Etiologies and predictors of mortality in an all-comer population of patients with non-ischemic heart failure.

BACKGROUND: Despite progress in diagnosis and therapy of heart failure (HF), etiology and risk stratification remain elusive in many patients. METHODS: The My Biopsy HF Study (German clinical trials register number: DRKS22178) is a retrospective monocentric study investigating an all-comer population of patients with unexplained HF based on a thorough workup including endomyocardial biopsy (EMB). RESULTS: 655 patients (70.9% men, median age 55 [45/66] years) with non-ischemic, non-valvular HF were included in the analyses. 489 patients were diagnosed with HF with reduced ejection fraction (HFrEF), 52 patients with HF with mildly reduced ejection fraction (HFmrEF) and 114 patients with HF with preserved ejection fraction (HFpEF). After a median follow-up of 4.6 (2.5/6.6) years, 94 deaths were enumerated (HFrEF: 68; HFmrEF: 8; HFpEF: 18), equating to mortality rates of 3.3% and 11.6% for patients with HFrEF, 7.7% and 15.4% for patients with HFmrEF and 5.3% and 11.4% for patients with HFpEF after 1 and 5 years, respectively. In EMB, we detected a variety of putative etiologies of HF, including incidental cardiac amyloidosis (CA, 5.8%). In multivariate logistic regression analysis adjusting for age, sex and comorbidities only CA, age and NYHA functional class III + IV remained independently associated with all-cause mortality (CA: HRperui 3.13, 95% CI 1.5-6.51; p = 0.002). CONCLUSIONS: In an all-comer population of patients presenting with HF of unknown etiology, incidental finding of CA stands out to be independently associated with all-cause mortality. Our findings suggest that prospective trials would be helpful to test the added value of a systematic and holistic work-up of HF of unknown etiology.

Increased C reactive protein, cardiac troponin I and GLS are associated with myocardial inflammation in patients with non-ischemic heart failure.

Inflammatory cardiomyopathy diagnosed by endomyocardial biopsy (EMB) is common in non-ischemic heart failure (HF) and might be associated with adverse outcome. We aimed to identify markers predicting myocardial inflammation in HF. We screened 517 patients with symptomatic non-ischemic HF who underwent EMB; 397 patients (median age 54 [IQR 43/64], 28.7% females) were included in this study. 230 patients were diagnosed with myocardial inflammation, defined as ≥ 7.0 CD3+ lymphocytes/mm2 and/or ≥ 35.0 Mac1 macrophages/mm2 and were compared to 167 inflammation negative patients. Patients with myocardial inflammation were more often smokers (52.4% vs. 39.8%, p = 0.013) and had higher C-reactive protein (CRP) levels (5.4 mg/dl vs. 3.7 mg/dl, p = 0.003). In logistic regression models CRP ≥ 8.15 mg/dl (OR 1.985 [95%CI 1.160-3.397]; p = 0.012) and Troponin I (TnI) ≥ 136.5 pg/ml (OR 3.011 [1.215-7.464]; p = 0.017) were independently associated with myocardial inflammation, whereas no association was found for elevated brain natriuretic peptide (OR 1.811 [0.873-3.757]; p = 0.111). In prognostic performance calculation the highest positive predictive value (90%) was detected for the combination of Global longitudinal strain (GLS) ≥ -13.95% and TnI ≥ 136.5 pg/ml (0.90 (0.74-0.96)). Elevated CRP, TnI and GLS in combination with TnI can be useful to detect myocardial inflammation. Smoking seems to predispose for myocardial inflammation.

[Lung ultrasonography in COVID-19 pneumonia]. / Sonographische Bildgebung der Lunge bei COVID-19.

BACKGROUND: Point-of-care ultrasound (POCUS) of the lung in patients with COVID-19 plays a key role in the emergency room and intensive care unit. Lung ultrasound is able to depict typical pulmonary findings of COVID-19 and is therefore suitable for diagnosis and follow-up of these patients. CLINICAL/METHODOLOGICAL ISSUE: Lung ultrasound in COVID-19 patients in the emergency room and intensive care unit. STANDARD RADIOLOGICAL METHODS: Computed tomography (low-dose CT) and X­ray of the lung. METHODOLOGICAL INNOVATIONS: Lung ultrasound in COVID-19 patients. RECOMMENDATIONS: Lung ultrasound in patients with COVID-19 offers similar performance as CT and is superior when compared to X­ray in evaluating pneumonia and acute respiratory distress syndrome (ARDS). Lung ultrasound plays an important role in the emergency room and intensive care unit. POCUS reduces exposure to radiation, therapy delays, and minimizes transport of high-risk patients. Differential diagnoses can also be clarified.

