Secondary tricuspid regurgitation: incidence, types, and outcomes in atrial fibrillation vs. sinus rhythm.

BACKGROUND AND AIMS: Incidence and types of secondary tricuspid regurgitation (TR) are not well defined in atrial fibrillation (AFib) and sinus rhythm (SR). Atrial secondary TR (A-STR) is associated with pre-existing AFib; however, close to 50% of patients with A-STR do not have AFib. The aim of this study was to assess incidence, types, and outcomes of ≥ moderate TR in AFib vs. SR. METHODS: Adults with and without new-onset AFib without structural heart disease or ≥ moderate TR at baseline were followed for the development of ≥ moderate TR. Tricuspid regurgitation types were pacemaker, left-sided valve disease, left ventricular (LV) dysfunction, pulmonary hypertension (PH), isolated ventricular, and A-STR. RESULTS: Among 1359 patients with AFib and 20 438 in SR, 109 and 378 patients developed ≥ moderate TR, respectively. The individual types of TR occurred more frequently in AFib related to the higher pacemaker implantation rates (1.12 vs. 0.19 per 100 person-years, P < .001), larger right atrial size (median 78 vs. 53 mL, P < .001), and higher pulmonary pressures (median 30 vs. 28 mmHg, P < .001). The most common TR types irrespective of rhythm were LV dysfunction-TR and A-STR. Among patients in SR, those with A-STR were older, predominantly women with more diastolic abnormalities and higher pulmonary pressures. All types of secondary TR were associated with all-cause mortality, highest in PH-TR and LV dysfunction-TR. CONCLUSIONS: New-onset AFib vs. SR conferred a higher risk of the individual TR types related to sequelae of AFib and higher pacemaker implantation rates, although the distribution of TR types was similar. Secondary TR was universally associated with increased mortality.

Magnetic Resonance Imaging Characterization and Clinical Outcomes of Dilated and Arrhythmogenic Left Ventricular Cardiomyopathies.

BACKGROUND: Nondilated left ventricular cardiomyopathy (NDLVC) has been recently differentiated from dilated cardiomyopathy (DCM). A comprehensive characterization of these 2 entities using cardiac magnetic resonance (CMR) and genetic testing has never been performed. OBJECTIVES: This study sought to provide a thorough characterization and assess clinical outcomes in a large multicenter cohort of patients with DCM and NDLVC. METHODS: A total of 462 patients with DCM (227) or NDLVC (235) with CMR data from 4 different referral centers were retrospectively analyzed. The study endpoint was a composite of sudden cardiac death or major ventricular arrhythmias. RESULTS: In comparison to DCM, NDLVC had a higher prevalence of pathogenic or likely pathogenic variants of arrhythmogenic genes (40% vs 23%; P < 0.001), higher left ventricular (LV) systolic function (LV ejection fraction: 51% ± 12% vs 36% ± 15%; P < 0.001) and higher prevalence of free-wall late gadolinium enhancement (LGE) (27% vs 14%; P < 0.001). Conversely, DCM showed higher prevalence of pathogenic or likely pathogenic variants of nonarrhythmogenic genes (23% vs 12%; P = 0.002) and septal LGE (45% vs 32%; P = 0.004). Over a median follow-up of 81 months (Q1-Q3: 40-132 months), the study outcome occurred in 98 (21%) patients. LGE with septal location (HR: 1.929; 95% CI: 1.033-3.601; P = 0.039) was independently associated with the risk of sudden cardiac death or major ventricular arrhythmias together with LV dilatation, older age, advanced NYHA functional class, frequent ventricular ectopic activity, and nonsustained ventricular tachycardia. CONCLUSIONS: In a multicenter cohort of patients with DCM and NDLVC, septal LGE together with LV dilatation, age, advanced disease, and frequent and repetitive ventricular arrhythmias were powerful predictors of major arrhythmic events.

Cutaneous Stigmata of Bacterial Endocarditis.

This case report describes Osler nodes and Janeway lesions on a man in his 70s.

Role of arrhythmic phenotype in prognostic stratification and management of dilated cardiomyopathy.

