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The Organ Care System is the only clinical platform for ex-vivo perfusion of human donor hearts. The system preserves the donor heart in a warm beating state during transport from the donor hospital to the recipient hospital. We aimed to assess the clinical outcomes of the Organ Care System compared with standard cold storage of human donor hearts for transplantation. We did this prospective, open-label, multicentre, randomised non-inferiority trial at ten heart-transplant centres in the USA and Europe. Eligible heart-transplant candidates (aged >18 years) were randomly assigned (1:1) to receive donor hearts preserved with either the Organ Care System or standard cold storage. Participants, investigators, and medical staff were not masked to group assignment. The primary endpoint was 30 day patient and graft survival, with a 10% non-inferiority margin. We did analyses in the intention-to-treat, as-treated, and per-protocol populations. This trial is registered with ClinicalTrials.gov, number NCT00855712. Between June 29, 2010, and Sept 16, 2013, we randomly assigned 130 patients to the Organ Care System group (n=67) or the standard cold storage group (n=63). 30 day patient and graft survival rates were 94% (n=63) in the Organ Care System group and 97% (n=61) in the standard cold storage group (difference 2·8%, one-sided 95% upper confidence bound 8·8; p=0·45). Eight (13%) patients in the Organ Care System group and nine (14%) patients in the standard cold storage group had cardiac-related serious adverse events. Heart transplantation using donor hearts adequately preserved with the Organ Care System or with standard cold storage yield similar short-term clinical outcomes. The metabolic assessment capability of the Organ Care System needs further study. TransMedics.

Abstract Cardiomyopathies are a heterogeneous group of myocardial disorders of mostly unknown etiology, and they occur commonly in cats. In some cats, they are well-tolerated and are associated with normal life expectancy, but in other cats they can result in congestive heart failure, arterial thromboembolism or sudden death. Cardiomyopathy classification in cats can be challenging, and in this consensus statement we outline a classification system based on cardiac structure and function (phenotype). We also introduce a staging system for cardiomyopathy that includes subdivision of cats with subclinical cardiomyopathy into those at low risk of life-threatening complications and those at higher risk. Based on the available literature, we offer recommendations for the approach to diagnosis and staging of cardiomyopathies, as well as for management at each stage.

This review gives an account of the molecular mechanisms that underlie various forms of inherited cardiomyopathies. Numerous, rare mutations occur in each category, and different mutations in the same genes can produce different phenotypes. Inherited cardiomyopathies are a major cause of heart disease in all age groups, often with an onset in adolescence or early adult life. Not only the patients but also their families can be severely burdened by these illnesses. More than 20 years ago, the first “disease gene” for hypertrophic cardiomyopathy was identified. 1 , 2 This finding led to the concept that hypertrophic cardiomyopathy is a disease of the sarcomere. 3 Similar advances in the elucidation of the genetic basis of other forms of cardiomyopathy, as well as in other inherited cardiovascular diseases, soon followed. The identification of disease genes in numerous inherited . . .

BackgroundThe utility of diagnostic genetic testing in cardiomyopathy has grown significantly, due to the discovery of novel genes and greater awareness among healthcare professionals. However, a substantial proportion of cases (around 50%) yield no causative genetic variants or have variants of unknown significance (VUS), limiting their use in clinical management and familial screening. The increase in data quantity and quality in reference databases, coupled with variant interpretation guidelines, allows for periodic reanalysis of VUS, potentially reducing diagnostic gaps.MethodsThis study presents a review of VUS results identified in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) probands over a 5-year period, using American College of Medical Genetics and Genomics criteria. A total of 248 VUS from 233 reports were reviewed, with the majority of patients with a diagnosis of HCM (n=112), followed by DCM (n=99) and ACM (n=22).ResultsFour (1.6%) VUS showed sufficient evidence to upgrade to likely pathogenic/pathogenic status, while 8 (3.2%) were downgraded to benign. The majority 236 (95.2%) remained VUS after reanalysis, of which 12 (4.7%) had potential to reclassification to benign or likely pathogenic/pathogenic depending on further data.ConclusionThe study emphasises the importance of periodic re-evaluation of VUS results for clinical management of probands as well as cascade testing. We show feasibility of conducting reclassification analysis in a referral centre, but highlight the need for ongoing collaboration between clinical and laboratory experts. Our work supports the current recommendation of reclassification every 3–5 years to keep pace with evolving evidence.

