COVID-19: The Heart of the Matter-Pathological Changes and a Proposed Mechanism.

The SARS-CoV-2 virus has resulted in over 88 million cases worldwide of COVID-19 as of January 2021. The heart is one of the most commonly affected organs in COVID-19, but the nature and extent of the cardiac pathology has remained controversial. It has been shown that patients infected with SARS-CoV-2 can sustain type 1 myocardial infarction in the absence of significant atherosclerotic coronary artery disease. However, many patients present with small elevations of troponin enzymes of unclear etiology which correlate with overall COVID-19 disease outcome. Early autopsy reports indicated variable levels of typical lymphocytic myocarditis, while radiology reports have indicated that myocarditis can be a persistent problem after recovery from acute illness, raising concern about participation in college athletics. In this communication, we review the literature to date regarding the gross and microscopic findings of COVID-19 cardiac involvement, present the findings from over 40 cases from our academic medical center, and propose mechanisms by which patients develop small elevations in troponin. .

Therapeutic Implications of COVID-19 for the Interventional Cardiologist.

Although COVID-19 is viewed primarily as a respiratory disease, cardiovascular risk factors and disease are prevalent among infected patients and are associated with worse outcomes. In addition, among multiple extra-pulmonary manifestations, there has been an increasing recognition of specific cardiovascular complications of COVID-19. Despite this, in the initial stages of the pandemic there was evidence of a reduction in patients presenting to acute cardiovascular services. In this masterclass review, with the aid of 2 exemplar cases, we will focus on the important therapeutic implications of COVID-19 for interventional cardiologists. We summarize the existing evidence base regarding the varied cardiovascular presentations seen in COVID-19 positive patients and the prognostic importance and potential mechanisms of acute myocardial injury in this setting. Importantly, through the use of a systematic review of the literature, we focus our discussion on the observed higher rates of coronary thrombus burden in patients with COVID-19 and acute coronary syndromes.

Troponin in critical care patients and outcomes.

Myocardial infarction is common in the critically unwell population with pre-existing cardiovascular disease and is associated with a greater overall mortality. This article explores guidelines for diagnosing myocardial infarction, and research into the use of troponin as both a diagnostic and prognostic tool. Currently, the majority of patients in the intensive care unit with acute myocardial infarction go unrecognised. The underlying cause is predominantly oxygen supply-demand imbalance, therefore identifying those at risk is important as there is the potential to modify elements of their care and reduce their overall mortality.

Lipocalin-2 promotes m1 macrophages polarization in a mouse cardiac ischaemia-reperfusion injury model.

Ischaemia-reperfusion (IR) injury is a major issue in cardiac transplantation. Inflammatory processes play a major role in myocardial IR injury. Lipocalin-2 (Lcn2), which is also known as neutrophil gelatinase-associated lipocalin, has multiple functions that include the regulation of cell death/survival, cell migration/invasion, cell differentiation and iron delivery. In our study, the hearts of C57BL/6 mice were flushed with and stored in cold Bretschneider solution for 8 h and then transplanted into a syngeneic recipient. We found that Lcn2 neutralization decreased the recruitment of neutrophils and macrophages. Troponin T (TnT) production, 24 h after myocardial IR injury, was reduced through anti-Lcn2 antibody administration. The cardiac output at 60 mmHg of afterload pressure was significantly increased in hearts administrated with anti-Lcn2 antibody administration (anti-Lcn-2: 58.9 ± 5.62 ml/min; control: 25.8 ± 4.1 ml/min; P < 0.05). Anti-Lcn2 antibody treatment suppressed M1 marker (IL-12, IL-23 and iNOS) expression but increased M2 marker (IL-10, Arg1 and Mrc1) expression. Furthermore, in our vitro and vivo experiments, we found that anti-Lcn2 antibody treatment failed to induce M1-related gene expression in response to LPS and that Lcn2 neutralization enhanced the expression of M2-related genes following IL-4 treatment. In conclusion, Lcn2 promotes M1 polarization, and Lcn2 neutralization attenuates cardiac IR injury.

Myocardial infarction marker levels are influenced by prothrombin and tumor necrosis factor-α gene polymorphisms in young patients.

