[Palliative care in the cardiac setting: a consensus document of the Italian Society of Cardiology/Italian Society of Palliative Care (SIC/SICP)]. / Documento di consenso sulle cure palliative in ambito cardiologico a cura del Gruppo di Lavoro congiunto della Società Italiana di Cardiologia (SIC) e della Società Italiana di Cure Palliative (SICP).

Palliative care is recognized as an approach that improves quality of life of patients and families facing life-threatening illnesses. This is achieved through prevention, early identification, assessment and treatment of symptoms and other psycho-social, spiritual and economic issues. Palliative care is not dependent on prognosis and can be delivered as "simultaneous care", together with disease-modifying treatments and adequate symptom relief. Palliative care relies on coordination across settings of care and offers open communication to patients and caregivers. Recently, there is increasing interest in the potential role of palliative care in refractory, advanced heart failure treated with optimal, maximized therapy.Heart failure is a chronic progressive syndrome characterized by periods of stability interrupted by acute exacerbations, usually leading to reduced functional status. It accounts for approximately one-third of deaths in industrialized countries and is a common cause of hospitalization. Fifty percent of patients with advanced heart failure die within 1 year of diagnosis and 50% of the remainder within 5 years. The trajectory of heart failure is often unpredictable and approximately 30% to 50% of patients die suddenly. Patients with heart failure suffer from numerous symptoms, often resistant to conventional treatments, frequently under-recognized and under-treated. Symptom assessment and control improve quality of life in patients with advanced heart failure; this can be managed at best by collaboration between specialistic teams.Although heart failure is a life-shortening condition, therapeutic and technological advances (such as left ventricular assist devices, coronary revascularization, percutaneous valve implantation, and implantable cardioverter defibrillators) can help healthcare professionals in the management of patients with advanced heart failure, improving global condition and reducing the risk of sudden death. On the other hand, it has to be acknowledged that management of cardiovascular implanted electronic devices towards end of life requires awareness of legal, ethical, religious principles regarding potential withdrawal of life-sustaining therapies.Adequate communication with patients regarding adverse events, end of life, benefits vs burdens of therapies and interventions, treatment preferences, and decision-making should be an issue in early stages of disease. The process of advanced care planning should be clearly documented and regularly reviewed.Barriers to the provision of palliative care in heart failure include clinical issues (disease trajectory), prognostic uncertainty, failure in identification of patients who need palliative care and timing of referral to specialist services, but also misconceptions of patients, families and sanitary staff regarding the role of palliative care, organization problems, and finally educational and time issues.This document focuses on the need of further, coordinated research and work-out on: (i) identification of heart failure patients eligible for palliative care, in terms of clinical and social-psychological issues, (ii) identification of trigger events and timing of referral; (iii) identification of adequate performance indicators/scales for measurement, assessment and follow-up of symptoms and quality of life in end-stage heart failure, including patient-reported outcome measures; (iv) treatment, care and organization strategies and models for advanced/end-stage heart failure ("care management"); and (v) implementation of knowledge and education of healthcare professionals in the fields of communication, ethics, and advanced care planning in heart failure.

Acute and Chronic Response to Exercise in Athletes: The "Supernormal Heart".

During last decades, most studies have examined the exercise-induced remodeling defined as "athlete's heart". During exercise, there is an increased cardiac output that causes morphological, functional, and electrical modification of the cardiac chambers. The cardiac remodeling depends also on the type of training, age, sex, ethnicity, genetic factors, and body size. The two main categories of exercise, endurance and strength, determine different effects on the cardiac remodeling. Even if most sport comprise both strength and endurance exercise, determining different scenarios of cardiac adaptation to the exercise. The aim of this paper is to assemble the current knowledge about physiologic and pathophysiologic response of both the left and the right heart in highly trained athletes.

Association between left ventricular perfusion defects and myocardial deformation indexes in heart transplantation recipients.

The aim of the study was to analyze possible correlations between strain echocardiography (STE) and PET myocardial perfusion in a population of heart transplantation (HTx) recipients showing preserved left ventricular (LV) ejection fraction. By STE, LV global longitudinal strain (LV GLS) was lower in HTx. PET showed no transient or chronic ischemia in 83 of 115 HTx (73%). Fixed perfusion defects were observed in 17% of HTx and reversible ischemia in 10%. Significant coronary stenosis was observed only in 10 cases. GLS was independently associated with age at HTx and fixed perfusion defects (HR 0.41; P<.001). Such relationships underline STE ability to early identify HTx pts with subclinical myocardial dysfunction during long-term follow-up.