AIMS: Dilated cardiomyopathy (DCM) with arrhythmic phenotype combines phenotypical aspects of DCM and predisposition to ventricular arrhythmias, typical of arrhythmogenic cardiomyopathy. The definition of DCM with arrhythmic phenotype is not universally accepted, leading to uncertainty in the identification of high-risk patients. This study aimed to assess the prognostic impact of arrhythmic phenotype in risk stratification and the correlation of arrhythmic markers with high-risk arrhythmogenic gene variants in DCM patients. METHODS AND RESULTS: In this multicentre study, DCM patients with available genetic testing were analysed. The following arrhythmic markers, present at baseline or within 1 year of enrolment, were tested: unexplained syncope, rapid non-sustained ventricular tachycardia (NSVT), ≥1000 premature ventricular contractions/24 h or ≥50 ventricular couplets/24 h. LMNA, FLNC, RBM20, and desmosomal pathogenic or likely pathogenic gene variants were considered high-risk arrhythmogenic genes. The study endpoint was a composite of sudden cardiac death and major ventricular arrhythmias (SCD/MVA). We studied 742 DCM patients (45 ± 14 years, 34% female, 410 [55%] with left ventricular ejection fraction [LVEF] <35%). During a median follow-up of 6 years (interquartile range 1.6-12.1), unexplained syncope and NSVT were the only arrhythmic markers associated with SCD/MVA, and the combination of the two markers carried a significant additive risk of SCD/MVA, incremental to LVEF and New York Heart Association class. The probability of identifying an arrhythmogenic genotype rose from 8% to 30% if both early syncope and NSVT were present. CONCLUSION: In DCM patients, the combination of early detected NSVT and unexplained syncope increases the risk of life-threatening arrhythmic outcomes and can aid the identification of carriers of malignant arrhythmogenic genotypes.

Clinical Response to Tumor Necrosis Factor-α Inhibitor Therapy in the Management of Cardiac Sarcoidosis.

Evidence that tumor necrosis factor-α (TNF-α) inhibitors may benefit patients with cardiac sarcoidosis (CS) is limited to small case series and both imaging and clinical outcomes in this population are not well known. This study aimed to evaluate the disease course of patients with CS treated with either infliximab or adalimumab therapy based on serial 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging and clinical outcomes. An institutional CS research database was queried for patients treated with TNF-α inhibitors between 2016 and 2021. Outcomes included (1) change in mean prednisone dose, (2) FDG-PET improvement, and (3) unplanned hospitalizations, advanced heart failure therapies, or death. Our query yielded 31 patients with CS. A total of 13 patients were on infliximab, 15 patients were on adalimumab, and 3 patients were on adalimumab before transitioning to infliximab. Mean prednisone dose decreased between FDG-PET immediately preceding TNF-α and second after TNF-α FDG-PET (18.6 ± 15.7 mg to 7.7 ± 12.4 mg, p = 0.018). A significant decrease was seen in the mean number of segments demonstrating FDG uptake between most recent pre-TNF-α and first after TNF-α inhibitor FDG-PET (mean segments = 4.2 vs 3.1, p = 0.048). Between earliest pre-TNF-α and first after TNF-α FDG-PET there was a numerical decrease in average myocardial maximum standard uptake values (SUVmax) (4.4 vs 3.1, p = 0.18), and the ratio of SUVmax myocardium:SUVmax blood pool (1.9 vs 1.5, p = 0.26). Within 36 months of initiating TNF-α inhibitor, 4 patients (13%) experienced unplanned cardiovascular hospitalization (median time to hospitalization = 12.1 months). In conclusion, in patients with CS, TNF-α inhibitor therapy is associated with decreased glucocorticoid use, numerical decrease in cardiac FDG uptake, and minimal cardiac morbidity.

An Introductory Tutorial on Cardiovascular Pharmacogenetics for Healthcare Providers.

Pharmacogenetics can improve clinical outcomes by reducing adverse drug effects and enhancing therapeutic efficacy for commonly used drugs that treat a wide range of cardiovascular diseases. One of the major barriers to the clinical implementation of cardiovascular pharmacogenetics is limited education on this field for current healthcare providers and students. The abundance of pharmacogenetic literature underscores its promise, but it can also be challenging to learn such a wealth of information. Moreover, current clinical recommendations for cardiovascular pharmacogenetics can be confusing because they are outdated, incomplete, or inconsistent. A myriad of misconceptions about the promise and feasibility of cardiovascular pharmacogenetics among healthcare providers also has halted clinical implementation. Therefore, the main goal of this tutorial is to provide introductory education on the use of cardiovascular pharmacogenetics in clinical practice. The target audience is any healthcare provider (or student) with patients that use or have indications for cardiovascular drugs. This tutorial is organized into the following 6 steps: (1) understand basic concepts in pharmacogenetics; (2) gain foundational knowledge of cardiovascular pharmacogenetics; (3) learn the different organizations that release cardiovascular pharmacogenetic guidelines and recommendations; (4) know the current cardiovascular drugs/drug classes to focus on clinically and the supporting evidence; (5) discuss an example patient case of cardiovascular pharmacogenetics; and (6) develop an appreciation for emerging areas in cardiovascular pharmacogenetics. Ultimately, improved education among healthcare providers on cardiovascular pharmacogenetics will lead to a greater understanding for its potential in improving outcomes for a leading cause of morbidity and mortality.