Polymorphisms of genes encoding key factors for the control and activation of inflammatory response and coagulation cascade regulation may play a role in genetic susceptibility to acute myocardial infarction (AMI). This study sought to analyze the effect of TNF -308G/A and pro-thrombin (FII) 20210G/A polymorphisms on the laboratory parameters of young patients affected by AMI. Results indicated that TNF -308A positive genotype frequencies were increased in these patients and that a genetically determined higher production of TNF-α is associated in young subjects to a more severe cardiac damage as depicted by higher levels of troponin, Creatine kinase-MB Isoenzyme (mCK-MB) and a significant increased plasma fibrinogen levels. Similar and probably additive effects on might have a genetically determined increased production of pro-thrombin even if no significant differences in genotype frequencies of pro-thrombin (FII) 20210G/A polymorphisms were observed in this study. All together these results, indicating the relationship among genetically determined TNFα and FII production and increased levels of tissue damage markers of AMI, suggest that a complex genetic background, might be involved in susceptibility to AMI in young men influencing the extension and severity of the disease.

Expression and assembly of active human cardiac troponin in Escherichia coli.

Cardiomyopathy-related mutations in human cardiac troponin subunits, including troponin C (hcTnC), troponin I (hcTnI), and troponin T (hcTnT), are well-documented. Recently, it has been recognised that human cardiac troponin (hcTn) is a sophisticated allosteric system. Therefore, the effect of drugs on this protein complex should be studied with assembled hcTn rather than a short fragment of a subunit or the subunit itself. Here, we describe the expression and assembly of active hcTn in Escherichia coli, a novel method that is rapid and simple, and produces large amounts of functional hcTn.

Controllable expansion of primary cardiomyocytes by reversible immortalization.

Cardiac tissue engineering will remain only a prospect unless large numbers of therapeutic cells can be provided, either from small samples of cardiac cells or from stem cell sources. In contrast to most adult cells, cardiomyocytes are terminally differentiated and cannot be expanded in culture. We explored the feasibility of enabling the in vitro expansion of primary neonatal rat cardiomyocytes by lentivector-mediated cell immortalization, and then reverting the phenotype of the expanded cells back to the cardiomyocyte state. Primary rat cardiomyocytes were transduced with simian virus 40 large T antigen (TAg), or with Bmi-1 followed by the human telomerase reverse transcriptase (hTERT) gene; the cells were expanded; and the transduced genes were removed by adenoviral vector expressing Cre recombinase. The TAg gene was more efficient in cell transduction than the Bmi-1/hTERT gene, based on the rate of cell proliferation. Immortalized cells exhibited the morphological features of dedifferentiation (increased vimentin expression, and reduced expression of troponin I and Nkx2.5) along with the continued expression of cardiac markers (alpha-actin, connexin-43, and calcium transients). After the immortalization was reversed, cells returned to their differentiated state. This strategy for controlled expansion of primary cardiomyocytes by gene transfer has potential for providing large amounts of a patient's own cardiomyocytes for cell therapy, and the cardiomyocytes derived by this method could be a useful cellular model by which to study cardiogenesis.

Cardiovascular problems in noncardiac surgery.

PURPOSE OF REVIEW: Perioperative cardiac complications remain a major area of concern as our surgical population increases in volume, age and frequency of comorbidity. A variety of strategies can be used to optimize patients and potentially reduce the incidence of these serious complications. RECENT FINDINGS: Recent literature suggests a trend towards less invasive testing for detection and quantification of coronary artery disease and greater interest in pharmacologic 'cardioprotection' using beta-blockers, statins and other agents targeting heart rate control and other mechanisms (e.g. reducing inflammatory responses). The recent Perioperative Ischemic Evaluation study has substantially altered this approach at least towards widespread application to lower/intermediate risk cohorts. Considerable attention has been focused on ensuring optimal standardized perioperative management of patients with a recent percutaneous coronary intervention, particularly those with an intracoronary stent. Widespread surveillance of postoperative troponin release and increasing recognition of the prognostic potential of elevated preoperative brain natriuretic peptides point towards changing strategies for long-term risk stratification. SUMMARY: The complexity of a particular patient's physiologic responses to a wide variety of surgical procedures, which are undergoing constant technological refinement generally associated with lesser degrees of invasivity and stress make calculation of patients' perioperative risk very challenging. At the present time, adequate information is available for the clinician to screen patients with high-risk preoperative predictors, delay elective surgery for patients with recent intracoronary stents and continue chronic beta-blockade in appropriate patients. New large-scale database and subanalyses of major trials (e.g. Perioperative Ischemic Evaluation and Coronary Artery Revascularization Prophylaxis) should provide additional information to minimize perioperative cardiac risk.