Allelic Complexity in Long QT Syndrome: A Family-Case Study.

Congenital long QT syndrome (LQTS) is associated with high genetic and allelic heterogeneity. In some cases, more than one genetic variant is identified in the same (compound heterozygosity) or different (digenic heterozygosity) genes, and subjects with multiple pathogenic mutations may have a more severe disease. Standard-of-care clinical genetic testing for this and other arrhythmia susceptibility syndromes improves the identification of complex genotypes. Therefore, it is important to distinguish between pathogenic mutations and benign rare variants. We identified four genetic variants (KCNQ1-p.R583H, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-p.C108Y, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and KCNE1-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and KCNE1-p.G38S could be LQTS modifiers.

Cardiac damage in athlete's heart: When the "supernormal" heart fails!

Intense exercise may cause heart remodeling to compensate increases in blood pressure or volume by increasing muscle mass. Cardiac changes do not involve only the left ventricle, but all heart chambers. Physiological cardiac modeling in athletes is associated with normal or enhanced cardiac function, but recent studies have documented decrements in left ventricular function during intense exercise and the release of cardiac markers of necrosis in athlete's blood of uncertain significance. Furthermore, cardiac remodeling may predispose athletes to heart disease and result in electrical remodeling, responsible for arrhythmias. Athlete's heart is a physiological condition and does not require a specific treatment. In some conditions, it is important to differentiate the physiological adaptations from pathological conditions, such as hypertrophic cardiomyopathy, arrhythmogenic dysplasia of the right ventricle, and non-compaction myocardium, for the greater risk of sudden cardiac death of these conditions. Moreover, some drugs and performance-enhancing drugs can cause structural alterations and arrhythmias, therefore, their use should be excluded.

Patient selection for transcatheter aortic valve replacement: A combined clinical and multimodality imaging approach.

Transcatheter aortic valve replacement (TAVR) has been validated as a new therapy for patients affected by severe symptomatic aortic stenosis who are not eligible for surgical intervention because of major contraindication or high operative risk. Patient selection for TAVR should be based not only on accurate assessment of aortic stenosis morphology, but also on several clinical and functional data. Multi-Imaging modalities should be preferred for assessing the anatomy and the dimensions of the aortic valve and annulus before TAVR. Ultrasounds represent the first line tool in evaluation of this patients giving detailed anatomic description of aortic valve complex and allowing estimating with enough reliability the hemodynamic entity of valvular stenosis. Angiography should be used to assess coronary involvement and plan a revascularization strategy before the implant. Multislice computed tomography play a central role as it can give anatomical details in order to choice the best fitting prosthesis, evaluate the morphology of the access path and detect other relevant comorbidities. Cardiovascular magnetic resonance and positron emission tomography are emergent modality helpful in aortic stenosis evaluation. The aim of this review is to give an overview on TAVR clinical and technical aspects essential for adequate selection.

The impact of age and gender on right ventricular diastolic function among healthy adults.

BACKGROUND: Doppler echocardiography is ideally suited for assessment of diastolic function, being widely available, non-invasive, and less expensive than other techniques. However, data regarding age- and gender-matched reference values of right ventricular diastolic function are limited. This study aims to explore the physiologic variations of right ventricle (RV) diastolic function in a large cohort of healthy adults, and to investigate clinical and echocardiographic correlates. METHODS: From June 2007 to February 2014, 1168 healthy Caucasian subjects [mean age 45.1±15.6 years, range 16-92; 555 (47.5%) men] underwent comprehensive transthoracic echocardiography (TTE) following current guidelines. The following RV main diastolic measurements were measured: peak early inflow velocity (E), annular both early (e') and atrial (a') velocities, E/e' ratio. RESULTS: RV E/e' constantly increases with age in females, but do not change substantially in males. RV E/A constantly decreases with age in both genders. Stepwise multiple linear regression analysis underlined a close significant association of RV diastolic function with both right and left heart morphologic measurements (right atrial area, RV diameters, left atrial volume) and functional indexes (TAPSE, RV tissue Doppler peak systolic velocity, left ventricular E/Ee'), as well as with indexes of increased pulmonary resistance. CONCLUSION: Our data highlight the potential usefulness of different normal reference values according to the age and gender to correctly evaluate RV diastolic function. Differences in terms of demographic and anthropometric parameters could be useful to avoid potential misclassification of RV diastolic function when based on dichotomously suggested normal cut-off values.

Clinical and genetic characterization of patients with hypertrophic cardiomyopathy and right atrial enlargement.