Pharmacogenetics of Antiplatelet Therapy.

Antiplatelet therapy is used in the treatment of patients with acute coronary syndromes, stroke, and those undergoing percutaneous coronary intervention. Clopidogrel is the most widely used antiplatelet P2Y12 inhibitor in clinical practice. Genetic variation in CYP2C19 may influence its enzymatic activity, resulting in individuals who are carriers of loss-of-function CYP2C19 alleles and thus have reduced active clopidogrel metabolites, high on-treatment platelet reactivity, and increased ischemic risk. Prospective studies have examined the utility of CYP2C19 genetic testing to guide antiplatelet therapy, and more recently published meta-analyses suggest that pharmacogenetics represents a key treatment strategy to individualize antiplatelet therapy. Rapid genetic tests, including bedside genotyping platforms that are validated and have high reproducibility, are available to guide selection of P2Y12 inhibitors in clinical practice. The aim of this review is to provide an overview of the background and rationale for the role of a guided antiplatelet approach to enhance patient care.

Prognostic Prediction of Genotype vs Phenotype in Genetic Cardiomyopathies.

BACKGROUND: Diverse genetic backgrounds often lead to phenotypic heterogeneity in cardiomyopathies (CMPs). Previous genotype-phenotype studies have primarily focused on the analysis of a single phenotype, and the diagnostic and prognostic features of the CMP genotype across different phenotypic expressions remain poorly understood. OBJECTIVES: We sought to define differences in outcome prediction when stratifying patients based on phenotype at presentation compared with genotype in a large cohort of patients with CMPs and positive genetic testing. METHODS: Dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy, left-dominant arrhythmogenic cardiomyopathy, and biventricular arrhythmogenic cardiomyopathy were examined in this study. A total of 281 patients (80% DCM) with pathogenic or likely pathogenic variants were included. The primary and secondary outcomes were: 1) all-cause mortality (D)/heart transplant (HT); 2) sudden cardiac death/major ventricular arrhythmias (SCD/MVA); and 3) heart failure-related death (DHF)/HT/left ventricular assist device implantation (LVAD). RESULTS: Survival analysis revealed that SCD/MVA events occurred more frequently in patients without a DCM phenotype and in carriers of DSP, PKP2, LMNA, and FLNC variants. However, after adjustment for age and sex, genotype-based classification, but not phenotype-based classification, was predictive of SCD/MVA. LMNA showed the worst trends in terms of D/HT and DHF/HT/LVAD. CONCLUSIONS: Genotypes were associated with significant phenotypic heterogeneity in genetic cardiomyopathies. Nevertheless, in our study, genotypic-based classification showed higher precision in predicting the outcome of patients with CMP than phenotype-based classification. These findings add to our current understanding of inherited CMPs and contribute to the risk stratification of patients with positive genetic testing.

Sex differences in natural history of cardiovascular magnetic resonance- and biopsy-proven lymphocytic myocarditis.

AIMS: The role of sex in determining the profile and the outcomes of patients with myocarditis is largely unexplored. We evaluated the impact of sex as a modifier factor in the clinical characterization and natural history of patients with definite diagnosis of myocarditis. METHODS AND RESULTS: We retrospectively analysed a single-centre cohort of consecutive patients with definite diagnosis of myocarditis (i.e. endomyocardial biopsy or cardiac magnetic resonance proven). Specific sub-analyses were performed in cohorts of patients with chest pain, ventricular arrhythmias, and heart failure as different main symptoms at presentation. The primary outcome measure was a composite of all-cause mortality or heart transplantation (HTx). We included 312 patients, of which 211, 68% of the whole population, were males. Despite no clinically relevant differences found at baseline presentation, males had a higher indexed left ventricular end-diastolic volume (62 ± 23 mL/m2 vs. 52 ± 20 mL/m2, P = 0.011 in males vs. females, respectively) at follow-up evaluation. At a median follow-up of 72 months, 36 (17%) males vs. 8 (8%) females experienced death or HTx (P = 0.033). Male sex emerged as predictors of all-cause mortality or HTx in every combination of covariates (HR 2.600; 1.163-5.809; P = 0.020). Results were agreeable regardless of the main symptom of presentation. CONCLUSIONS: In a large cohort of patients with definite diagnosis of myocarditis, females experienced a more favourable long-term prognosis than males, despite a similar clinical profile at presentation.