When and how do patients with cardiac amyloidosis die?

BACKGROUND: Cardiac amyloidosis (CA) is an underappreciated cause of morbidity and mortality. Light-chain (AL) and transthyretin (ATTR) amyloidosis have different disease trajectories. No data are available on subtype-specific modes of death (MOD) in patients with CA. METHODS AND RESULTS: We retrospectively investigated 66 with AL and 48 with wild-type ATTR amyloidosis (ATTRwt) from 2000 to 2018. ATTRwt differed from AL by age (74.6 ± 5.4 years vs. 63 ± 10.8 years), posterior wall thickness (16.8 ± 3.3 mm vs. 14.3 ± 2.2 mm), left ventricular mass index (180.7 ± 63.2 g/m2 vs. 133.5 ± 42.2 g/m2), and the proportions of male gender (91.7% vs. 59.1%), atrial enlargement (92% vs. 68.2%) and atrial fibrillation (50% vs. 12.1%). In AL NYHA Functional Class and proteinuria (72.7% vs. 39.6%) were greater; mean arterial pressure (84.4 ± 13.5 mmHg vs. 90.0 ± 11.3 mmHg) was lower. Unadjusted 5-year mortality rate was 65% in AL-CA vs. 44% in the ATTRwt group. Individuals with AL-CA were 2.28 times ([95%CI 1.27-4.10]; p = 0.006) more likely to die than were individuals with ATTRwt-CA. Information on MOD was available in 56 (94.9%) of 59 deceased patients. MOD was cardiovascular in 40 (66.8%) and non-cardiovascular in 16 (27.1%) patients. Cardiovascular [28 (68.3%) vs. 13 (80%)] death events were distributed equally between AL and ATTRwt (p = 0.51). CONCLUSION: Our data indicate no differences in MOD between patients with AL and ATTRwt cardiac amyloidosis despite significant differences in clinical presentation and disease progression. Cardiovascular events account for more than two-thirds of fatal casualties in both groups.

Aggravation of left ventricular dysfunction in patients with biopsy-proven cardiac human herpesvirus A and B infection.

BACKGROUND: Human herpesvirus 6 (HHV-6) A and B are lymphotropic viruses with life-long persistence, primarily associated with non-cardiac diseases, and discussed as a possible etiologic factor of myocarditis and cardiomyopathy. OBJECTIVE: To analyze the long-term spontaneous course of cardiac patients suffering from suspected inflammatory cardiomyopathy (CMi) with persisting HHV-6 A and B infections by follow-up biopsies. STUDY DESIGN: We prospectively evaluated patients (n=73) with biopsy-proven viral HHV-6 A and B infection in endomyocardial biopsies (EMBs), followed up by reanalysis of EMBs and left ventricular ejection fraction (LV-EF) measurements after a median period of 8.8 months (range 4-73 months). Beyond, we studied HHV-6 prevalence in isolated peripheral blood cells (PBCs) and HHV-6 species in EMBs. HHV-6 species-specific cellular infection sites within the myocardium were identified by immunohistochemistry (IHC). RESULTS: We identified 73 patients with cardiac HHV-6 A and B persistence or newly detected in follow-up EMB (95.0% B). Proof of HHV-6 in PBCs was primarily associated with A. Persistence of cardiac HHV-6 B genome was significantly associated with cardiac dysfunction at follow-up (LV-EF deteriorated from 58.2±16.0 to 51.8±17.2%, p<0.001), and LV improvement was observed when HHV-6 B persistence resolved (LV-EF increased from 54.9±15.4 to 60.7±13.1%, p<0.001). CONCLUSIONS: Persistence of cardiac HHV-6 B genomes was significantly associated with cardiac dysfunction, and hemodynamic parameters improved in association with HHV-6 B clearance.

Improved diagnosis of idiopathic giant cell myocarditis and cardiac sarcoidosis by myocardial gene expression profiling.

