New categorization of chest pain: noncardiac is in, atypical is out!

Chest pain poses a diagnostic challenge in the emergency department and requires a thorough clinical assessment. The traditional distinction between "atypical" and "typical" chest pain carries the risk of not addressing nonischemic clinical pictures. The newly conceived subdivision into cardiac, possibly cardiac, and (probably) noncardiac causes of the presenting symptom complex addresses a much more interdisciplinary approach to a symptom-oriented diagnostic algorithm. The diagnostic structures of the chest pain units in Germany do not currently reflect this. An adaptation should therefore be considered.

Imaging of Cardiac Fibrosis: How Far Have We Moved From Extracellular to Cellular?

Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Myocardial fibrosis plays an important role in adverse outcomes such as heart failure and arrhythmias. As the pathological response and degree of scarring, and therefore clinical presentation varies from patient to patient, early detection of fibrosis is crucial for identifying the appropriate treatment approach and forecasting the progression of a disease along with the likelihood of disease-related mortality. Current imaging modalities provides information about either decreased function or extracellular signs of fibrosis. Targeting activated fibroblasts represents a burgeoning approach that could offer insights prior to observable functional alterations, presenting a promising focus for potential anti-fibrotic therapeutic interventions at cellular level. In this article, we provide an overview of imaging cardiac fibrosis and discuss the role of different advanced imaging modalities with the focus on novel non-invasive imaging of activated fibroblasts.

Molecular Imaging Biomarkers in Cardiooncology: A View on Established Technologies and Future Perspectives.

Novel therapeutic options have significantly improved survival and long-term outcomes in many cancer entities. Unfortunately, this improvement in outcome is often accompanied by new and increasingly relevant therapy-related cardiovascular toxicity. In this context, cardiooncology has emerged as a new field of interdisciplinary individual patient care. Important tasks are pretherapeutic risk stratification and early detection and treatment of cardiotoxicity, which comprises cardiac damage in relation to cardiovascular comorbidities, the tumor disease, and cancer treatment. Clinical manifestations can cover a broad spectrum, ranging from subtle and usually asymptomatic abnormalities to serious acute or chronic complications. Typical manifestations include acute and chronic heart failure, myo- and pericarditis, arrythmias, ischemia, and endothelial damage. They can be related to almost all current cancer treatments, including cytotoxic chemotherapy, targeted therapy, immunotherapy, hormonal therapy, and radiotherapy. Molecular imaging biomarkers can aid in pretherapeutic cardiooncologic assessment for primary prevention and personalized surveillance, detection, and differential diagnosis of cardiotoxic complications. Potential advantages over conventional diagnostics are the higher detection sensitivity for subtle changes in cardiac homeostasis, higher reproducibility, and better observer independence. Hybrid imaging with highly sensitive PET/MRI may be particularly suited for early diagnosis. Important technologies that are encouraged in current multidisciplinary guidelines are equilibrium radionuclide angiography for evaluation of ventricular function and chamber morphology, as well as myocardial perfusion imaging for additional detection of ischemia. Novel modalities that may detect even earlier signs of cardiotoxicity comprise 123I-metaiodobenzylguanidine SPECT to visualize sympathetic innervation, 18F-FDG and somatostatin receptor (68Ga-DOTATOC/DOTATATE) PET to indicate a metabolic shift and inflammation, and 68Ga-fibroblast activation protein inhibitor PET to monitor cardiac remodeling. In addition, PET imaging of mitochondrial function has recently been introduced in preclinical models and will potentially broaden the field of application through higher sensitivity and specificity and by enabling higher individualization of diagnostic concepts.

Demonstration of the Early Cardiac Bioavailability of a Non-Specific Cell-Targeted Peptide Using Radionuclide-Based Imaging In Vivo.

