Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK).

Systemic forms of amyloidosis affecting the heart are mostly light-chain (AL) and transthyretin (ATTR) amyloidoses. The latter is caused by deposition of misfolded transthyretin, either in wild-type (ATTRwt) or mutant (ATTRv) conformation. For diagnostics, specific serum biomarkers and modern non-invasive imaging techniques, such as cardiovascular magnetic resonance imaging (CMR) and scintigraphic methods, are available today. These imaging techniques do not only complement conventional echocardiography, but also allow for accurate assessment of the extent of cardiac involvement, in addition to diagnosing cardiac amyloidosis. Endomyocardial biopsy still plays a major role in the histopathological diagnosis and subtyping of cardiac amyloidosis. The main objective of the diagnostic algorithm outlined in this position statement is to detect cardiac amyloidosis as reliably and early as possible, to accurately determine its extent, and to reliably identify the underlying subtype of amyloidosis, thereby enabling subsequent targeted treatment.

[Diagnostics and Treatment of Cardiac Sarcoidosis - Consensus Paper of the German Respiratory Society (DGP) and the German Cardiac Society (DGK)]. / Diagnostik und Therapie der kardialen Sarkoidose.

Sarcoidosis is a multisystemic granulomatous disorder which affects the respiratory system in the majority of the cases. Symptomatic cardiac manifestations are found in less than 10 % of the affected cohorts and show a large heterogeneity based on the ethnic background. Cardiac sarcoidosis is not only found in patients with rhythmogenic heart disease, such as atrial and ventricular fibrillation but also in all phenotypes of cardiomyopathy. The overall morbidity and mortality caused by cardiac sarcoidosis in Germany remains unclear and large prospective international observational studies.underline the importance of this disease entity. This consensus paper on diagnostic and therapeutic algorithms for cardiac sarcoidosis is based on a current literature search and forms an expert opinion statement under the auspices of the German Respiratory Society and the German Cardiac Society. The rationale of this statement is to provide algorithms to facilitate clinical decision-making based on the individual case situation.

Precision medicine for cardiovascular disease : Learning lessons from cardiomyopathies.

Evidence-based medicine has considerably advanced the treatment of highly prevalent cardiovascular diseases. Its implementation was driven by multicenter interventional trials in treatment and placebo cohorts, propelling numerous biomedical innovations toward standard of care. While a uniform treatment can be effective in such disease cohorts ("one size fits all"), it neglects the genetic and phenotypic individuality of a single patient and his or her disease. Accordingly, a recent observation was made that several newer "mega" trials, demanding considerable resources for their execution, showed statistically significant differences in outcome, however, with small overall efficacies that render implementation in the clinics unlikely. To overcome this concerning development, new methods for individualized treatment of cardiovascular disease are required. Rarer conditions, such as distinct cardiomyopathies, may deliver the blueprint for a paradigm shift: deep and precise phenotyping of individual patients by a multimodal approach and development of targeted treatments for smaller groups ("one treatment for many") or even for single patients ("one treatment of some").

Identification of circular RNAs with host gene-independent expression in human model systems for cardiac differentiation and disease.

AIMS: Cardiovascular disease, one of the most common causes of death in western populations, is characterized by changes in RNA splicing and expression. Circular RNAs (circRNA) originate from back-splicing events, which link a downstream 5' splice site to an upstream 3' splice site. Several back-splicing junctions (BSJ) have been described in heart biopsies from human, rat and mouse hearts (Werfel et al., 2016; Jakobi et al., 2016 ). Here, we use human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to identify circRNA and host gene dynamics in cardiac development and disease. In parallel, we explore candidate interactions of selected homologs in mouse and rat via RIP-seq experiments. METHODS AND RESULTS: Deep RNA sequencing of cardiomyocyte development and ß-adrenergic stimulation uncovered 4518 circRNAs. The set of circular RNA host genes is enriched for chromatin modifiers and GTPase activity regulators. RNA-seq and qRT-PCR data showed that circular RNA expression is highly dynamic in the hiPSC-CM model with 320 circRNAs showing significant expression changes. Intriguingly, 82 circRNAs are independently regulated to their host genes. We validated the same circRNA dynamics for circRNAs from ATXN10, CHD7, DNAJC6 and SLC8A1 in biopsy material from human dilated cardiomyopathy (DCM) and control patients. Finally, we could show that rodent homologs of circMYOD, circSLC8A1, circATXN7 and circPHF21A interact with either the ribosome or Argonaute2 protein complexes. CONCLUSION: CircRNAs are dynamically expressed in a hiPSC-CM model of cardiac development and stress response. Some circRNAs show similar, host-gene independent expression dynamics in patient samples and may interact with the ribosome and RISC complex. In summary, the hiPSC-CM model uncovered a new signature of potentially disease relevant circRNAs which may serve as novel therapeutic targets.