AIMS: Improvement of clinical diagnostics of idiopathic giant cell myocarditis (IGCM) and cardiac sarcoidosis (CS), two frequently fatal human myocardial diseases. Currently, IGCM and CS are diagnosed based on differential patterns of inflammatory cell infiltration and non-caseating granulomas in histological sections of endomyocardial biopsies (EMBs), after heart explantation or postmortem. We report on a method for improved differential diagnosis by myocardial gene expression profiling in EMBs. METHODS AND RESULTS: We examined gene expression profiles in EMBs from 10 patients with histopathologically proven IGCM, 10 with CS, 18 with active myocarditis (MCA), and 80 inflammation-free control subjects by quantitative RT-QPCR. We identified distinct differential profiles that allowed a clear discrimination of tissues harbouring giant cells (IGCS, CS) from those with MCA or inflammation-free controls. The expression levels of genes coding for cytokines or chemokines (CCL20, IFNB1, IL6, IL17D; P < 0.05), cellular receptors (ADIPOR2, CCR5, CCR6, TLR4, TLR8; P < 0.05), and proteins involved in the mitochondrial energy metabolism (CPT1, CYB, DHODH; P < 0.05) were deregulated in 2- to 300-fold, respectively. Bioinformatic analyses and correlation of the gene expression data with immunohistochemical findings provided novel information regarding the differential cellular and molecular pathomechanisms in IGCM, CS, and MCA. CONCLUSION: Myocardial gene expression profiling is a reliable method to predict the presence of multinuclear giant cells in the myocardium, even without a direct histological proof, in single small EMB sections, and thus to reduce the risk of sampling errors. This profiling also facilitates the discrimination between IGCM and CS, as two different clinical entities that require immediate and tailored differential therapy.

Fractalkine in human inflammatory cardiomyopathy.

BACKGROUND: Cardiac inflammation is important for the prognosis of patients with inflammatory cardiomyopathy (CMi), but the mechanisms leading to it are not fully elucidated. OBJECTIVE: To study the role of fractalkine (CX3CL1) in chemotactic and adhesive properties of peripheral blood mononuclear cells (PBMCs) in patients with CMi. METHODS AND RESULTS: Patients with enterovirus (EV)-positive CMi, patients with virus-negative CMi, patients with parvovirus B19 (B19) genomes with low intramyocardial inflammation and patients without cardiac inflammation and viral infection in the endomyocardial biopsy (EMB) were enrolled (n=10/group). The expression of CX3CL1 and monocyte chemoattractant protein (MCP-1) in EMBs was significantly increased in EV-positive and virus-negative patients with CMi in contrast to controls and B19-positive patients (EV+ vs controls: CX3CL1-area fraction (AF) % 0.078±0.012 vs 0.009±0.003 p<0.05; MCP-1-AF % 0.093±0.023 vs 0.011±0.009). The receptor (CX3CR1)-mediated chemotaxis was increased twofold in PBMCs in comparison with those of controls. The MCP-1 secretion was 3.1-fold higher in PBMCs from EV-positive patients compared with controls, and this elevation was further increased by CX3CL1 in EV-positive patients. No significant CX3CL1-mediated MCP-1 increase was seen in PBMCs from healthy controls. Moreover, spontaneously beating neonatal rat cardiomyocytes exposed to CX3CL1 exhibited an attenuated positive chronotropic response to ß-adrenergic stimulation with isoproterenol. CONCLUSION: The cardiac and plasma CX3CL1/CX3CR1 system is upregulated in CMi and this affects the functional potential of PBMCs. Moreover, a direct cardiodepressive effect of CX3CL1 in cardiac tissue was demonstrated since neonatal cardiomyocytes exhibited an attenuated positive chronotropic response to ß-adrenergic stimulation.

Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction.

BACKGROUND: The pathophysiology of heart failure with normal ejection fraction (HFNEF) is still under discussion. Here we report the influence of cardiac inflammation on extracellular matrix (ECM) remodeling in patients with HFNEF. METHODS AND RESULTS: We investigated left ventricular systolic and diastolic function in 20 patients with HFNEF and 8 control patients by conductance catheter methods and echocardiography. Endomyocardial biopsy samples were also obtained, and ECM proteins as well as cardiac inflammatory cells were investigated. Primary human cardiac fibroblasts were outgrown from the endomyocardial biopsy samples to investigate the gene expression of ECM proteins after stimulation with transforming growth factor-ß. Diastolic dysfunction was present in the HFNEF patients compared with the control patients. In endomyocardial biopsy samples from HFNEF patients, we found an accumulation of cardiac collagen, which was accompanied by a decrease in the major collagenase system (matrix metalloproteinase-1) in the heart. Moreover, a subset of inflammatory cells, which expressed the profibrotic growth factor transforming growth factor-ß, could be documented in the HFNEF patients. Stimulation of primary human cardiac fibroblasts from HFNEF patients with transforming growth factor-ß resulted in transdifferentiation of fibroblasts to myofibroblasts, which produced more collagen and decreased the amount of matrix metalloproteinase-1, the major collagenase in the human heart. A positive correlation between cardiac collagen, as well as the amount of inflammatory cells, and diastolic dysfunction was evident and suggests a direct influence of inflammation on fibrosis triggering diastolic dysfunction. CONCLUSIONS: Cardiac inflammation contributes to diastolic dysfunction in HFNEF by triggering the accumulation of ECM.

Induction of neutral endopeptidase and angiotensin-converting enzyme activity of SK-N-SH cells in vitro by quercetin and resveratrol.

