Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases.

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

The impact of diabetes mellitus on the clinical phenotype of hypertrophic cardiomyopathy.

AIMS: Diabetes mellitus (DM) aggravates the clinical features of ischaemic and hypertensive heart diseases and worsens the prognosis of heart failure patients. Hypertrophic cardiomyopathy (HCM) and diabetes coexist fairly frequently in elderly patients but the impact of DM on the clinical phenotype of HCM is yet unknown. We sought to describe if predominant features of heart failure in DM patients exist independently in HCM. METHODS AND RESULTS: We reviewed clinical characteristics of 937 patients, age ≥40, diagnosed with HCM, from two tertiary medical centres in Spain and Israel. A propensity score matched cohort of 294 patients was also analysed. Our cohort comprised 102 HCM patients with diabetes (8.7%). Patients with DM were older at diagnosis {median 56 [interquartile range (IQR) 47-67] vs. 53 (IQR 43-63), P = 0.02} and had a higher prevalence of comorbidities. Hypertrophic cardiomyopathy patients with DM had a higher prevalence of diastolic dysfunction, pulmonary hypertension, significant mitral regurgitation, and pacemaker implantation. Hypertrophic cardiomyopathy patients with DM had a higher New York Heart Association (NYHA) class (P < 0.001) and lower exercise capacity [7.0 METS (IQR 5.0-10.0) vs. 9.0 METS (IQR 6.6-11.0), P = 0.002]. These findings were independent of age, gender, country of origin, hypertension, and coronary artery disease. Patients with diabetes had a significantly higher 15-year mortality (22% vs. 15%, P = 0.03), with no differences in sudden cardiac death, appropriate implanted cardioverter-defibrillator therapy, or heart transplantation. CONCLUSION: Hypertrophic cardiomyopathy patients with diabetes are older and have a higher cardiovascular risk profile. They have a lower functional capacity and more heart failure symptoms due to diastolic dysfunction.

Metastatic cardiac tumors: from clinical presentation through diagnosis to treatment.

BACKGROUND: To evaluate the prevalence of metastatic tumors involving the myocardium and study their presentation in order to increase awareness to their existence. METHODS: Pathological reports from Sheba Medical Center (Israel, January 1, 2010 through December 31, 2015) and medical records from The Institute for Cardiovascular Diseases of Vojvodina, Sremska Kamenica (Serbia, 23 years period) were screened for cases of metastatic cardiac tumors. Medical, radiological and pathological data of identified cases was retrieved and reviewed. RESULTS: Out of thousands of registered cardiac surgeries we found less than a dozen cases of metastatic cardiac tumors classified as melanoma, carcinomas of lung, colon and kidney and sarcomas of uterine origin. We found that metastatic cardiac tumors comprised 15.8% of all the cardiac tumors. CONCLUSIONS: Metastatic cardiac tumors are extremely rare. As new diagnostic technologies and improved survival of oncological patients may increase the incidence of metastatic cardiac tumors in the future, awareness to their existence and knowledge of their presentation are key factors in their timely recognition.

Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases.

In this paper the Working Group on Myocardial and Pericardial Disease proposes a revised definition of dilated cardiomyopathy (DCM) in an attempt to bridge the gap between our recent understanding of the disease spectrum and its clinical presentation in relatives, which is key for early diagnosis and the institution of potential preventative measures. We also provide practical hints to identify subsets of the DCM syndrome where aetiology directed management has great clinical relevance.

[NOVELTIES IN PERICARDIAL DISEASES: A FOCUSED REVIEW OF THE LATEST EUROPEAN GUIDELINES].

INTRODUCTION: More than a decade has elapsed since the first international guidelines on the diagnosis and management of pericardial diseases were issued by the European Society of Cardiology (ESC) in 2004. Since then, significant advances have been made in this field due to several randomized double blinded controlled trials and also retrospective, as well as prospective, cohort studies that were conducted during this time frame. However, despite the amount of knowledge that has been accumulated, only Spanish and Brazilian national societies of cardiology have so far published national guidelines on the management of pericardial diseases. No official guidelines were issued by the American College of Cardiology/American Heart Association. Therefore, a demand for an updated document has become inevitable in order to summarize all new data and translate them into a set of recommendations which could be implemented in clinical practice. For this purpose, the new guidelines, focused on the clinical management of patients with pericardial diseases were issued by the ESC in 2015. The full text of the 2015 guidelines reflects the progress that has been made so far: the manuscript contains 9 sections (excluding appendix and references), nearly 30 second-level subsections and covers 44 pages. Several new chapters are introduced for the first time in the current guidelines, as compared with the previous version. Therefore, the aim of this review is to summarize and emphasize the most clinically relevant new aspects of the current guidelines as compared with its previous version published in 2004.

