Cardiac Tumors: Diagnosis, Prognosis, and Treatment.

PURPOSE OF REVIEW: Cardiac masses frequently present significant diagnostic and therapeutic clinical challenges and encompass a broad set of lesions that can be either neoplastic or non-neoplastic. We sought to provide an overview of cardiac tumors using a cardiac chamber prevalence approach and providing epidemiology, imaging, histopathology, diagnostic workup, treatment, and prognoses of cardiac tumors. RECENT FINDINGS: Cardiac tumors are rare but remain an important component of cardio-oncology practice. Over the past decade, the advances in imaging techniques have enabled a noninvasive diagnosis in many cases. Indeed, imaging modalities such as cardiac magnetic resonance, computed tomography, and positron emission tomography are important tools for diagnosing and characterizing the lesions. Although an epidemiological and multimodality imaging approach is useful, the definite diagnosis requires histologic examination in challenging scenarios, and histopathological characterization remains the diagnostic gold standard. A comprehensive clinical and multimodality imaging evaluation of cardiac tumors is fundamental to obtain a proper differential diagnosis, but histopathology is necessary to reach the final diagnosis and subsequent clinical management.

Arrhythmic Risk Stratification in Patients With Idiopathic Dilated Cardiomyopathy.

Arrhythmic risk stratification in idiopathic dilated cardiomyopathy (IDC) remains a major concern. As the ventricles remodel in time, risk factors for arrhythmic death may change. A cohort of 710 patients with idiopathic dilated cardiomyopathy, without previous ventricular arrhythmias, was retrospectively studied to understand how risks vary in time. The primary end point was a composite of sudden cardiac death, ventricular fibrillation, sustained ventricular tachycardia, and appropriate implantable cardioverter-defibrillator interventions. The prediction of the arrhythmic outcome was assessed dynamically through landmark analysis. Patients were assessed at baseline, short term (12 months, interquartile range 6 to 18), and long-term (72 months, interquartile range 60 to 84). The strongest risk predictors at each evaluation were combined in 3 multivariate models. During a median follow-up of 102 months, 80 patients (11%) experienced the primary end point. At baseline, QRS duration (p = 0.008), disease duration (p <0.001), and mitral regurgitation (p = 0.010) were significantly associated with the primary end point. The 12 months' landmark model included disease duration (p = 0.049), syncope (p = 0.005), New York Heart Association classes III and IV (p = 0.02), and indexed left ventricular end-diastolic volume (p = 0.001). Finally, the 72 months' landmark model combined the indexed left ventricular end-diastolic volume (p = 0.048), the left ventricular ejection fraction (p = 0.008), and the left atrial area (p = 0.001). All the 3 models provided a satisfactory accuracy (area under the curve ranging from 0.76 to 0.82, p <0.001). With an implantable cardioverter-defibrillator, the natural course of the disease influences the effect of arrhythmic risk factors overtime. Different predictors should be considered for the risk stratification according to the timing of assessment. Impaired left ventricular ejection fraction was significantly associated with major arrhythmias only in the long term.

Lifelong arrhythmic risk stratification in arrhythmogenic right ventricular cardiomyopathy: distribution of events and impact of periodical reassessment.

Aims: The arrhythmic risk stratification of arrhythmogenic right ventricular cardiomyopathy (ARVC) remains controversial. We evaluated the long-term distribution of life-threatening arrhythmic events assessing the impact of periodical risk reassessment. Methods and results: Ninety-eight ARVC patients with no previous major ventricular arrhythmias were retrospectively analysed. Patients were assessed at baseline, at 22 [inter-quartile range (IQR) 16-26], 49 (IQR 41-55) and 97 months (IQR 90-108). The primary endpoint was a composite of sudden cardiac death, ventricular fibrillation, sustained ventricular tachycardia or appropriate implanted cardioverter-defibrillator intervention. During a median follow-up of 91 months (IQR 34-222) 28 patients (29%) experienced the composite endpoint. The median time for the primary event was 35 months (IQR 18-86 months), and 39% of events occurred beyond 49 months of follow-up. History of syncope (HR 4.034; 95% CI, 1.488 to 10.932; P-value = 0.006), non-sustained ventricular tachycardia (NSVT; HR 3.534; 95% CI 1.265-9.877; P-value = 0.016), premature ventricular contractions (PVC) >1000/24h (HR 2.761; 95% CI 1.120-6.807; P-value = 0.027), and right ventricular fractional area change (RVFAC; HR 0.945; 95% CI 0.906-0.985; P-value = 0.008) were found as independent predictors at baseline multivariate analysis. Nevertheless, when the prognostic impact of each variable was reassessed overtime only NSVT (HR 3.282; 95% CI, 1.122 to 9.598, P-value = 0.023) and RVFAC (HR 0.351, 95% CI, 0.157 to 0.780; P-value = 0.010) remained independent predictors throughout the whole follow-up. Conclusion: In our cohort of ARVC patients only NSVT and RVFAC maintained their independent prognostic impact in predicting arrhythmic events during the long-term follow-up. Periodical re-assessment of risk in these patients is strongly recommended.

Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy.

OBJECTIVE: To explore the genetic landscape of a well selected dilated cardiomyopathy (DCM) cohort, assessing the possible relation between different genotypes and left ventricular reverse remodelling (LVRR). METHODS: A cohort of 152 patients with DCM from the Heart Muscle Disease Registry of Trieste has been studied by next-generation sequencing (NGS). Patients were grouped into different 'gene-clusters' with functionally homogeneous genetic backgrounds. LVRR was defined by left ventricular ejection fraction normalisation or increase ≥10% associated with normalisation in indexed left ventricular end-diastolic diameter or relative decrease ≥10% at 24 months follow-up. RESULTS: A pathogenic disease-related gene variant was identified in 57% of patients: 28 (18%) TTN; 7 (5%) LMNA; 16 (11%) structural cytoskeleton Z-disk genes; 9 (6%) desmosomal genes; 18 (12%) motor sarcomeric genes and 9 (6%) other genes. Baseline clinical features were similar throughout the different genotypes. A significant relationship was found between gene cluster subgroups and LVRR, with a lower rate of LVRR in structural cytoskeleton Z-disk gene mutation carriers (1/16 patients, 6%, p<0.05 vs the other subgroups). Of note, structural cytoskeleton Z-disk gene rare variants were independently and inversely associated with LVRR when adjusted for clinical predictors of LVRR (OR 0.065; 95% CI 0.008 to 0.535, p=0.011). CONCLUSIONS: NGS confirmed a high genetic diagnostic yield in DCM. A specific 'gene-clusters' classification based on functional similarities in different genes might be helpful in the clinical management of genetically determined DCM. In this study, structural cytoskeleton Z-disk gene rare variants were independently associated with a lower rate of LVRR at follow-up.

The Prognostic Impact of the Evolution of RV Function in Idiopathic DCM.

OBJECTIVES: In this study, the authors analyzed the prognostic role of right ventricular systolic function (RVF) longitudinal trends in a large cohort of patients affected by dilated cardiomyopathy (DCM). BACKGROUND: RVF is a known prognostic predictor in DCM; however, whether RVF changes over time to better predict the long-term disease progression has not been investigated. METHODS: From 1993 to 2008, we analyzed 512 patients with DCM (46 years of age [36 to 55 years of age], left ventricular ejection fraction 32% [25% to 41%]) with a potential follow-up of ≥72 months and available data at baseline and at least 1 pre-specified follow-up evaluation (i.e., 6, 24, 48, or 72 months). RV dysfunction was defined as RV fractional area change <35% at 2-dimensional echocardiography. The primary outcome measure was a composite of death or heart transplantation. RESULTS: At enrollment, 103 (20%) patients had RV dysfunction. During follow-up, 89 of them (86%, 17% of the overall cohort) normalized RVF at a median time of 6 months, whereas 38 of the remaining 409 patients with normal baseline RVF (9%; 7% of the overall population) exhibited a new-onset RV dysfunction (median time: 36 months). RVF normalization was significantly associated with subsequent left ventricular reverse remodeling that was observed at a median time of 24 months (odds ratio: 2.49; 95% confidence interval [CI]: 1.17 to 5.3; p = 0.018). At baseline multivariate analysis, RV dysfunction was independently associated with the primary outcome measure (hazard ratio: 1.71; 95% CI: 1.02 to 2.85; p = 0.0413). At time-dependent model, RVF revaluation over time maintained an independent predictive value (hazard ratio: 2.83; 95% CI: 1.57 to 5.11; p = 0.0006). CONCLUSIONS: Patients with DCM frequently present RV dysfunction at first evaluation. However, a complete RVF recovery is largely observed early after optimization of medical therapy and predates subsequent left ventricular reverse remodeling. Systematic revaluation of patients including RVF throughout regular follow-up conferred additive long-term prognostic value to the baseline evaluation.