Clinical significance of cardiac damage and changes in function after exercise.

Acute bouts of ultraendurance exercise may result in the appearance of biomarkers of cardiac cell damage and a transient reduction in left ventricular function. The clinical significance of these changes is not fully understood. There seems to be two competing issues to be resolved. First, could prolonged endurance exercise produce a degree of cardiac stress and/or damage that results, during the short or long term, in deleterious consequences for cardiac health. Second, there is a clear need to educate those responsible for the medical care of endurance athletes about the possibility of a transient reduction in cardiac function and the appearance of cTnT/cTnI after an exercise. Minor elevations in cardiac troponins are commonplace after an endurance exercise in elite and recreational athletes and may occur alongside exercise-associated collapse. Misdiagnosis of myocardial injury and subsequent mismanagement can be unnecessarily expensive and psychologically damaging to the athlete. Diagnosis of myocardial injury after prolonged exercise should be made on the basis of all available information and not blood tests alone. The clinical significance of chronic exposure to endurance exercise is unknown. The development of myocardial fibrosis has been suggested as a long-term outcome to chronic exposure to repetitive bouts of endurance exercise and has been linked to an exercise-induced inflammatory process observed in an animal model. This hypothesis is supported by a limited number of studies reporting postmortem studies in athletes and an increased prevalence of complex arrhythmia in veteran athletes. Care is warranted in promoting this hypothesis without further detailed work, given the unequivocal link between exercise and mortality and morbidity. It would seem erroneous, however, to assume that a linear relationship exists between exercise volume and cardiac health.

Co-culture induces alignment in engineered cardiac constructs via MMP-2 expression.

Cardiac tissue engineering has been limited by the inability to recreate native myocardial structural features. We hypothesized that heart cell elongation and alignment in 3D engineered cardiac constructs would be enhanced by using physiologic ratios of cardiomyocytes (CM) and cardiac fibroblasts (CF) via matrix metalloprotease (MMP)-dependent mechanisms. Co-cultured CM and CF constructs were compared to CM-enriched constructs using either basal media or media with a general MMP inhibitor for 8 days. Co-cultured constructs exhibited significantly increased cell alignment (p<0.0002), which was eliminated by MMP inhibition. Co-cultured constructs expressed substantial active MMP-2 protein that was not present in CM-enriched constructs, increased pro-MMP-2 (p<0.001), and reduced pro-MMP-9 (p<0.001) expression. Apoptosis was decreased by co-culture (p<0.05), independent of MMP inhibition. These results demonstrated that co-culture of CF in physiologic ratios within engineered cardiac constructs improved cell elongation and alignment via increased MMP-2 expression and activation, and also improved viability independent of MMP activity.

Plant troponoids: chemistry, biological activity, and biosynthesis.

Tropone or tropolone and its derivatives (here together called troponoids) belong to a family of natural products with a seven-membered aromatic ring and various side groups. They are mainly synthesized by plants and fungi, and most troponoids play roles of antibacterial defenses in these organisms. With an increasingly severe situation of antibiotic resistant bacteria, as well as a requirement for antifungal medicines, troponoids have attracted extensive studies since they have powerful antibacterial and antifungal activity, particularly against antibiotic-resistant bacteria. In addition, many other biological activities such as antiviral, antitumor, antioxidant, anti-inflammatory, insecticidal, or enzyme inhibitor activities are associated with troponoids. After extensive studies in the 1960s-70s, interests in natural troponoids dedclined. However, chemical and biomedical studies on troponoids bloom again from the 1990s. To date great progress has been made with troponoid study in terms of identification of new natural troponoids, chemical synthesis and properties, biological activity, biosynthesis and metabolism. Particularly, bioassay-guided screening strategy and structure-activity relation-directed structure modification and drug design has resulted in the synthesis and discovery of many new derivatives. Many of them have great promise to be developed into new medicines for their potent and specific activities. This review presents the recent advances in troponoid studies and highlights multiple faceted biological activities of troponoids, as well as their relationships with chemical structures. Chemistry, biosynthesis, and production via biotechnology of troponoids are also briefly reviewed. Applications of troponoids in daily life, agriculture, medicine, and industry, and the related patents have been considered to further extend our understanding of the increasing impact of troponoids on humans.