A randomized trial of colchicine for acute pericarditis.

BACKGROUND: Colchicine is effective for the treatment of recurrent pericarditis. However, conclusive data are lacking regarding the use of colchicine during a first attack of acute pericarditis and in the prevention of recurrent symptoms. METHODS: In a multicenter, double-blind trial, eligible adults with acute pericarditis were randomly assigned to receive either colchicine (at a dose of 0.5 mg twice daily for 3 months for patients weighing >70 kg or 0.5 mg once daily for patients weighing ≤70 kg) or placebo in addition to conventional antiinflammatory therapy with aspirin or ibuprofen. The primary study outcome was incessant or recurrent pericarditis. RESULTS: A total of 240 patients were enrolled, and 120 were randomly assigned to each of the two study groups. The primary outcome occurred in 20 patients (16.7%) in the colchicine group and 45 patients (37.5%) in the placebo group (relative risk reduction in the colchicine group, 0.56; 95% confidence interval, 0.30 to 0.72; number needed to treat, 4; P<0.001). Colchicine reduced the rate of symptom persistence at 72 hours (19.2% vs. 40.0%, P=0.001), the number of recurrences per patient (0.21 vs. 0.52, P=0.001), and the hospitalization rate (5.0% vs. 14.2%, P=0.02). Colchicine also improved the remission rate at 1 week (85.0% vs. 58.3%, P<0.001). Overall adverse effects and rates of study-drug discontinuation were similar in the two study groups. No serious adverse events were observed. CONCLUSIONS: In patients with acute pericarditis, colchicine, when added to conventional antiinflammatory therapy, significantly reduced the rate of incessant or recurrent pericarditis. (Funded by former Azienda Sanitaria Locale 3 of Turin [now Azienda Sanitaria Locale 2] and Acarpia; ICAP ClinicalTrials.gov number, NCT00128453.).

Recurrent Pericarditis: Modern Approach in 2016.

Recurrent pericarditis is one of the most troublesome complications of pericarditis occurring in about one third of patients with a previous attack of pericarditis. The pathogenesis is presumed to be autoimmune and/or autoinflammatory in most cases. The mainstay of therapy for recurrences is physical restriction and anti-inflammatory therapy based on aspirin or NSAID plus colchicine. Corticosteroids at low to moderate doses (e.g., prednisone 0.2 to 0.5 mg/kg/day) should be considered only after failure of aspirin/NSAID (and more than one of these drugs) or for specific indications (e.g., pregnancy, systemic inflammatory diseases on steroids, renal failure, concomitant oral anticoagulant therapy). One of the most challenging issues is how to cope with patients who have recurrences despite colchicine. A small subset of patients (about 5 %) may develop corticosteroid-dependence and colchicine resistance. Among the emerging treatments, the three most common and evidence-based therapies are based on azathioprine, human intravenous immunoglobulin (IVIG), and anakinra. After failure of all options of medical therapy or for those patients who do not tolerate medical therapy or have serious adverse events related to medical therapy, the last possible option is the surgical removal of the pericardium. Total or radical pericardiectomy is recommended in these cases in experienced centers performing this surgery. A stepwise approach is recommended starting from NSAID and colchicine, corticosteroid and colchicine, a combination of the three options (NSAID, colchicine and corticosteroids), then azathioprine, IVIG, or anakinra as last medical options before pericardiectomy.

European Guidelines on Pericardial Diseases: a Focused Review of Novel Aspects.

Pericardial diseases are not uncommon in daily clinical practice. The spectrum of these syndromes includes acute and chronic pericarditis, pericardial effusion, constrictive pericarditis, congenital defects, and neoplasms. The extent of the high-quality evidence on pericardial diseases has expanded significantly since the first international guidelines on pericardial disease management were published by the European Society of Cardiology in 2004. The clinical practice guidelines provide a useful reference for physicians in selecting the best management strategy for an individual patient by summarizing the current state of knowledge in a particular field. The new clinical guidelines on the diagnosis and management of pericardial diseases that have been published by the European Society of Cardiology in 2015 represent such a tool and focus on assisting the physicians in their daily clinical practice. The aim of this review is to outline and emphasize the most clinically relevant new aspects of the current guidelines as compared with its previous version published in 2004.

Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised trial.