AIMS: Prevalence and clinical significance of right atrial enlargement (RAE) has been poorly characterized in hypertrophic cardiomyopathy. METHODS: One hundred and sixty consecutive patients with hypertrophic cardiomyopathy (35.5 ±â€Š20 years; 64% men) were studied. They underwent clinical examination, standard ECG, M-mode, 2D and Doppler echocardiography, stress test and ECG Holter monitoring. Major adverse cardiac events were considered: cardiac death (sudden death, heart failure death); cardiac transplant; resuscitated cardiac arrest or appropriate implantable cardioverter defibrillator discharge. Genetic analysis of eight sarcomeric genes was performed using Sanger sequencing. RESULTS: RAE was observed in 22 patients (14%), associated with left atrial enlargement in all cases. Patients with RAE were likely to have restrictive mitral pattern (P < 0.001) and had higher New York Heart Association (P < 0.001), N-terminal prohormone of brain natriuretic peptide (P < 0.001), left atrial volume index (P < 0.001), lateral (P = 0.04) and septal (P = 0.002) E/e', systolic pulmonary artery pressure (P < 0.001) and lower ejection fraction (all P < 0.001). On cardiopulmonary exercise testing, peak VO2 was lower and VE/VCO2 higher in patients with RAE (P < 0.001). During a mean follow-up of 4 ±â€Š2.1 years, 30 major adverse cardiac events in 24 patients (15%) were observed. Cox proportional hazards regression analysis identified RAE as an independent predictor of major adverse cardiac events (odds ratio = 2.6; confidence interval 1.5-4.6; P = 0.001). In patients with RAE who were genetically tested, there was a higher prevalence of sarcomeric gene mutations (68%), double mutations (16%) and troponin T mutations (21%). CONCLUSION: RAE is present in a small subset of patients with hypertrophic cardiomyopathy, and largely reflects increased pulmonary pressures because of severe diastolic and/or systolic left ventricular dysfunction. Patients with RAE had a higher prevalence of sarcomeric gene mutations, troponin T mutations and complex genotypes. In conclusion, RAE may serve as a very useful marker of disease progression and adverse outcome in patients with sarcomeric hypertrophic cardiomyopathy.

Exercise speckle-tracking strain imaging demonstrates impaired right ventricular contractile reserve in hypertrophic cardiomyopathy.

AIMS: To analyse right ventricular (RV) systolic function in patients with hypertrophic cardiomyopathy (HCM) at rest and during exercise, and its possible correlation with left ventricular(LV) morphology and function. METHODS AND RESULTS: Standard echo, exercise stress echo, and RV 2D speckle-tracking strain (2DSE) were performed in 45 patients with HCM and in 45 age- and sex-comparable healthy controls. RV global longitudinal strain (GLS) was calculated by averaging local strains along the entire right ventricle. LV mass index and IVS wall thickness were significantly increased in HCM, while LV ejection fraction, RV diameters, RV tissue Doppler systolic peak and the RV end-systolic pressure-area relationship at rest were comparable between the two groups. Conversely, all transmitral Doppler indexes were significantly impaired in HCM. In addition, RV GLS and regional peak myocardial RV strains were significantly reduced in patients with HCM (all P<0.001). During physical effort, LV ejection fraction was comparable between the two groups. Conversely, LV E/Em ratio was significantly increased in HCM. Increase in TAPSE and RV tissue Doppler Sm peak velocity during effort were similar between the two groups. Conversely, increases of RV end-systolic pressure-area, regional and global RV strain were significantly lower in HCM patients (RV lateral strain: 10.3±3.5% of increase in HCM vs 20.5±4.5% in controls; p<0.0001). Multivariable analysis detected independent associations of RV lateral strain at peak stress with LV IVS thickness, maximal workload during exercise, and LV E/Em ratio during effort (all p<0.0001). An RV lateral 2DSE cut-off point of -14% differentiated controls and HCM with an 86%sensitivity and a 92% specificity. CONCLUSIONS: RV contractile reserve for HCM is impaired and this suggests that the lower resting values of RV in HCM may represent early subclinical myocardial damage, closely associated with exercise capacity.

Functional Studies and In Silico Analyses to Evaluate Non-Coding Variants in Inherited Cardiomyopathies.