[Dilated cardiomyopathy: a dynamic disease - clinical course, reverse remodeling and prognostic stratification]. / La cardiomiopatia dilatativa come malattia dinamica: storia naturale, rimodellamento inverso e stratificazione prognostica.

Dilated cardiomyopathy (DCM) is a relatively rare primary heart muscle disease with genetic or post-inflammatory etiology. In the last decade, the incidence and prevalence of the disease have significantly increased as a consequence of an earlier diagnosis supported by extensive familial screening programs and by the improvement in diagnostic techniques. Moreover, current therapeutic strategies have deeply modified the prognosis of DCM with a dramatic reduction in mortality. A significant number of patients with DCM present an impressive response to pharmacological and non-pharmacological therapy in terms of left ventricular reverse remodeling (reduction in ventricular size with improvement of systolic function), which confers a more favorable prognosis in the long term. However, the identification of patients with an increased likelihood of improvement after therapeutic optimization remains a challenging issue; in particular the assessment of arrhythmic risk carries important implications. Finally, the long-term follow-up of patients showing a significant left ventricular functional recovery under optimal treatment is still poorly known. Hence, the aim of the present review is to provide an insight into the clinical evolution/long-term follow-up of DCM, which should be actually considered a dynamic process rather than a static and chronic disease. Left ventricular reverse remodeling should be considered a key therapeutic goal, mostly associated with a long-standing recovery, but cannot be considered the expression of permanent "healing", confirming the need for a systematic and careful follow-up over time in this setting.

Long-term prognostic impact of therapeutic strategies in patients with idiopathic dilated cardiomyopathy: changing mortality over the last 30 years.

AIMS: ACE-inhibitors, ß-blockers, implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) improved prognosis of heart failure. We sought to analyse the long-term prognostic impact of evidence-based integrated therapeutic strategies in patients with idiopathic dilated cardiomyopathy (IDCM). METHODS AND RESULTS: From 1978 to 2007, 853 IDCM patients (45 ± 15 years, 72% males) were enrolled and classified as follows: Group 1, 110 patients (12.8%) enrolled during 1978-1987; Group 2, 376 patients (44.1%) enrolled during 1988-1997; Group 3, 367 patients (43.1%) enrolled during 1998-2007. ACE-inhibitors/angiotensin receptor blockers were administered in 34%, 93%, and 93% (P <0.001), and ß-blockers in 11%, 82%, and 86% (P <0.001) in Groups 1, 2, and 3, respectively; ICDs were implanted in 2%, 14%, and 13% (P = 0.005); mean time to device implantation was lower in Group 3. At 8 years, heart transplant (HTx)-free survival rates were 55%, 71%, and 87% in Groups 1, 2, and 3, respectively (P <0.001). Similar progressive improvement was found for pump-failure death (DHF)/HTx, while survival free from sudden death (SD) was significantly improved only in Group 3. Multivariable models considering competing risk indicated early diagnosis (i.e. a baseline less advanced disease stage) and tailored medical therapy (HR 0.44, CI 95% 0.19-0.98) as independent protectors against DHF/HTx. Concerning SD, lower left ventricular ejection fraction emerged as a predictor, while ICD was the only therapy with a protective role (HR 0.08, CI 95% 0.01-0.61). Treatment with digitalis emerged as a predictor of both DHF/HTx and SD. CONCLUSIONS: An effective management and evidence-based integrated therapeutic approach progressively and significantly improved the long-term prognosis of IDCM during the last three decades.

Focus on cardiac amyloidosis: a single-center experience with a long-term follow-up.

AIM: Amyloidosis is a systemic disease, related to different underlying causes, with frequent cardiac involvement. Clinical evaluation, echocardiography and electrocardiography represent important noninvasive tools in identification of cardiac involvement. The aim of this study was to assess the clinical-laboratory features of a series of patients affected by cardiac amyloidosis in order to evaluate the risk of cardiac mortality. METHODS: We evaluated 48 patients (men 65%, mean age 63 ±â€Š11 years) with biopsy-proven diagnosis of amyloidosis and heart involvement observed from 1991 to 2009. All patients underwent clinical-laboratory evaluation at baseline and were followed up. RESULTS: During a median follow-up of 9.5 months (first to third interquartile: 3-41.5 months), 24 patients (50%) died as a result of a cardiac cause. Survival free from cardiac death was 69, 50, 48 and 41% at 6, 12, 24 and 60 months from diagnosis, respectively. At multivariable Cox regression analysis, the presence of heart failure at enrolment [hazard ratio (HR) 4.67, 95% confidence interval (CI) 1.07-20.27, P = 0.04] and history of recent syncope (HR 3.97, 95% CI 1.28-12.34, P = 0.017) emerged as independent predictors of cardiac death. By using the equation derived from the multivariate analysis, individual survival probability at different times of follow-up was calculated. CONCLUSION: We confirm the particularly poor outcome of cardiac amyloidosis in the short term. A careful clinical evaluation emerges as the most important tool for the prognostic stratification and quantification of risk in patients with cardiac amyloidosis.