BACKGROUND: Colchicine is effective for the treatment of acute pericarditis and first recurrences. However, conclusive data are lacking for the efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis. METHODS: We did this multicentre, double-blind trial at four general hospitals in northern Italy. Adult patients with multiple recurrences of pericarditis (≥two) were randomly assigned (1:1) to placebo or colchicine (0·5 mg twice daily for 6 months for patients weighing more than 70 kg or 0·5 mg once daily for patients weighing 70 kg or less) in addition to conventional anti-inflammatory treatment with aspirin, ibuprofen, or indometacin. Permuted block randomisation (size four) was done with a central computer-based automated sequence. Patients and all investigators were masked to treatment allocation. The primary outcome was recurrent pericarditis in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00235079. FINDINGS: 240 patients were enrolled and 120 were assigned to each group. The proportion of patients who had recurrent pericarditis was 26 (21·6%) of 120 in the colchicine group and 51 (42·5%) of 120 in the placebo group (relative risk 0·49; 95% CI 0·24-0·65; p=0·0009; number needed to treat 5). Adverse effects and discontinuation of study drug occurred in much the same proportions in each group. The most common adverse events were gastrointestinal intolerance (nine patients in the colchicine group vs nine in the placebo group) and hepatotoxicity (three vs one). No serious adverse events were reported. INTERPRETATION: Colchicine added to conventional anti-inflammatory treatment significantly reduced the rate of subsequent recurrences of pericarditis in patients with multiple recurrences. Taken together with results from other randomised controlled trials, these findings suggest that colchicine should be probably regarded as a first-line treatment for either acute or recurrent pericarditis in the absence of contraindications or specific indications. FUNDING: Azienda Sanitaria 3 of Torino (now ASLTO2).

["The Talpiot medical leadership program"--advancing the brightest young physicians and researchers to fill future leadership roles].

BACKGROUND: The modern medical world is dynamic and boundless. There is a need for the medical training system currently existing in Israel to undergo a thorough conceptual change in order to strive for excellence and innovation on the one hand and to prevent the "brain drain" from Israel on the other. OBJECTIVE: To report on the "Talpiot" program at the "Sheba Medical Center", which identifies, promotes and prepares the most talented young doctors to fill key positions in the fields of medicine and health in Israel. METHODS: This study is based on a project with the same name in the Israeli Defense Forces (IDF). It promotes an elite group of physicians and researchers at the medical center and includes the provision of scholarships, personal guidance and customized educational opportunities for its members. Conversely, every member in the program is committed to complete five years of training followed by another five years as a senior physician or a researcher at the medical center. RESULTS: Since 2002, there have been six cycles of "Talpionaires". The current 46 members of the program fill key leadership roles in the medical center and are considered leaders in their field. Among the program's alumni are managers of institutes, units and research institutes. This group is responsible for the publication of hundreds of scientific papers studies and dozens of patents in medical technology. Some of them have progressed academically far beyond their peers. CONCLUSIONS: Excellence programs are an integral part of any institution which considers itself a leader, both in medicine and beyond. The exciting and visionary "Talpiot" program is Sheba's contribution to the quality of the medical system in the country of Israel in the long run. Promoting young doctors and researchers to become leaders in the Israeli medical system is an integral part of national interests.

Management of pericardial effusion.

Pericardial effusion is a common finding in clinical practice either as incidental finding or manifestation of a systemic or cardiac disease. The spectrum of pericardial effusions ranges from mild asymptomatic effusions to cardiac tamponade. The aetiology is varied (infectious, neoplastic, autoimmune, metabolic, and drug-related), being tuberculosis the leading cause of pericardial effusions in developing countries and all over the world, while concurrent HIV infection may have an important promoting role in this setting. Management is guided by the haemodynamic impact, size, presence of inflammation (i.e. pericarditis), associated medical conditions, and the aetiology whenever possible. Pericardiocentesis is mandatory for cardiac tamponade and when a bacterial or neoplastic aetiology is suspected. Pericardial biopsy is generally reserved for cases with recurrent cardiac tamponade or persistence without a defined aetiology, especially when a bacterial or neoplastic aetiology is suspected and cannot be assessed by other conventional and less invasive means. A true isolated effusion may not require a specific treatment if the patient is asymptomatic, but large ones are at risk of progression to cardiac tamponade (up to one third). Pericardiocentesis alone may be curative for large effusions, but recurrences are also common and pericardiectomy or less invasive options (i.e. pericardial window) should be considered with recurrent cardiac tamponade or symptomatic pericardial effusion (either circumferential or loculated). The aim of this paper was to summarize and critically evaluate current knowledge on the management of pericardial effusion.