Quercetin and resveratrol are weak inhibitors of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) activity of the neuroblastoma cell line SK-N-SH. The long term incubation of the cells for 4 days with quercetin, resveratrol and a combination of both substances in concentrations lower than necessary for inhibition of NEP and ACE activity induced the cellular enzyme activity of NEP and ACE associated with an inhibition of cellular proliferation. The long term treatment of neuroblastoma cells with quercetin and resveratrol enhanced the differentiation state of the cells. Taking into account the significance of NEP and ACE for the degradation of amyloid beta peptides, the effect of quercetin and resveratrol as constituents of red wine for a neuroprotective activity is discussed.

[Therapy of Zenker's diverticula]. / Zur Therapie des Zenkerschen Divertikels.

The etiology and symptoms of Zenker's hypopharynx diverticulum are reviewed. The significance of stenosis formation by the pars fundiformis segment of the crico-pharyngeal muscle is emphasized. Careful preparation and dissection, followed by splitting of the constricting musculature, is the precondition for successful surgery. It can be demonstrated that invagination (closed operation) is usually sufficient, while keeping resection for large diverticula invading the mediastinum. Complications are rare and operative risks are minimal, even in the elderly. A report is presented on 40 cases in which surgery was performed.

[Clinical aspects and pathology of chondromatous tumors of the larynx]. / Zur Klinik und Pathologie chondromatöser Tumoren des Larynx.

Two cases of chondroma of the larynx are presented: After the first laryngofissure and excision both tumours recurred so that several operations became necessary. A transformation from chondroma to chondrosarcoma was observed based on repeated histological examinations. In the first patient pulmonary metastases and a recurrence at the tracheostomy appeared 11 years after presentation and 41/2 years after laryngectomy. In the other female patient no obvious signs of the neoplasm are present 9 years after presentation, and 4 months after the last operation for recurrence, but the prognosis remains undetermined. 101 cases of chondrosarcoma from the literature plus our 2 observations are listed and compared with 130 chondrosarcomas of the skeleton. Contrary to previous opinions, we conclude that chondrosarcoma of the larynx behaves in the same malignant manner as those of the skeleton. Some develop metastases quickly, others only after years and after at least one operation for recurrence. We could demonstrate that a detailed histological examination allows the prognosis to be assessed. Additional risk factors were also investigated. These two cases enable a better and more reliable judgement to be made of the prospective biological behaviour of chondromatous tumours of the larynx and at an earlier period of time of the process.

[On the problem of the congenital (?) cholesteatoma of the petrous bone (author's transl)]. / Zum Problem des kongenitalen (?) Felsenbeincholesteatoms.

The congenital cholesteatoma of the petrous bone is a rarity. The topographic situation corresponds to a congenital dermoid. The evolution is typic. On the beginning the ear drum is intact, very early one will find a loss of the labyrinth function, often accompanied by a facial paresis. The suppuration of the middle ear comes in a later state. The drainage operation is insufficient. The subtotal petrosectomy with permanent anterior dislocation of the facial nerve gives the chance for a definitive healing.

[Middle ear tuberculosis (author's transl)]. / Es gibt noch Mittelohrtuberkulosen.

With the decrease in tuberculosis in general that of the middle ear has become a rarity, such that it is almost unknown to the younger generation of doctors. Nevertheless one must consider this diagnosis in all relapsing and treatment-resistant inflammations of the middle ear, especially when tympanoplasty procedures have been unsuccessful. Bacteriological findings are less reliable than histological proof and therefore examination of granulation tissue is always indicated. A precise history into earlier tuberculosis is important, since the disease is mostly disseminated haematologically. Two clinical examples with pathological descriptions are presented. In the first case fresh exudative disease similar to that of tubotympanitis occurred and quickly passed on to a chronic destructive middle ear inflammatory process. One year previously the patient had pleurisy. A complete cure followed surgery and antituberculosis therapy. In the second case a chronic proliferative and destructive inflammatory process was present with obviously less favourable reparative properties since two tympanoplasties were ineffectively performed.

[Psychopathology in patients with presumed nasal deformities (author's transl)]. / Zur Psychopathologie einer vermeintlichen Nasendeformität.

If a patient with a "normal" nose desires rhinoplastic surgery, psychopathologic behavior should be recognized. In such patients, surgery is contra-indicated and the origin for the neurosis should be investigated. Two patients are presented in whom psychoanalysis was useful in correcting complex neurotic fixations on the nose with their attendant psychic dysharmonias. Therapy provided each patient with a more satisfying personal image. Each patient's desire for corrective nasal surgery was eliminated and patients were better able to accept their nasal features as well as gain positive social adjustments in their future lives.