Point mutations are the most common cause of inherited diseases. Bioinformatics tools can help to predict the pathogenicity of mutations found during genetic screening, but they may work less well in determining the effect of point mutations in non-coding regions. In silico analysis of intronic variants can reveal their impact on the splicing process, but the consequence of a given substitution is generally not predictable. The aim of this study was to functionally test five intronic variants (MYBPC3-c.506-2A>C, MYBPC3-c.906-7G>T, MYBPC3-c.2308+3G>C, SCN5A-c.393-5C>A, and ACTC1-c.617-7T>C) found in five patients affected by inherited cardiomyopathies in the attempt to verify their pathogenic role. Analysis of the MYBPC3-c.506-2A>C mutation in mRNA from the peripheral blood of one of the patients affected by hypertrophic cardiac myopathy revealed the loss of the canonical splice site and the use of an alternative splicing site, which caused the loss of the first seven nucleotides of exon 5 (MYBPC3-G169AfsX14). In the other four patients, we generated minigene constructs and transfected them in HEK-293 cells. This minigene approach showed that MYBPC3-c.2308+3G>C and SCN5A-c.393-5C>A altered pre-mRNA processing, thus resulting in the skipping of one exon. No alterations were found in either MYBPC3-c.906-7G>T or ACTC1-c.617-7T>C. In conclusion, functional in vitro analysis of the effects of potential splicing mutations can confirm or otherwise the putative pathogenicity of non-coding mutations, and thus help to guide the patient's clinical management and improve genetic counseling in affected families.

Exercise-Induced Atrial Remodeling: The Forgotten Chamber.

Cardiac changes in athletes involve the left ventricle and atrium. Mild left atrial enlargement is common among competitive athletes, possibly a physiologic adaptation to exercise conditioning. The prevalence of this remodeling and the association with supraventricular arrhythmias has not been systematically addressed. Echocardiography screens for patients with disease involving the left atrium. New techniques like speckle tracking can recognize early atrial dysfunction and assess left atrial myocardial function in patients with either physiologic or pathologic left ventricular hypertrophy. This article reviews echocardiographic techniques in delineating the athlete's morphology and functional properties of the left atrium.

Genetics of Takotsubo Syndrome.

Takotsubo syndrome (TTS) is an enigmatic disease with a multifactorial and still unresolved pathogenesis. A genetic predisposition has been suggested based on the few familial TTS cases. Conflicting results have been published regarding the role of functional polymorphisms in relevant candidate genes, such as α1-, ß1-, and ß2-adrenergic receptors; G protein-coupled receptor kinase 5; and estrogen receptors. Further research is required to help clarify the role of genetic susceptibility in TTS.

Transcranial Doppler ultrasonography: From methodology to major clinical applications.

Non-invasive Doppler ultrasonographic study of cerebral arteries [transcranial Doppler (TCD)] has been extensively applied on both outpatient and inpatient settings. It is performed placing a low-frequency (≤ 2 MHz) transducer on the scalp of the patient over specific acoustic windows, in order to visualize the intracranial arterial vessels and to evaluate the cerebral blood flow velocity and its alteration in many different conditions. Nowadays the most widespread indication for TCD in outpatient setting is the research of right to left shunting, responsable of so called "paradoxical embolism", most often due to patency of foramen ovale which is responsable of the majority of cryptogenic strokes occuring in patients younger than 55 years old. TCD also allows to classify the grade of severity of such shunts using the so called "microembolic signal grading score". In addition TCD has found many useful applications in neurocritical care practice. It is useful on both adults and children for day-to-day bedside assessment of critical conditions including vasospasm in subarachnoidal haemorrhage (caused by aneurysm rupture or traumatic injury), traumatic brain injury, brain stem death. It is used also to evaluate cerebral hemodynamic changes after stroke. It also allows to investigate cerebral pressure autoregulation and for the clinical evaluation of cerebral autoregulatory reserve.

Acute and Chronic Effects of Noninvasive Ventilation on Left and Right Myocardial Function in Patients with Obstructive Sleep Apnea Syndrome: A Speckle Tracking Echocardiographic Study.