How can optimization of medical treatment avoid unnecessary implantable cardioverter-defibrillator implantations in patients with idiopathic dilated cardiomyopathy presenting with "SCD-HeFT criteria?".

To assess the proportion and long-term outcomes of patients with idiopathic dilated cardiomyopathy and potential indications for implantable cardioverter-defibrillator before and after optimization of medical treatment, 503 consecutive patients with idiopathic dilated cardiomyopathy were evaluated from 1988 to 2006. A total of 245 patients (49%) satisfied the "Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) criteria," defined as a left ventricular ejection fraction of ≤0.35 and New York Heart Association (NYHA) class II-III on registration. Among these, 162 (group A) were re-evaluated 5.4 ± 2 months later with concurrent ß-blockers and angiotensin-converting enzyme inhibitor use. Of the 162 patients, 50 (31%) still had "SCD-HeFT criteria" (group A1), 109 (67%) had an improved left ventricular ejection fraction and/or New York Heart Association class (group A2), and 3 (2%) were in NYHA class IV. Of the 227 patients without baseline "SCD-HeFT criteria" (left ventricular ejection fraction >0.35 or NYHA class I), 125 were evaluated after 5.5 ± 2 months. Of these 227 patients, 13 (10%) developed "SCD-HeFT criteria" (group B1), 111 (89%) remained without "SCD-HeFT criteria" (group B2), and 1 (1%) had worsened to NYHA class IV. The 10-year mortality/heart transplantation and sudden death/sustained ventricular arrhythmia rate was 57% and 37% in group A1, 23% and 20% in group A2 (p <0.001 for mortality/heart transplantation and p = 0.014 for sudden death/sustained ventricular arrhythmia vs group A1), 45% and 41% in group B1 (p = NS vs group A1), 16% and 14% in group B2 (p = NS vs group A2), respectively. In conclusion, two thirds of patients with idiopathic dilated cardiomyopathy and "SCD-HeFT criteria" at presentation did not maintain implantable cardioverter-defibrillator indications 3 to 9 months later with optimal medical therapy. Their long-term outcome was excellent, similar to that observed for patients who had never met the "SCD-HeFT criteria."

Prognostic predictors in arrhythmogenic right ventricular cardiomyopathy: results from a 10-year registry.

AIMS: We sought to examine the clinical presentation and natural history and to identify long-term prognostic predictors in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) as information concerning the natural history and risk stratification of ARVC is still incomplete. METHODS AND RESULTS: A cohort of 96 ARVC patients (68% males, 35 ± 15 years) was enrolled and underwent structured diagnostic protocol and follow-up. Primary study endpoints were death and heart transplantation (HTx). Clinical and echo-Doppler data were assessed as prognostic indicators. Sixty-five per cent of patients had right ventricular (RV) systolic dysfunction (RV fractional area change < 33%) and 24% had left ventricular (LV) systolic dysfunction (LV ejection fraction <50%). During a mean follow-up of 128 ± 92 months, 20 patients (21%) experienced cardiac death or underwent HTx. At multivariate analysis (Model 1), RV dysfunction [hazard ratio (HR): 4.12; 95% confidence interval (CI): 1.01-18.0; P = 0.05], significant tricuspid regurgitation (HR: 7.6; 95% CI: 2.6-22.0; P < 0.001), and amiodarone treatment (HR: 3.4; 95% CI: 1.3-8.8; P = 0.01) resulted as predictors of death/HTx. When inserting in the model, the 'ordinal dysfunction' (Model 2), which considers the presence of both RV and LV dysfunctions, this variable emerged as an independent prognostic predictor (HR: 6.3; 95% CI: 2.17-17.45; P < 0.001). At the receiver operating characteristic analysis, Model 2 was significantly more accurate in predicting long-term outcome compared with Model 1 (area under the curve 0.84 vs. 0.78, respectively; P = 0.04). CONCLUSION: In our tertiary referral centre ARVC population, the presence of LV dysfunction at diagnosis has an incremental power in predicting adverse outcome compared with RV dysfunction alone.