Letter to the Editor

We assessed Takotsubo (ampulla) cardiomyopathy compared with acute coronary syndrome (ACS) using two-dimensional echocardiography and 99mTc-tetrofosmin myocardial SPECT. We examined 10 patients with Takotsubo cardiomyopathy and 16 with ACS at the time of emergency admission (acute phase), at three to nine days after the attack (subacute phase) and at one month after the attack (chronic phase). The left ventricle was divided into nine regions on echocardiograms and SPECT images, and the degree of abnormalities in each region was scored in five grades from normal (0) to severely abnormal (4). Coronary angiography revealed total or subtotal occlusion in patients with ACS but no stenotic legions in those with Takotsubo cardiomyopathy. The amount of ST segment elevation (mm) was 7.9 +/- 3.4 in patients with Takotsubo cardiomyopathy and 7.3 +/- 3.7 in those with ACS (N.S.). Abnormal wall motion scores on echocardiograms were 13.8 +/- 4.4, 4.4 +/- 3.8 and 1.8 +/- 2.3 during the acute, subacute and chronic phases in patients with Takotsubo cardiomyopathy, and 13.9 +/- 4.0, 11.7 +/- 3.7, 7.6 +/- 4.2, respectively in patients with ACS. The value of MB fraction of creatine phosphokinase (IU/l) was 34 +/- 23 in patients with Takotsubo cardiomyopathy and 326 +/- 98 in those with ACS (p < 0.001). Abnormal myocardial perfusion scores on 99mTc-tetrofosmin myocardial SPECT were 11.4 +/- 3.2, 3.2 +/- 3.3 and 0.7 +/- 1.1 during the acute, subacute and chronic phases respectively, in patients with Takotsubo cardiomyopathy, and 15.8 +/- 4.1, 13.5 +/- 4.4, 8.2 +/- 4.4, respectively, in those with ACS. The numbers of myocardial segments that did not uptake 99mTc-tetrofosmin during the acute phase were 0.5 +/- 0.8 and 3.6 +/- 2.8 in patients with Takotsubo cardiomyopathy and ACS, respectively. Impaired coronary microcirculation might be a causative mechanism of Takotsubo cardiomyopathy.

ObjectivesThe prognostic value of genetic studies in cardiomyopathies is still controversial. Our objective was to evaluate the outcome of patients with cardiomyopathy with mutations in the converter domain of β myosin heavy chain (MYH7).MethodsClinical characteristics and survival of 117 affected members with mutations in the converter domain of MYH7 were compared with 409 patients described in the literature with mutations in the same region.ResultsTwenty-five mutations were evaluated (9 in our families including 3 novel (Ile730Asn, Asp717Gly and Arg719Pro)). Clinical diagnoses were hypertrophic (n=407), dilated (n=15), non-compaction (n=4) and restrictive (n=5) cardiomyopathies, unspecified cardiomyopathy (n=11), sudden death (n=50) and 35 healthy carriers. One hundred eighty-four had events (cardiovascular death or transplant). Median event-free survival was 50±2 years in our patients and 53±3 years in the literature (p=0.27). There were significant differences in the outcome between mutation: Ile736Thr had fewer events than other mutations in the region (p=0.01), while Arg719Gln (p<0.01) had reduced event-free survival.ConclusionsMutations in the converter region are generally associated with adverse prognosis although there are differences between mutations. The identification of a mutation in this particular region provides important prognostic information that should be considered in the clinical management of affected patients.