Current understanding of biochemical markers in heart failure.

Chronic heart failure (CHF) is a major cause of morbidity and mortality in industrialized countries. As societies are aging, efforts are directed toward early interventions to preserve quality of life as well as lower mortality. However, because of the paucity of specific symptoms, an early diagnosis and management of CHF might be challenging. In contrast, biochemical markers, which can be measured easily and without inter-observer variability, are now being carefully examined. Since CHF is a complex syndrome, a single biochemical marker cannot reflect its multiple manifestations. An ideal biochemical marker should 1) be a prognostic indicator, 2) reflect the therapeutic response, 3) be heart specific 4) be independent from other markers 5) reflect the pathophysiology of CHF, 6) assist in the early diagnosis of CHF, and 7) be reliable throughout the various phases of the syndrome, from before the onset of its clinical manifestations through its end-stage. This review summarizes our current understanding of biochemical markers of CHF based on its pathophysiology.

Avaliação das alterações morfológicas cardíacas secundárias ao enfisema pulmonar: estudo experimental em ratos / Evaluation of the cardiac morphological alterations secondary to the pulmonary emphysema: experimental study in rats

OBJETIVO: Este trabalho tem como objetivo avaliar a ocorrência e as repercussões de enfisema pulmonar quimicamente induzido e as alterações morfológicas presentes em corações de ratos após sua indução, acompanhando sua progressão ao longo do tempo. MÉTODO: Foram avaliados 75 ratos divididos em dois grupos, papaína (N=50) e controle (N=25), submetidos à instilação intratraqueal de papaína e solução fisiológica, respectivamente. Os animais foram sacrificados 30, 60, 90, 120 ou 180 dias após a instilação. Foi realizada gasometria do sangue arterial, análise morfométrica dos pulmões e coração. RESULTADOS: A instilação de papaína produziu destruição do tecido alveolar, mimetizando alterações morfológicas encontradas no enfisema pulmonar, com diâmetro alveolar médio maior no grupo papaína em relação ao controle em todos os momentos avaliados (p<0,05). A espessura da parede do ventrículo direito e do septo interventricular não apresentou alterações macroscópicas significativas no período de até seis meses após a indução do enfisema. A cavidade do ventrículo direito apresentou dilatação, a partir de 120 dias após indução do enfisema, com área média superior aos respectivos controles aos 120 e 180 dias (p=0,001). O ventrículo esquerdo apresentou significativa redução da área de sua cavidade, 90 dias após a indução do enfisema pulmonar, acompanhada de discreto espessamento de sua parede. CONCLUSÕES: O modelo experimental empregado foi eficiente para induzir morfologicamente o enfisema pulmonar. A presença de enfisema pulmonar não provocou alterações morfológicas na parede do ventrículo direito e septo interventricular. A destruição alveolar induziu hipertrofia do ventrículo esquerdo e dilatação do ventrículo direito.