Colchicine for prevention of postpericardiotomy syndrome and postoperative atrial fibrillation: the COPPS-2 randomized clinical trial.

IMPORTANCE: Postpericardiotomy syndrome, postoperative atrial fibrillation (AF), and postoperative effusions may be responsible for increased morbidity and health care costs after cardiac surgery. Postoperative use of colchicine prevented these complications in a single trial. OBJECTIVE: To determine the efficacy and safety of perioperative use of oral colchicine in reducing postpericardiotomy syndrome, postoperative AF, and postoperative pericardial or pleural effusions. DESIGN, SETTING, AND PARTICIPANTS: Investigator-initiated, double-blind, placebo-controlled, randomized clinical trial among 360 consecutive candidates for cardiac surgery enrolled in 11 Italian centers between March 2012 and March 2014. At enrollment, mean age of the trial participants was 67.5 years (SD, 10.6 years), 69% were men, and 36% had planned valvular surgery. Main exclusion criteria were absence of sinus rhythm at enrollment, cardiac transplantation, and contraindications to colchicine. INTERVENTIONS: Patients were randomized to receive placebo (n=180) or colchicine (0.5 mg twice daily in patients ≥70 kg or 0.5 mg once daily in patients <70 kg; n=180) starting between 48 and 72 hours before surgery and continued for 1 month after surgery. MAIN OUTCOMES AND MEASURES: Occurrence of postpericardiotomy syndrome within 3 months; main secondary study end points were postoperative AF and pericardial or pleural effusion. RESULTS: The primary end point of postpericardiotomy syndrome occurred in 35 patients (19.4%) assigned to colchicine and in 53 (29.4%) assigned to placebo (absolute difference, 10.0%; 95% CI, 1.1%-18.7%; number needed to treat = 10). There were no significant differences between the colchicine and placebo groups for the secondary end points of postoperative AF (colchicine, 61 patients [33.9%]; placebo, 75 patients [41.7%]; absolute difference, 7.8%; 95% CI, -2.2% to 17.6%) or postoperative pericardial/pleural effusion (colchicine, 103 patients [57.2%]; placebo, 106 patients [58.9%]; absolute difference, 1.7%; 95% CI, -8.5% to 11.7%), although there was a reduction in postoperative AF in the prespecified on-treatment analysis (placebo, 61/148 patients [41.2%]; colchicine, 38/141 patients [27.0%]; absolute difference, 14.2%; 95% CI, 3.3%-24.7%). Adverse events occurred in 21 patients (11.7%) in the placebo group vs 36 (20.0%) in the colchicine group (absolute difference, 8.3%; 95% CI; 0.76%-15.9%; number needed to harm = 12), but discontinuation rates were similar. No serious adverse events were observed. CONCLUSIONS AND RELEVANCE: Among patients undergoing cardiac surgery, perioperative use of colchicine compared with placebo reduced the incidence of postpericardiotomy syndrome but not of postoperative AF or postoperative pericardial/pleural effusion. The increased risk of gastrointestinal adverse effects reduced the potential benefits of colchicine in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01552187.

Rationale and design of the COlchicine for Prevention of the Post-pericardiotomy Syndrome and Post-operative Atrial Fibrillation (COPPS-2 trial): a randomized, placebo-controlled, multicenter study on the use of colchicine for the primary prevention of the postpericardiotomy syndrome, postoperative effusions, and postoperative atrial fibrillation.

BACKGROUND: The efficacy and safety of colchicine for the primary prevention of the postpericardiotomy syndrome (PPS), postoperative effusions, and postoperative atrial fibrillation (POAF) remain uncertain. Although preliminary data from a single trial of colchicine given for 1 month postoperatively (COPPS trial) were promising, the results have not been confirmed in a large, multicenter trial. Moreover, in the COPPS trial, colchicine was given 3 days postoperatively. METHODS: The COPPS-2 study is a multicenter, double-blind, placebo-controlled randomized trial. Forty-eight to 72 hours before planned cardiac surgery, 360 patients, 180 in each treatment arm, will be randomized to receive placebo or colchicine without a loading dose (0.5 mg twice a day for 1 month in patients weighing ≥70 kg and 0.5 mg once for patients weighing <70 kg or intolerant to the highest dose). The primary efficacy end point is the incidence of PPS, postoperative effusions, and POAF at 3 months after surgery. Secondary end points are the incidence of cardiac tamponade or need for pericardiocentesis or thoracentesis, PPS recurrence, disease-related admissions, stroke, and overall mortality. CONCLUSIONS: The COPPS-2 trial will evaluate the use of colchicine for the primary prevention of PPS, postoperative effusions, and POAF, potentially providing stronger evidence to support the use of preoperative colchicine without a loading dose to prevent several postoperative complications. ClinicalTrials.gov Identifier: NCT01552187.