The cardiac bioavailability of peptide drugs that inhibit harmful intracellular protein-protein interactions in cardiovascular diseases remains a challenging task in drug development. This study investigates whether a non-specific cell-targeted peptide drug is available in a timely manner at its intended biological destination, the heart, using a combined stepwise nuclear molecular imaging approach. An octapeptide (heart8P) was covalently coupled with the trans-activator of transcription (TAT) protein transduction domain residues 48-59 of human immunodeficiency virus-1 (TAT-heart8P) for efficient internalization into mammalian cells. The pharmacokinetics of TAT-heart8P were evaluated in dogs and rats. The cellular internalization of TAT-heart8P-Cy(5.5) was examined on cardiomyocytes. The real-time cardiac delivery of 68Ga-NODAGA-TAT-heart8P was tested in mice under physiological and pathological conditions. Pharmacokinetic studies of TAT-heart8P in dogs and rats revealed a fast blood clearance, high tissue distribution, and high extraction by the liver. TAT-heart-8P-Cy(5.5) was rapidly internalized in mouse and human cardiomyocytes. Correspondingly, organ uptake of hydrophilic 68Ga-NODAGA-TAT-heart8P occurred rapidly after injection with an initial cardiac bioavailability already 10 min post-injection. The saturable cardiac uptake was revailed by the pre-injection of the unlabeled compound. The cardiac uptake of 68Ga-NODAGA-TAT-heart8P did not change in a model of cell membrane toxicity. This study provides a sequential stepwise workflow to evaluate the cardiac delivery of a hydrophilic, non-specific cell-targeting peptide. 68Ga-NODAGA-TAT-heart8P showed rapid accumulation in the target tissue early after injection. The implementation of PET/CT radionuclide-based imaging methodology as a means to assess effective and temporal cardiac uptake represents a useful and critical application in drug development and pharmacological research and can be extended to the evaluation of comparable drug candidates.

Anthracycline Therapy Modifies Immune Checkpoint Signaling in the Heart.

Cancer survival rates have increased significantly because of improvements in therapy regimes and novel immunomodulatory drugs. Recently, combination therapies of anthracyclines and immune checkpoint inhibitors (ICIs) have been proposed to maximize neoplastic cell removal. However, it has been speculated that a priori anthracycline exposure may prone the heart vulnerable to increased toxicity from subsequent ICI therapy, such as an anti-programmed cell death protein 1 (PD1) inhibitor. Here, we used a high-dose anthracycline mouse model to characterize the role of the PD1 immune checkpoint signaling pathway in cardiac tissue using flow cytometry and immunostaining. Anthracycline treatment led to decreased heart function, increased concentration of markers of cell death after six days and a change in heart cell population composition with fewer cardiomyocytes. At the same time point, the number of PD1 ligand (PDL1)-positive immune cells and endothelial cells in the heart decreased significantly. The results suggest that PD1/PDL1 signaling is affected after anthracycline treatment, which may contribute to an increased susceptibility to immune-related adverse events of subsequent anti-PD1/PDL1 cancer therapy.

Shining Damaged Hearts: Immunotherapy-Related Cardiotoxicity in the Spotlight of Nuclear Cardiology.

The emerging use of immunotherapies in cancer treatment increases the risk of immunotherapy-related cardiotoxicity. In contrast to conventional chemotherapy, these novel therapies have expanded the forms and presentations of cardiovascular damage to a broad spectrum from asymptomatic changes to fulminant short- and long-term complications in terms of cardiomyopathy, arrythmia, and vascular disease. In cancer patients and, particularly, cancer patients undergoing (immune-)therapy, cardio-oncological monitoring is a complex interplay between pretherapeutic risk assessment, identification of impending cardiotoxicity, and post-therapeutic surveillance. For these purposes, the cardio-oncologist can revert to a broad spectrum of nuclear cardiological diagnostic workup. The most promising commonly used nuclear medicine imaging techniques in relation to immunotherapy will be discussed in this review article with a special focus on the continuous development of highly specific molecular markers and steadily improving methods of image generation. The review closes with an outlook on possible new developments of molecular imaging and advanced image evaluation techniques in this exciting and increasingly growing field of immunotherapy-related cardiotoxicity.

Unexpected high level of severe events even in low-risk profile chest pain unit patients.