BACKGROUND: In patients with obstructive sleep apnea syndrome (OSAS), repetitive hypoxia due to sleep-induced apnea adversely affects the interaction between myocardial oxygen demand and supply, resulting in the development of subclinical cardiac dysfunction. The purpose of the study was to analyze the different involvement of left and right heart myocardial function in patients with OSAS treated with noninvasive ventilation (NIV). METHODS: Conventional Doppler echocardiography, Doppler myocardial imaging (DMI), and two-dimensional speckle tracking echocardiography (2DSTE) of left (LV) and right ventricular (RV) longitudinal and right atrial (RA) deformation were performed in 55 patients with OSAS undergoing NIV (M/F 38/17; mean age 67.8 ± 11.2 years). LV and RV global longitudinal strain (GLS) was calculated by averaging local strain along the entire right and left ventricle, before and during NIV, and after 6 months of nocturnal NIV therapy. RESULTS: LV morphology was comparable before and during NIV, whereas LV ejection fraction and LV DMI early diastolic peak velocity were significantly improved in patients with OSAS during NIV, as was LV regional peak myocardial strain (P < 0.001). RV diameters were slightly increased in patients with OSAS during ventilation, whereas pulmonary artery systolic pressure (PASP), RV GLS, and regional peak myocardial RV strain were significantly reduced during ventilation (P < 0.0001). RA transverse diameters and RA area were also slightly increased during NIV, whereas RA lateral wall strain was reduced (P < 0.001). Acute RV myocardial impairment completely reversed at follow-up, with a decrease in PASP and subsequent increase in both RV and RA myocardial performance. CONCLUSIONS: Conventional 2DSTE is a useful tool for assessing left and right heart morphology and myocardial deformation in patients with OSAS and for monitoring both acute and chronic effects of NIV.

Right atrial morphology and function in patients with systemic sclerosis compared to healthy controls: a two-dimensional strain study.

Enlargement and dysfunction of the right atrium might be an early sign for pulmonary hypertension in systemic sclerosis (SSc). This is the first study to analyse right atrial morphology and function in SSc patients compared to healthy controls by speckle-tracking two-dimensional strain echocardiography (2DSE) at rest and during exercise. Furthermore, right atrial function was correlated with further clinical findings. Adult patients with SSc for >3 years (n = 90) and 55 age- and gender-matched healthy controls underwent a panel of non-invasive assessments including transthoracic echocardiography, pulsed Doppler myocardial imaging and 2DSE at rest and during exercise. Furthermore, serological tests and high-resolution chest computed tomography were performed. SSc patients showed significant impairment of right atrial function and the right atrial enlargement, measured by 2DSE at rest and during exercise compared to controls (both p < 0.001). These findings were more evident in SSc patients with pulmonary fibrosis (p < 0.001) and in patients with high pulmonary artery systolic pressures (PAPs) during exercise. In the SSC patients, right atrial lateral strain was significantly associated with PAPs during effort, right atrial area, left ventricle stroke volume and inferior vena cava diameter using multivariable analysis. The findings of this study suggest that a high proportion of SSc patients reveal right atrial dysfunction even without manifest pulmonary hypertension. Impaired right atrial function occurred mostly in patients with pulmonary fibrosis and/or elevated PAPs during exercise, was independently associated with prognostic factors and may therefore be useful for risk stratification. Further studies are needed to analyse if right atrial dysfunction assessed by 2DSE may help to improve early diagnosis of pulmonary hypertension.

The metabolic exercise test data combined with Cardiac And Kidney Indexes (MECKI) score and prognosis in heart failure. A validation study.

BACKGROUND: The Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score is a prognostic model to identify heart failure (HF) patients at risk for cardiovascular mortality (CVM) and urgent heart transplantation (uHT) based on 6 routine clinical parameters: hemoglobin, sodium, kidney function by the Modification of Diet in Renal Disease (MDRD) equation, left ventricle ejection fraction (LVEF), percentage of predicted peak oxygen consumption (VO2) and VE/VCO2 slope. OBJECTIVES: MECKI score must be generalizable to be considered useful: therefore, its performance was validated in a new sequence of HF patients. METHODS: Both the development (MECKI-D) and the validation (MECKI-V) cohorts were composed of consecutive HF patients with LVEF <40% able to perform a symptom-limited cardiopulmonary exercise testing. The CVM or uHT rates were analyzed at one, two and three years in both cohorts: all patients with a censoring time shorter than the scheduled follow-up were excluded, while those with events occurring after 1, 2 and 3 years were considered as censored. RESULTS: MECKI-D and MECKI-V consisted of 2009 and 992 patients, respectively. MECKI-V patients had a higher LVEF, higher peak VO2 and lower VE/VCO2 slope, higher prescription of beta-blockers and device therapy: after the 3-year follow-up, CVM or uHT occurred in 206 (18%) MECKI-D and 44 (13%) MECKI-V patients (p<0.000), respectively. MECKI-V AUC values at one, two and three years were 0.81 ± 0.04, 0.76 ± 0.04, and 0.80 ± 0.03, respectively, not significantly different from MECKI-D. CONCLUSIONS: MECKI score preserves its predictive ability in a HF population at a lower risk.