Lyme Carditis: From Pathophysiology to Clinical Management.

Cardiac involvement is a rare but relevant manifestation of Lyme disease that frequently presents as atrioventricular block (AVB). Immune-mediated injury has been implicated in the pathogenesis of Lyme carditis due to possible cross-reaction between Borrelia burgdorferi antigens and cardiac epitopes. The degree of the AVB can fluctuate rapidly, with two-thirds of patients progressing to complete AVB. Thus, continuous heart rhythm monitoring is essential, and a temporary pacemaker may be necessary. Routinely permanent pacemaker implantation, however, is contraindicated because of the frequent transient nature of the condition. Antibiotic therapy should be initiated as soon as the clinical suspicion of Lyme carditis arises to reduce the duration of the disease and minimize the risk of complications. Diagnosis is challenging and is based on geographical epidemiology, clinical history, signs and symptoms, serological testing, ECG and echocardiographic findings, and exclusion of other pathologies. This paper aims to explain the pathophysiological basis of Lyme carditis, describe its clinical features, and delineate the treatment principles.

Global longitudinal strain by CMR improves prognostic stratification in acute myocarditis presenting with normal LVEF.

BACKGROUND: Prognostic stratification of acute myocarditis (AM) presenting with normal left ventricular ejection fraction (LVEF) relies mostly on late gadolinium enhancement (LGE) characterization. Left ventricular peak global longitudinal strain (LV-GLS) measured by feature tracking analysis might improve prognostication of AM presenting with normal LVEF. METHODS: Data of patients undergoing cardiac magnetic resonance (CMR) for clinically suspected AM in seven European Centres (2013-2020) were retrospectively analysed. Patients with AM confirmed by CMR and LVEF ≥50% were included. LGE was visually characterized: localized versus. non-localized, subepicardial versus midwall. LV-GLS was measured by dedicated software. The primary outcome was the first occurrence of an adverse cardiovascular event (ACE) including cardiac death, life-threatening arrhythmias, development of heart failure or of LVEF <50%. RESULTS: Of 389 screened patients, 256 (66%) fulfilled inclusion criteria: median age 36 years, 71% males, median LVEF 60%, median LV-GLS -17.3%. CMR was performed at 4 days from hospitalization. At 27 months, 24 (9%) patients experienced ≥1 ACE (71% developed LVEF <50%). Compared to the others, they had lower median LV-GLS values (-13.9% vs. -17.5%, p = .001). At Kaplan-Meier analysis, impaired LV-GLS (both considered as > -20% or quartiles), non-localized and midwall LGE were associated with ACEs. Patients with LV-GLS ≤-20% did not experience ACEs. LV-GLS remained associated with ACEs after adjustment for non-localized and midwall LGE. CONCLUSION: In AM presenting with LVEF ≥50%, LV-GLS provides independent prognostic value over LGE characterization, improving risk stratification and representing a rationale for further studies of therapy in this cohort.

The right ventricular involvement in dilated cardiomyopathy: prevalence and prognostic implications of the often-neglected child.

Dilated cardiomyopathy (DCM) is a primary heart muscle disease characterized by left or biventricular systolic impairment. Historically, most of the clinical attention has been devoted to the evaluation of left ventricular function and morphology, while right ventricle (RV) has been for many years the forgotten chamber. Recently, progresses in cardiac imaging gave clinicians precious tools for the evaluation of RV, raising the awareness of the importance of biventricular assessment in DCM. Indeed, RV involvement is far from being uncommon in DCM, and the presence of right ventricular dysfunction (RVD) is one of the major negative prognostic determinants in DCM patients. However, some aspects such as the possible role of specific genetic mutations in determining the biventricular phenotype in DCM, or the lack of specific treatments able to primarily counteract RVD, still need research. In this review, we summarized the current knowledge on RV involvement in DCM, giving an overview on the epidemiology and pathogenetic mechanisms implicated in determining RVD. Furthermore, we discussed the imaging techniques to evaluate RV function and the role of RV failure in advanced heart failure.