AIMS: Early heart attack awareness programs are thought to increase efficacy of chest pain units (CPU) by providing live-saving information to the community. We hypothesized that self-referral might be a feasible alternative to activation of emergency medical services (EMS) in selected chest pain patients with a specific low-risk profile. METHODS AND RESULTS: In this observational registry-based study, data from 4743 CPU patients were analyzed for differences between those with or without severe or fatal prehospital or in-unit events (out-of-hospital cardiac arrest and/or in-unit death, resuscitation or ventricular tachycardia). In order to identify a low-risk subset in which early self-referral might be recommended to reduce prehospital critical time intervals, the Global Registry of Acute Coronary Events (GRACE) score for in-hospital mortality and a specific low-risk CPU score developed from the data by multivariate regression analysis were applied and corresponding event rates were calculated. Male gender, cardiac symptoms other than chest pain, first onset of symptoms and a history of myocardial infarction, heart failure or cardioverter defibrillator implantation increased propensity for critical events. Event rates within the low-risk subsets varied from 0.5-2.8%. Those patients with preinfarction angina experienced fewer events. CONCLUSIONS: When educating patients and the general population about angina pectoris symptoms and early admission, activation of EMS remains recommended. Even in patients without any CPU-specific risk factor, self-referral bears the risk of severe or fatal pre- or in-unit events of 0.6%. However, admission should not be delayed, and self-referral might be feasible in patients with previous symptoms of preinfarction angina.

Survey of clinical practice pattern in Germany's certified chest pain units : Adherence to the European Society of Cardiology guidelines on non-ST-segment elevation acute coronary syndrome.

BACKGROUND: We aimed to analyze the 2020 standard of care in certified German chest pain units (CPU) with a special focus on non-ST-segment elevation acute coronary syndrome (NSTE-ACS) through a voluntary survey obtained from all certified units, using a prespecified questionnaire. METHODS: The assessment included the collection of information on diagnostic protocols, risk assessment, management and treatment strategies in suspected NSTE-ACS, the timing of invasive therapy in non-ST-segment elevation myocardial infarction (NSTEMI), and the choice of antiplatelet therapy. RESULTS: The response rate was 75%. Among all CPUs, 77% are currently using the European Society of Cardiology (ESC) 0/3­h high-sensitive troponin protocol, and only 20% use the ESC 0/1­h high-sensitive troponin protocol as a default strategy. Conventional ergometry is still the commonly performed stress test with a utilization rate of 47%. Among NSTEMI patients, coronary angiography is planned within 24 h in 96% of all CPUs, irrespective of the day of the week. Prasugrel is the P2Y12 inhibitor of choice in ST-segment elevation myocardial infarction (STEMI), but despite the impact of the ISAR-REACT 5 trial on selection of antiplatelet therapy, ticagrelor is still favored over prasugrel in NSTE-ACS. If triple therapy is used in NSTE-ACS with atrial fibrillation, it is maintained up to 4 weeks in 51% of these patients. CONCLUSION: This survey provides evidence that Germany's certified CPUs ensure a high level of guideline adherence and quality of care. The survey also identified areas in need of improvement such as the high utilization rate of stress electrocardiogram (ECG).

Superiority of focused ion beam-scanning electron microscope tomography of cardiomyocytes over standard 2D analyses highlighted by unmasking mitochondrial heterogeneity.