Precision medicine approach to genetic cardiomyopathy.

Precision medicine aims to achieve improved survival by strategies that recognize the genetic and phenotypic individuality of patients and stratify treatment accordingly. Genetic cardiomyopathies represent an ideal disease group to fully embark on this concept: they are in total frequent diseases with a marked morbidity and mortality and there is ample knowledge about their predisposing genetic factors and associated functional mechanisms. The current review highlights the genetic etiology and gives examples of the diverse treatment strategies that are envisaged in the future.

Genetic cardiomyopathies. Lessons learned from humans, mice, and zebrafish.

Dilated cardiomyopathy (DCM) is a multifactorial disease of the heart muscle and a leading cause of congestive heart failure. Human genetic studies and the establishment of suitable animal models such as mice and zebrafish have already revealed parts of its genetic etiology. With the next generation of genomic sequencing technologies (NGS) on the rise, the comprehensive genetic dissection of DCM patients will reveal clinically relevant information, novel causes, and modifiers of this complex disorder. The recent exploration of the epigenome as another mechanism of cardiac gene regulation will further elucidate unexplained variations observed in the correlation between the patient's genotype and phenotype. Some of these intriguing advances being made in basic genetic research will soon find their way into clinical practice for more individualized treatment of cardiomyopathy patients.

[Clinical and genetic aspects of hypertrophic and dilated cardiomyopathy]. / Klinik und Genetik der hypertrophen und dilatativen Kardiomyopathie.

Primary cardiomyopathies are frequent heart diseases with an estimated prevalence of 0.3-0.4% in the general population, significantly contributing to systolic heart failure and sudden cardiac death in the young. Molecular genetic studies have identified 49 different disease genes for hypertrophic and dilated cardiomyopathy, often involving proteins of the sarcomere, the cardiac Z-disc and the cytoskeleton. With the development of new, advanced technologies based on next-generation sequencing, it is now possible to efficiently screen all known disease genes in an individual patient. The clinical workup of cardiomyopathies should always include the investigation of the patient's family to account for the familial aggregation of cardiomyopathies and identify diseased as well as asymptomatic carriers of mutations. The detection of specific genotypes facilitates diagnostic classification and can improve risk stratification in affected patients.

Sultamicillin versus amoxicillin in the treatment of tonsillitis and pharyngitis: a European multicenter study.

In this multicenter open, comparative study, 135 patients were treated with sultamicillin (67 subjects; 500 mg every 12 h) or amoxicillin (68 subjects; 500 mg every 8 h) for 10 d. Of the pathogens isolated pre-treatment, 24 of 29 (including 4 of 6 resistant strains) in the sultamicillin group were eradicated at the end of treatment, as were 17 of 22 in the amoxicillin group. At follow-up, the figures were 17 of 25 and 16 of 19, respectively. Clinical success was achieved in 55 of 55 sultamicillin and 40 of 43 amoxicillin patients at the end of treatment, and in 40 of 42 and 29 of 31, respectively, at follow-up. Overall success was recorded in 20 of 25 and 15 of 23 sultamicillin, and 14 of 19 and 13 of 17 amoxicillin patients at the two assessments. Side effects were reported for 21 sultamicillin patients, 1 of whom withdrew because of diarrhea, and 15 amoxicillin patients, 4 of whom withdrew because of rash. One sultamicillin and 4 amoxicillin patients developed minor abnormalities in laboratory safety parameters.

Clinical and laboratory evaluation of the effect of cephradine on patients with ear, nose and throat infections.

27 patients with ear, nose and throat infections have been treated with cephradine orally. Ten patients received 250 mg and 17 patients 500 mg every 6 h during 10 days. 26 patients were cured. One patient failed to respond to treatment but reinfection could not be excluded. Determination of plasma concentrations showed that cephradine was well absorbed. The drug showed no severe adverse effects. Cephradine is a good replacement in patients with allergy to penicillins. It is also suitable when broad-spectrum therapy is needed.