Importância da troponina-I cardíaca nos portadores de obstrução no tronco da artéria coronária esquerda sem evento cardíaco prévio / Importance of cardiac troponin-I in the preoperative period of patients without prior cardiac events but suffering from left coronary branch obstruction

OBJETIVO: Avaliar a importância dos níveis séricos de troponina I-cardíaca no pré-operatório de pacientes portadores de obstrução no tronco da artéria coronária esquerda (OTCE) sem evento cardíaco prévio. MÉTODO: Foram analisados os níveis séricos da troponina I-cardíaca de 115 pacientes com doença coronariana obstrutiva, com idade variando entre 32 e 81 anos (média e desvio-padrão de 59,7±10,5 anos). Os pacientes foram divididos em dois grupos: Grupo A - 41 pacientes portadores de OTCE, variando o grau de obstrução entre 20 por cento de perda do diâmetro e subtotal (moda de 60 por cento); Grupo B - 74 pacientes sem OTCE. Todos os pacientes foram submetidos a cineangiocoronariografia de forma eletiva e não apresentavam infarto agudo do miocárdio prévio. O método empregado na dosagem da troponina-I cardíaca foi o da Quimioluminiscência, admitindo-se como valor normal abaixo de 0,1 nanogramas por mililitro (ng/ml). RESULTADOS: Não houve correlação entre o grau de OTCE e os níveis séricos de troponina-Ic (P= 0,4617), porém a média dos níveis séricos da troponina-I nos grupos A e B foi, respectivamente, 0,3841 ng/ml e 0,1711 ng/ml (P=0,0324); teste de Mann-Whithey; OR= 4,44 (IC95 por cento 1,60 _ 12,31). CONCLUSÕES: Os pacientes do grupo A têm 3,44 vezes mais chance de apresentar lesão miocárdica representada por elevação de troponina I-cardíaca que o grupo B, independente do grau da OTCE. A sensibilidade para suspeita clínica de mionecrose foi relativamente baixa (31,7 por cento), porém a especificidade foi elevada (90,5 por cento). Destaca-se, entretanto, a importância clínica da documentação de mionecrose em uma determinada porcentagem de pacientes com lesão de tronco, sem constatação eletrocardiográfica. Assim, os pacientes com OTCE devem ser submetidos com rapidez a procedimento operatório, a fim de evitar extensão da mionecrose.

Titin isoform changes in rat myocardium during development.

Developmental changes in the alternative splicing patterns of titin were observed in rat cardiac muscle. Titin from 16-day fetal hearts consisted of a single 3710 kDa band on SDS agarose gels, and it disappeared by 10 days after birth. The major adult N2B isoform (2990 kDa) first appeared in 18-day fetal hearts and its proportion in the ventricle increased to approximately 85% from 20 days of age and older. Changes in three other intermediate-sized N2BA isoform bands also occurred during this same time period. The cDNA sequences of fetal cardiac, adult ventricle, and adult soleus were different in the PEVK and alternatively spliced middle Ig domain. Extensive heterogeneity in splice patterns was found in the N2BA PEVK region. The extra length of the fetal titin isoforms appeared to be due to both a greater number of middle Ig domains expressed plus the inclusion of more PEVK exons. Passive tension measurements on myocyte-sized fragments indicated a significantly lower tension in neonate versus adult ventricles at sarcomere lengths greater than 2.1 microm, consistent with the protein and cDNA sequence results. The time course of the titin isoform switching was similar to that occurring with myosin and troponin I during development.

Force-calcium relationship depends on myosin heavy chain and troponin isoforms in rat diaphragm muscle fibers.

The present study examined Ca(2+) sensitivity of diaphragm muscle (Dia(m)) fibers expressing different myosin heavy chain (MHC) isoforms. We hypothesized that Dia(m) fibers expressing the MHC(slow) isoform have greater Ca(2+) sensitivity than fibers expressing fast MHC isoforms and that this fiber-type difference in Ca(2+) sensitivity reflects the isoform composition of the troponin (Tn) complex (TnC, TnT, and TnI). Studies were performed in single Triton-X-permeabilized Dia(m) fibers. The Ca(2+) concentration at which 50% maximal force was generated (pCa(50)) was determined for each fiber. SDS-PAGE and Western analyses were used to determine the MHC and Tn isoform composition of single fibers. The pCa(50) for Dia(m) fibers expressing MHC(slow) was significantly greater than that of fibers expressing fast MHC isoforms, and this greater Ca(2+) sensitivity was associated with expression of slow isoforms of the Tn complex. However, some Dia(m) fibers expressing MHC(slow) contained the fast TnC isoform. These results suggest that the combination of TnT, TnI, and TnC isoforms may determine Ca(2+) sensitivity in Dia(m) fibers.