BACKGROUND: Cardioprotection by preventing or repairing mitochondrial damage is an unmet therapeutic need. To understand the role of cardiomyocyte mitochondria in physiopathology, the reliable characterization of the mitochondrial morphology and compartment is pivotal. Previous studies mostly relied on two-dimensional (2D) routine transmission electron microscopy (TEM), thereby neglecting the real three-dimensional (3D) mitochondrial organization. This study aimed to determine whether classical 2D TEM analysis of the cardiomyocyte ultrastructure is sufficient to comprehensively describe the mitochondrial compartment and to reflect mitochondrial number, size, dispersion, distribution, and morphology. METHODS: Spatial distribution of the complex mitochondrial network and morphology, number, and size heterogeneity of cardiac mitochondria in isolated adult mouse cardiomyocytes and adult wild-type left ventricular tissues (C57BL/6) were assessed using a comparative 3D imaging system based on focused ion beam-scanning electron microscopy (FIB-SEM) nanotomography. For comparison of 2D vs. 3D data sets, analytical strategies and mathematical comparative approaches were performed. To confirm the value of 3D data for mitochondrial changes, we compared the obtained values for number, coverage area, size heterogeneity, and complexity of wild-type cardiomyocyte mitochondria with data sets from mice lacking the cytosolic and mitochondrial protein BNIP3 (BCL-2/adenovirus E1B 19-kDa interacting protein 3; Bnip3-/- ) using FIB-SEM. Mitochondrial respiration was assessed on isolated mitochondria using the Seahorse XF analyser. A cardiac biopsy was obtained from a male patient (48 years) suffering from myocarditis. RESULTS: The FIB-SEM nanotomographic analysis revealed that no linear relationship exists for mitochondrial number (r = 0.02; P = 0.9511), dispersion (r = -0.03; P = 0.9188), and shape (roundness: r = 0.15, P = 0.6397; elongation: r = -0.09, P = 0.7804) between 3D and 2D results. Cumulative frequency distribution analysis showed a diverse abundance of mitochondria with different sizes in 3D and 2D. Qualitatively, 2D data could not reflect mitochondrial distribution and dynamics existing in 3D tissue. 3D analyses enabled the discovery that BNIP3 deletion resulted in more smaller, less complex cardiomyocyte mitochondria (number: P < 0.01; heterogeneity: C.V. wild-type 89% vs. Bnip3-/- 68%; complexity: P < 0.001) forming large myofibril-distorting clusters, as seen in human myocarditis with disturbed mitochondrial dynamics. Bnip3-/- mice also show a higher respiration rate (P < 0.01). CONCLUSIONS: Here, we demonstrate the need of 3D analyses for the characterization of mitochondrial features in cardiac tissue samples. Hence, we observed that BNIP3 deletion physiologically acts as a molecular brake on mitochondrial number, suggesting a role in mitochondrial fusion/fission processes and thereby regulating the homeostasis of cardiac bioenergetics.

Revealing Subtle Changes in Cardiac Function using Transthoracic Dobutamine Stress Echocardiography in Mice.

Left ventricular (LV) dysfunction paves the final pathway for a multitude of cardiac disorders. With the non-invasive high-frequency transthoracic dobutamine stress echocardiography in humans, a reductionist investigation approach to unmask subtle changes in cardiac function has become possible. Here, we provide a protocol for using this technique in mice to facilitate expanded analysis of LV architecture and function in physiology and pathology enabling the observation of alterations in models of cardiac disease hidden in unstressed hearts. This investigation can be performed in one and the same animal and allows both, basal and pharmacologically stress-induced measurements. We outline detailed criteria for appropriate anesthesia, imaging-based LV analysis, consideration of intra- and interobserver variability, and obtaining positive inotrope response that can be attained in mice after intraperitoneal injection of dobutamine under near physiological conditions. To recapitulate the characteristics of human physiology and disease in small animal models, we highlight critical pitfalls in evaluation, e.g., a pronounced Bowditch effect in mice. To further meet translational objectives, we compare stress-induced effects in humans and mice. When used in translational studies, attention must be paid to physiological differences between mice and human. Experimental rigor dictates that some parameters assessed in patients can only be used with caution due to restrictions in spatial and temporal resolution in mouse models.

Management of Pulmonary Embolism: Results from the German Chest Pain Unit Registry.

