertrophic phenotype is of utmost importance for better management and prognosis. Ota et al. [33] demonstrated that paradoxical hypertrophy (e.g., morphological LVH without electrical voltages augmentation on ECG) can be used for early identifying CA with high diagnostic value even in non-specialized hospitals and proposed a novel diagnostic algorithm for patients with LVH and suspicion of CA. On echocardiography, LV apical sparing is considered a specific marker for CA and a reliable marker of disease progression. In a cohort of patients with wild-type transthyretin CA, only 52% of patients had LV apical sparing at diagnosis, but 29% developed LV apical sparing during the follow-up remarking the relevance of two-dimensional speckle tracking analysis in the follow-up [34]. Furthermore, semi-automatic assessment of apical sparing using novel automated software is reliable, reproducible and time-saving [35]. Increased myocardial extracellular volume (ECV) on CMR is related to expanded interstitium in the myocardium and is therefore associated to CA. Cardiac CT is more widely available, and CT-derived ECV was found to be feasible and associated with ECV derived on CMR, thus making easier the diagnosis of CA even in those setting where CMR is not widely available [36].

Anthracycline cardiac toxicity can limit the use of this anti-cancer agent. Early risk prediction and identification of subtle cardiac dysfunction due to anthracycline cardiotoxicity are clinically relevant to ensure appropriate treatment [37], [38]. Serrano et al. found that diastolic dysfunction detected by echocardiogram in the first year after chemotherapy is a strong predictor of anthracycline cardiotoxicity in a prospective study [39]. Harries et al. identified baseline CMR-derived MAPSE and specific circulating miRNA as markers of poor recovery in LVEF 6 months among patients who underwent anthracycline chemotherapy [40]. In this setting, a multiparametric PET/CMR approach can likely outperform a single parameter or imaging modality in the screening and follow-up of cardiotoxicity [41].

Ventricular arrhythmias (VA) increase the morbidity and mortality of patients with structural heart diseases. Catheter ablation is a mainstay of the treatment of scar related VA, but is associated with risk of heart transplantation or death. Bennet et al. developed the MORTALITIES-VA score including independent predictors of adverse outcomes after VA ablation like LVEF ≤ 35%, age ≥ 65 years, renal impairment, malignancy, and VA recurrence on amiodarone [42]. Wearable cardioverter defibrillator (WCD) is an alternative temporary therapy for primary and secondary prevention of sudden cardiac death (SCD). A systematic review showed that the only available randomized controlled trial failed to demonstrate a prognostic benefit in post-myocardial infarction patients, while observational evidence suggested a good compliance with few serious adverse events. Thus, there is a clear need for more robust evidence on the efficacy of WCD [43].

HCM may manifest with SCD, which occurs mainly in younger patients with a low prevalence in the advanced phases of the disease [44]. Clinical risk stratification scores are used to estimate SCD risk, but appropriate selection of patients requiring a primary prevention with implantable cardioverter defibrillator is still challenging especially in patients with moderate risk. Among moderate-risk patients, scores have lower predictive value and genetic background and LGE on CMR should be exploited as additional tools [45].

Atrial fibrillation (AF) is the most common atrial tachyarrhythmia in patients with obstructive HCM and is associated with increased morbidity and mortality. A recent metanalysis highlighted that surgical AF ablation with Maze procedure at the time of myectomy is safe and effective [46]. In addition, patients with HCM and left atrial dilatation are at high thromboembolic risk regardless of AF, as confirmed by studies based on cardiac implantable electronic device long-term monitoring [47]. AF is a common in patients with CA. In a large retrospective cohort of patients with wild-type transthyretin CA, longer PR and QRS duration and left atrial dilation emerged as risk factors for AF recurrences [48].

Patients with cardiomyopathy may present with HF with reduced EF (HFrEF), HF with mildly reduced EF (HFmrEF), or HF with preserved EF (HFpEF). Patients with HFrEF have the worst prognosis, although patients with HFpEF also show substantial morbidity and mortality [49]. A study conducted in black individuals affected by dilated cardiomyopathy showed that patients with new-onset HFrEF have a younger age at presentation with a relatively high mortality rate of 19% at 1 year [50].

The risk assessment of HF progression is a milestone in the management of patients with cardiomyopathies. In patients with CA, chest pain reflects a more advanced cardiac impairment and confers a higher risk for future HF hospitalizations [51]. Moreover, in patients with established cardiovascular disease, metabolic syndrome and insulin resistance increase the risk of incident HF with either reduced or preserved EF [52]. An analysis of asymptomatic patients with cardiovascular diseases enrolled in the CHART-2 multicentric study found that serial chest X-ray assessments may be useful in predicting progression to symptomatic HF [53].

HF is often associated with systemic inflammation and high levels of circulating inflammatory cytokines have been detected, particularly in patients with obesity. A metanalysis showed the efficacy of aerobic exercise and training interventions for improving inflammatory markers in patients with HF across the LVEF spectrum [54]. The benefits of exercise were confirmed in patients with chronic Chagas cardiomyopathy, in which exercise-based training programs improve the quality of life and exercise capacity [55]. Of note, HF treatments improving quality of life did not demonstrate a significant effect on cardiovascular and all-cause mortality even if correlated with a lower risk of HF hospitalization [56].

The International Journal of Cardiology and the International Journal of Cardiology: Heart & Vasculature have recently published many manuscripts related to myocarditis and cardiomyopathy and their complications, and will continue to contribute new knowledge about the diagnosis, treatment, and prognosis of frequent cardiac diseases, thereby serving as publishing platforms for the dissemination of new insights related to cardiovascular diseases.

Sources of funding

The authors’ work is supported by grants from Italian Ministry of Health [GR-2019-12368506, to E.A.], the National Institutes of Health [R01-HL131517, R01-HL136389, R01-HL089598, R01HL163277, R01HL160992, and R01HL165704 to D.D.], and European Union [large-scale integrative project MAESTRIA, No. 965286 to D.D.].

Disclosures

Dr. Ammirati received a grant from the Italian Ministry of Health (GR-2019-12368506; principal investigator of the investigator-driven MYTHS [Myocarditis Therapy with Steroids] trial) and a grant from the European Union NextGenerationEU (PNRR-MAD-2022-12376225) and is a consultant for Kiniksa and Cytokinetics. The other authors have nothing to disclose related to this work.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.