Clinical and genetic features of arrhythmogenic cardiomyopathy: diagnosis, management and the heart failure perspective.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an emerging new concept of a life-threatening heart muscle disorder due not only to desmosome gene mutations, but also to non-desmosome genes, such as filamin C, lamin A/C, phospholamban, transmembrane protein 43, titin, SCN5A and RNA binding motif protein 20.Multi-modality imaging along with genetic testing are important tools for risk stratification to tailor treatment to a single patient. Cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE) is the gold standard for evaluating left and right ventricular structure and function, edema, and fibrosis. The identification of regional fibrosis with LGE has prognostic value. The management of ACM involves several aspects: treatment of arrhythmias and heart failure, risk stratification, implantable cardioverter-defibrillator (ICD) placement, exercise restrictions, and life-style changes. The decision for ICD placement in ACM patients is not well established and should be made weighing risks and benefits. However, the presence of specific genotypes can allow a precision medicine approach. In ACM patients with only mild left ventricular dysfunction but phospholamban, filamin C or lamin A/C mutations, an ICD is now considered a reasonable approach. AIM OF REVIEW: We sought to provide an overview of clinical and genetic feature of arrhythmogenic cardiomyopathy providing epidemiology, imaging, diagnostic and treatment information, using a systematic genetic approach.

Clinical impact of myocardial fibrosis in severe aortic stenosis.

The pressure overload due to the progressive narrowing of the valve area determines the development of the left ventricular hypertrophy which characterizes aortic stenosis (AS). The onset of myocardial fibrosis marks the inexorable decline of an initially compensatory response towards heart failure. However, myocardial fibrosis does not yet represent a key element in the prognostic and therapeutic framework of AS. In this context, cardiac magnetic resonance imaging plays a major role by highlighting both the focal irreversible fibrotic replacement, using the late gadolinium enhancement (LGE) technique, and the earlier diffuse reversible interstitial fibrosis, using the T1 mapping techniques. For this reason, the presence of myocardial fibrosis would be useful to identify a subgroup of patients at greater risk of events among the subjects with severe AS. Actually, more and more evidences seem to identify the presence of LGE as a powerful prognostic factor to be used to optimize the timing of prosthetic valve replacement. Randomized clinical trials, such as the EVoLVeD trial currently underway, will be needed to better define the importance of myocardial fibrosis assessment in the management of patients with AS.

Impact on clinical outcomes of right ventricular response to percutaneous correction of secondary mitral regurgitation.

AIMS: In patients with heart failure and reduced ejection fraction (HFrEF) and secondary mitral regurgitation (SMR), impaired right ventricular function (RVF) may negatively influence the prognosis. Percutaneous mitral valve repair (pMVR) can promote the recovery of RVF. We sought to characterize the response of the right ventricle to pMVR in HFrEF with SMR and to assess the association between improved RVF after pMVR and outcomes. METHODS AND RESULTS: Overall, 221 patients with HFrEF and SMR ≥3+ successfully treated with pMVR in four tertiary care centres for heart failure were included. Improved RVF was defined as Δ right ventricular fractional area change (ΔRVFAC) ≥5% at early follow-up (median time 4 months). The primary endpoint was a composite of death/heart transplantation (D/HT). Mean age was 69 ± 11 years, mean left ventricular ejection fraction was 31 ± 8% and mean RVFAC was 34 ± 9%. ΔRVFAC ≥5% occurred in 88 patients (40%) and was independent of the measures of left ventricular reverse remodelling. During a median follow-up of 29 months (interquartile range 12-46), 81 patients (37%) reached the primary endpoint. After adjustment for other significant covariates, ΔRVFAC ≥5% was significantly associated with lower risk of D/HT (hazard ratio 0.52, 95% confidence interval 0.29-0.94, P = 0.030). In the secondary outcome analysis exploring the risk of heart failure hospitalizations, ΔRVFAC ≥5% confirmed the prognostic association with the endpoint. CONCLUSIONS: In patients with HFrEF and SMR, about 40% of patients improved RVF after pMVR. RVF improvement was associated with better long-term survival free from HT and lower risk of heart failure hospitalization.