INTRODUCTION: Since 2008, specialized chest pain units (CPUs) were implemented across Germany ensuring structured diagnostics in acute chest pain. This study aims to analyze the management of pulmonary embolism (PE) patients in such certified CPUs. METHODS: Data were retrieved from 13,902 patients enrolled in the German CPU registry and analyzed for the diagnosis of PE including patient characteristics, critical time intervals, diagnostic workup, treatment, and prognosis. PE patients were compared to the overall CPU patient cohort. Only patients with a complete 3-month follow-up were included. RESULTS: Overall, 1.1% of all CPU patients were diagnosed with PE. Chest pain and dyspnea were the leading symptoms. Patients with PE were older, presented with higher heart rates, and more frequently exhibited signs of heart failure, despite a normal left ventricular function. PE patients showed significantly longer time delays between symptom onset and the first medical contact, while PE patients with chest pain presented earlier than PE patients with dyspnea only. Whereas more PE patients had to be transferred to the intensive care unit, in-CPU mortality and event rates over 3 months were low. DISCUSSION/CONCLUSION: This study suggests a certain risk for underdiagnosis and consecutive potential undertreatment of PE patients in German Cardiac Society (GCS)-certified CPUs, which is thought to result from an anticipated focus on patients with acute coronary syndrome (ACS). Public awareness for PE beyond chest pain should be improved. Certified CPUs should be urged to implement strategic pathways for a better simultaneous diagnostic workup of differential diagnosis beyond ACS.

Ventricular assist device for a coronavirus disease 2019-affected heart.

Coronavirus disease 2019 (COVID-19) is challenging the care for cardiovascular patients, resulting in serious consequences with increasing mortality in pre-diseased heart failure patients. In the current state of the pandemic, the physiopathology of COVID-19 affecting pre-diseased hearts and the management of terminal heart failure in COVID-19 patients remain unclear. We outline the findings of a young COVID-19 patient suffering from idiopathic cardiomyopathy who was treated for acute multi-organ failure and required cardiac surgery with implantation of a temporary right ventricular and durable left ventricular assist device (LVAD). For deeper translational insights, we used in-depth tissue analysis by electron and light sheet fluorescence microscopy revealing evidence for spatial distribution of severe acute respiratory syndrome coronavirus 2 in the heart. This indicates that in-depth analysis may represent a valuable tool in understanding indistinct clinical cases. We conclude that COVID-19 directly affects pre-diseased hearts, but the consequences can be treated successfully with LVAD implantation.

Gender Differences in Patients Admitted to a Certified German Chest Pain Unit: Results from the German Chest Pain Unit Registry.

INTRODUCTION: Gender-specific atypical clinical presentation in acute coronary syndrome and sex-specific outcomes in cardiovascular disease in women are well known. The aim of this study is to analyze possible differences between men and women presenting to certified German chest pain units (CPUs). METHODS: Data from 13,900 patients derived from the German CPU registry were analyzed for gender differences in patient characteristics, cardiovascular disease manifestation, critical time intervals, treatment and prognosis. RESULTS: A total of 37.8% of patients were female. Typical chest pain occurred more frequently in men, while atypical symptoms occurred more frequently in women. Female gender was associated with longer pre- and in-hospital time delays. Women were more often diagnosed with a nonischemic origin of pain. In a 3-month follow-up, there was no gender-specific difference in combined major adverse coronary and cerebrovascular events. DISCUSSION/CONCLUSION: This study points out gender-specific differences in prehospital time intervals and a significantly higher percentage of atypical symptoms in suspected myocardial ischemia as well as more noncoronary diagnoses in women. Symptom awareness and a broader diagnostic workup in women are essential.

Capacity changes in German certified chest pain units during COVID-19 outbreak response.

BACKGROUND: We sought to determine structure and changes in organisation and bed capacities of certified German chest pain units (CPU) in response to the emergency plan set-up as a response to the SARS-CoV-2 pandemic. METHODS AND RESULTS: The study was conducted in the form of a standardised telephone interview survey in certified German CPUs. Analyses comprised the overall setting of the CPU, bed capacities, possibilities for ventilation, possible changes in organisation and resources, chest pain patient admittance, overall availability of CPUs and bail-out strategies. The response rate was 91%. Nationwide, CPU bed capacities decreased by 3% in the early phase of COVID-19 pandemic response, exhibiting differences within and between the federal states. Pre-pandemic and pandemic bed capacities stayed below 1 CPU bed per 50,000 inhabitants. 97% of CPUs were affected by internal reorganisation pandemic plans at variable extent. While we observed a decrease of CPU beds within an emergency room (ER) set-up and on intermediate care units (ICU), beds in units being separated from ER and ICU were even increased in numbers. CONCLUSIONS: Certified German CPUs are able to maintain adequate coverage for chest pain patients in COVID-19 pandemic despite structural changes. However, at this time, it appears important to add operating procedures during pandemic outbreaks to the certification criteria of forthcoming guidelines either at the individual CPU level or more centrally steered by the German Cardiac Society or the European Society of Cardiology.