Treatment with aspirin, NSAID, corticosteroids, and colchicine in acute and recurrent pericarditis.

Empiric anti-inflammatory therapy for acute and recurrent pericarditis is warranted for viral and idiopathic cases that represent most cases of pericarditis in developed countries. For specific uncomplicated etiologies, such as systemic autoimmune diseases and postpericardiotomy syndromes, the same drugs are also indicated. Aspirin and non-steroidal anti-inflammatory drugs (NSAID) are mainstay of therapy with the possible adjunct of colchicine, especially for recurrences. Corticosteroids are a second choice for difficult cases requiring multi-drug therapies and specific medical conditions (i.e., specific cases with systemic autoimmune diseases, postpericardiotomy syndrome, and pregnancy). Medical therapy of pericarditis should be individualized as much as possible providing the attack dose every 8 h to ensure full daily control of symptoms and till remission and C-reactive protein normalization, and then tapering should be considered. The present paper will review current evidence for the treatment of acute and recurrent pericarditis with aspirin, NSAID, corticosteroids, and colchicine.

Cardiac tamponade.

Cardiac tamponade is a medical emergency caused by the progressive accumulation of pericardial fluid (effusion), blood, pus or air in the pericardium, compressing the heart chambers and leading to haemodynamic compromise, circulatory shock, cardiac arrest and death. Pericardial diseases of any aetiology as well as complications of interventional and surgical procedures or chest trauma can cause cardiac tamponade. Tamponade can be precipitated in patients with pericardial effusion by dehydration or exposure to certain medications, particularly vasodilators or intravenous diuretics. Key clinical findings in patients with cardiac tamponade are hypotension, increased jugular venous pressure and distant heart sounds (Beck triad). Dyspnoea can progress to orthopnoea (with no rales on lung auscultation) accompanied by weakness, fatigue, tachycardia and oliguria. In tamponade caused by acute pericarditis, the patient can experience fever and typical chest pain increasing on inspiration and radiating to the trapezius ridge. Generally, cardiac tamponade is a clinical diagnosis that can be confirmed using various imaging modalities, principally echocardiography. Cardiac tamponade is preferably resolved by echocardiography-guided pericardiocentesis. In patients who have recently undergone cardiac surgery and in those with neoplastic infiltration, effusive-constrictive pericarditis, or loculated effusions, fluoroscopic guidance can increase the feasibility and safety of the procedure. Surgical management is indicated in patients with aortic dissection, chest trauma, bleeding or purulent infection that cannot be controlled percutaneously. After pericardiocentesis or pericardiotomy, NSAIDs and colchicine can be considered to prevent recurrence and effusive-constrictive pericarditis.

Risk of constrictive pericarditis after acute pericarditis.

BACKGROUND: Constrictive pericarditis (CP) is considered a rare, dreaded possible complication of acute pericarditis. Nevertheless, there is a lack of prospective studies that have evaluated the specific risk according to different etiologies. The aim of this study is to evaluate the risk of CP after acute pericarditis in a prospective cohort study with long-term follow-up. METHODS AND RESULTS: From January 2000 to December 2008, 500 consecutive cases with a first episode of acute pericarditis (age, 51±16 years; 270 men) were prospectively studied to evaluate the evolution toward CP. Etiologies were viral/idiopathic in 416 cases (83.2%), connective tissue disease/pericardial injury syndromes in 36 cases (7.2%), neoplastic pericarditis in 25 cases (5.0%), tuberculosis in 20 cases (4.0%), and purulent in 3 cases (0.6%). During a median follow-up of 72 months (range, 24 to 120 months), CP developed in 9 of 500 patients (1.8%): 2 of 416 patients with idiopathic/viral pericarditis (0.48%) versus 7 of 84 patients with a nonviral/nonidiopathic etiology (8.3%). The incidence rate of CP was 0.76 cases per 1000 person-years for idiopathic/viral pericarditis, 4.40 cases per 1000 person-years for connective tissue disease/pericardial injury syndrome, 6.33 cases per 1000 person-years for neoplastic pericarditis, 31.65 cases for 1000 person-years for tuberculous pericarditis, and 52.74 cases per 1000 person-years for purulent pericarditis. CONCLUSIONS: CP is a relatively rare complication of viral or idiopathic acute pericarditis (<0.5%) but, in contrast, is relatively frequent for specific etiologies, especially bacterial.