Right ventricular cardiomyocyte apoptosis in patients with acute myocardial infarction of the left ventricular wall.

Cardiac remodeling after acute myocardial infarction (AMI) is characterized by molecular and cellular mechanisms involving both the left (LV) and right ventricular (RV) walls. Cardiomyoycte apoptosis in the peri-infarct and remote LV myocardium has a central role in cardiac remodeling. Whether apoptosis also occurs in the right ventricle of patients with ischemic heart disease has not been investigated. The aim of the present study was to investigate the presence of cardiomyocyte apoptosis in the right ventricle in patients with AMI. We assessed the number of apoptotic cardiomyocytes using multiple samplings in the LV and RV walls of 12 patients selected at autopsy who died 4 to 42 days after AMI. Five patients without cardiac disease were also selected at autopsy as controls. Apoptotic rates were calculated from the number of cardiomyocytes showing double positive staining for in situ end-labeling of DNA fragmentation (TUNEL) and for activated caspase-3. Potentially false-positive results (DNA synthesis and RNA splicing) were excluded from cell counts. The apoptotic rate in the right ventricle in patients with AMI was significantly higher than in control hearts (median 0.8%, interquartile range 0.3 to 1.0 vs median 0.01%, interquartile range 0.01 to 0.03, p <0.001). RV apoptosis significantly correlated with such parameters of global adverse remodeling as cardiac diameter to LV free wall thickness (R = +0.57, p = 0.050). RV apoptosis was significantly higher in five cases (42%) with infarct involving the ventricular septum and an adjacent small area of the RV walls (median 1.0%, interquartile range 0.8 to 2.2 vs median 0.5%, interquartile range 0.2 to 1.0, p = 0.048, p <0.001 vs controls). The association between apoptotic rate in the right ventricle and cardiac remodeling was apparent even after exclusion of cases with RV AMI involvement (R = +0.82, p = 0.023 for diameter to LV wall thickness ratio and R = -0.91, p = 0.002 for RV free wall thickness). In conclusion, patients with cardiac remodeling after AMI had a significant increase in RV apoptosis even when ischemic involvement of the RV wall was not apparent.

Are nonsustained ventricular tachycardias predictive of major arrhythmias in patients with dilated cardiomyopathy on optimal medical treatment?

BACKGROUND: To evaluate the role of nonsustained ventricular tachycardias (NSVT) for the prediction of major ventricular arrhythmias (MVA) in patients with idiopathic dilated cardiomyopathy (DCM) after optimization of medical treatment. METHODS AND RESULTS: Three hundred nineteen consecutive DCM patients were evaluated after adequate stabilization on optimal angiotensin-converting enzyme (ACE) inhibitor (88%) and beta-blocker (82%) therapy. Frequency, length, and rate of NSVT at 24-hour Holter monitoring were analyzed to assess their values in predicting MVA (unexpected sudden death, SVT, ventricular fibrillation, and appropriate implantable cardioverter defibrillator interventions). During follow-up (median 96 months, 1(st)-3(rd) interquartile range 52-130), MVA incidence was low, and not statistically different between patients with and without NSVT (3 and 2 per 100 patient-years, respectively, P = nonsignificant [NS] at log-rank analysis). At multivariable analysis, the number of NSVT was predictive of MVA only if left ventricular ejection fraction (LVEF) was > 0.35 (two NSVT/day vs no NSVT/day: hazard ratio [HR] 5.3, 95% confidence interval [CI] 1.59-17.85 in LVEF > 0.35 vs HR 0.93, 95% CI 0.3-2.81 in LVEF < or = 0.35). Consequently, in patients with LVEF < or = 0.35, MVA incidence rates were similar regardless of NSVT (3.6 and 4.1 patient-years, respectively, in those with and without NSVT, P = NS), while in patients with LVEF > 0.35, MVA incidence (3.1 per 100 patient-years vs 0.9 per 100 patient-years, P = 0.003) was significantly higher when NSVT were present. CONCLUSIONS: After medical stabilization, NSVT did not increase the risk of MVA in patients with DCM and LVEF < or = 0.35. Conversely, the number and length of NSVT runs were significantly related to the occurrence of MVA in the patients with LVEF > 0.35.