Prolyl hydroxylase domain 2 reduction enhances skeletal muscle tissue regeneration after soft tissue trauma in mice.

The transcription factor Hypoxia-inducible factor 1 (HIF-1) plays a pivotal role in tissue regeneration. HIF-1 is negatively controlled by O2-dependent prolyl hydroxylases with a predominant role of prolyl hydroxylase 2 isoform (Phd2). Transgenic mice, hypomorphic for this isoform, accumulate more HIF-1 under normoxic conditions. Using these mice, we investigated the influence of Phd2 and HIF-1 on the regenerative capability of skeletal muscle tissue after myotrauma. Phd2-hypomorphic and wild type mice (on C57Bl/6 background) were grouped with regeneration times from 6 to 168 hours after closed mechanic muscle trauma to the hind limb. Tissue samples were analysed by immuno-staining and real-time PCR. Bone marrow derived macrophages of wild type and Phd2-hypomorphic mice were isolated and analysed via flow cytometry and quantitative real-time PCR. Phd2 reduction led to a higher regenerative capability due to enhanced activation of myogenic factors accompanied by induction of genes responsible for glucose and lactate metabolism in Phd2-hypomorphic mice. Macrophage infiltration into the trauma areas in hypomorphic mice started earlier and was more pronounced compared to wild type mice. Phd2-hypomorphic mice also showed higher numbers of macrophages in areas with sustained trauma 72 hours after myotrauma application. In conclusion, we postulate that the HIF-1 pathway is activated secondary to a Phd2 reduction which may lead to i) higher activation of myogenic factors, ii) increased number of positive stem cell proliferation markers, and iii) accelerated macrophage recruitment to areas of trauma, resulting in faster muscle tissue regeneration after myotrauma. With the current development of prolyl hydroxylase domain inhibitors, our findings point towards a potential clinical benefit after myotrauma.

Troponins and brain natriuretic peptides for the prediction of cardiotoxicity in cancer patients: a meta-analysis.

AIMS: Cardiac biomarkers are a mainstay in diagnosis of cardiovascular disease but their role in cardio-oncology has not yet been systematically evaluated. This meta-analysis aims to determine whether cardiac troponins and (N-terminal pro) brain natriuretic peptide (BNP/NT-proBNP) predict cancer therapy-related left ventricular (LV) dysfunction. METHODS AND RESULTS: Scientific databases were searched for studies that assessed troponins or BNP/NT-proBNP in adult patients undergoing cancer therapy. Data from 61 trials with 5691 patients were included. Cancer therapy was associated with an increase in troponin levels [odds ratio (OR) 14.3, 95% confidence interval (CI) 6.0-34.1; n = 3049]. Patients with elevated troponins receiving chemotherapy or human epidermal growth factor receptor 2 inhibitor therapy were at higher risk for LV dysfunction (OR 11.9, 95% CI 4.4-32.1; n = 2163). Troponin had a negative predictive value of 93%. Mean BNP/NT-proBNP levels were increased in patients post-treatment (standardized mean difference 0.6, 95% CI 0.3-0.9; n = 912), but the available evidence did not consistently indicate prediction of LV dysfunction (OR 1.7, 95% CI 0.7-4.2; n = 197). ß-blocker and angiotensin-converting enzyme inhibitor therapy to mitigate cardiotoxicity during cancer therapy was associated with a decline in serum troponins (OR 4.1, 95% CI 1.7-9.8; n = 466). CONCLUSION: Elevated troponin levels predict LV dysfunction in patients receiving cancer therapy. Assessment of troponin levels may qualify as a screening test to identify patients who require referral to cardio-oncology units and benefit from preventive strategies. Further evidence is required for both biomarkers.