In the WHO/ISFC classification of 1996, cardiomyopathies were defined as primary myocardial disorders of unknown cause. Heart muscle disorders of known etiology or associated with systemic disorders were classified as secondary or specific heart muscle diseases. An expert panel of the American Heart Association has recently suggested a new scheme that combines genetic and clinical criteria. In this system, the term primary is used to describe cardiac diseases in which the heart is the sole or predominantly involved organ and secondary to describe diseases in which myocardial dysfunction is part of a systemic disorder. In a radical departure from convention, they also suggested that ion channelopathies and disorders of conduction should be considered cardiomyopathies as well. The ESC Working Group on Myocardial and Pericardial Diseases has taken a different approach based on the belief that a clinically oriented classification system in which heart muscle disorders are grouped according to ventricular morphology and function remains the clinically most useful method for diagnosing and managing patients and families with heart muscle disease. In the ESC position statement, cardiomyopathies are defined as myocardial disorders in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality. In this article, this is illustrated by examples of dilated cardiomyopathy as familial/genetic forms and nonfamilial/nongenetic forms.

Cardiomyopathies are complex diseases of multifactorial pathogenesis and have a high morbidity and mortality. Over the past decades, several revisions of classifications and definitions of cardiomyopathies have been proposed, primarily focusing on the phenotypic characterization of cardiomyopathies. The MOGE(S) classification system published in 2013 encompasses the classification of rapidly growing knowledge on genetic mutations, acquired causes (i.e., intramyocardial inflammation, viral infections), and further conditions involved in the induction of cardiomyopathies (e.g., storage diseases, toxicity). It is based on five attributes, including morphofunctional characteristics (M), organ involvement (O), genetic or familial inheritance pattern (G), etiological annotation (E), and optional information about the heart failure functional status (S). This review summarizes the development, the cornerstones of the MOGE(S) classification, and the published data on the clinical relevance of the MOGE(S) classification. We furthermore discuss new issues which might be considered for future updates of the MOGE(S) classification of cardiomyopathies.

In the WHO 1996 classification of cardiomyopathies, myocarditis is defined as an “inflammatory disease of the myocardium associated with cardiac dysfunction” and is listed among “specific cardiomyopathies”. Myocarditis is diagnosed on endomyocardial biopsy (EMB) by established histological, immunological, and immunohistochemical criteria, and molecular techniques are recommended to identify viral etiology. Infectious, autoimmune, and idiopathic forms of inflammatory cardiomyopathy are recognized that may lead to dilated cardiomyopathy. According to Dallas criteria, myocarditis is diagnosed in the setting of an “inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes, not typical of ischemic damage associated with coronary artery disease”. The majority of experts in the field agree that an actual increase in sensitivity of EMB has now been reached by using immunohistochemistry together with histology. A value of >14 leukocytes/mm 2 with the presence of T lymphocytes >7 cells/mm 2 has been considered a realistic cut off to reach a diagnosis of myocarditis. The development of molecular biological techniques, particularly amplification methods like polymerase chain reaction (PCR) or nested-PCR, allows the detection of low copy viral genomes even from an extremely small amount of tissue such as in EMB specimens. Positive PCR results obtained on EMB should always be accompanied by a parallel investigation on blood samples collected at the time of the EMB. According to the recent Association for European Cardiovascular Pathology guidelines, optimal specimen procurement and triage indicates at least three, preferably four, EMB fragments, each 1–2 mm in size, that should immediately be fixed in 10 % buffered formalin at room temperature for light microscopic examination. In expected focal myocardial lesions, additional sampling is recommended. Moreover, one or two specimens should be snap-frozen in liquid nitrogen and stored at −80 °C or alternatively stored in RNA-later for possible molecular tests or specific stains. A sample of peripheral blood (5–10 ml) in EDTA or citrate from patients with suspected myocarditis allows molecular testing for the same viral genomes sought in the myocardial tissue.