How we approach the perioperative management of patients with chronic lymphocytic leukaemia receiving continuous cancer-directed therapies.

Historically, invasive procedures and surgeries were deferred in patients with haematological malignancies including advanced stage chronic lymphocytic leukaemia (CLL) because of limited life expectancy. However, novel, and often continuous, treatments have markedly improved outcomes in CLL. Some patients may expect years of treatment response and disease control, overcoming the short life expectancy that deters interventionalists. Such patients now often undergo various invasive procedures including major surgery. To inform peri-operative management, we summarize the relevant side effects and drug interactions of continuous CLL therapies, highlight potential surgical risks, and provide recommendations on withholding specific CLL drugs around invasive procedures.

Preferences and Attitudes of Cardiologists in Management of Patients with Cancer.

Background: With recent improvements in survival of cancer patients and common use of high-value care at end of life, the management of cardiovascular disease (CVD) in patients with cancer is increasingly important. To our knowledge, there are no current U.S. data examining how the presence and extent of cancer influence cardiologists' decision making for common cardiovascular conditions. Methods: An anonymous online vignette-based survey of cardiologists was conducted at five U.S. institutions investigating how the extent of gastrointestinal and thoracic malignancies (prior/localized, metastatic) would influence treatment recommendations for atrial fibrillation (AF), aortic stenosis, unstable angina (UA), and obstructive coronary artery disease (CAD). Results: Thirty-three percent (86/259) of cardiologists completed the survey between September and November 2019. Participants were 67% male, 51% below age 40, and 58% had five or more years of clinical experience. Majority of cardiologists practiced at teaching hospitals (72%) and were noninterventional (63%). Cardiologists were more likely to recommend procedural interventions for patients with localized cancer than for those with metastatic disease: AF (left atrial appendage occlusion: 20% vs. 8%), atrial stenosis (aortic valve repair: 83% vs. 11%), UA (left heart catheter: 70% vs. 27%), and obstructive CAD (percutaneous coronary intervention: 81% vs. 38%). In patients with metastatic cancer, most cardiologists sought an oncology (82%) or a palliative care (69%) consultation. However, a persistent trend of undertreatment in patients with localized cancers and overtreatment in patients with end-of-life disease was apparent. Conclusions: Cardiologists were less likely to recommend invasive cardiovascular therapies to patients with metastatic cancer. This preference pattern likely reflects the influence of comorbidities and quality of life expectation on cardiologists' treatment recommendations but may also be related to the stigma of advanced cancer. Better communication between cardiologists and oncologists is necessary to provide a personalized care of patients with cancer and CVD that would maximize treatment benefit with least morbidity.

Potential of Endogenous Oxytocin in Endocrine Treatment and Prevention of COVID-19.

Coronavirus disease 2019 or COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a significant threat to the health of human beings. While wearing mask, maintaining social distance and performing self-quarantine can reduce virus spreading passively, vaccination actively enhances immune defense against COVID-19. However, mutations of SARS-CoV-2 and presence of asymptomatic carriers frustrate the effort of completely conquering COVID-19. A strategy that can reduce the susceptibility and thus prevent COVID-19 while blocking viral invasion and pathogenesis independent of viral antigen stability is highly desirable. In the pathogenesis of COVID-19, endocrine disorders have been implicated. Correspondingly, many hormones have been identified to possess therapeutic potential of treating COVID-19, such as estrogen, melatonin, corticosteroids, thyroid hormone and oxytocin. Among them, oxytocin has the potential of both treatment and prevention of COVID-19. This is based on oxytocin promotion of immune-metabolic homeostasis, suppression of inflammation and pre-existing comorbidities, acceleration of damage repair, and reduction of individuals' susceptibility to pathogen infection. Oxytocin may specifically inactivate SARS-COV-2 spike protein and block viral entry into cells via angiotensin-converting enzyme 2 by suppressing serine protease and increasing interferon levels and number of T-lymphocytes. In addition, oxytocin can promote parasympathetic outflow and the secretion of body fluids that could dilute and even inactivate SARS-CoV-2 on the surface of cornea, oral cavity and gastrointestinal tract. What we need to do now is clinical trials. Such trials should fully balance the advantages and disadvantages of oxytocin application, consider the time- and dose-dependency of oxytocin effects, optimize the dosage form and administration approach, combine oxytocin with inhibitors of SARS-CoV-2 replication, apply specific passive immunization, and timely utilize efficient vaccines. Meanwhile, blocking COVID-19 transmission chain and developing other efficient anti-SARS-CoV-2 drugs are also important. In addition, relative to the complex issues with drug applications over a long term, oxytocin can be mobilized through many physiological stimuli, and thus used as a general prevention measure. In this review, we explore the potential of oxytocin for treatment and prevention of COVID-19 and perhaps other similar pathogens.

Neural Functions of Hypothalamic Oxytocin and its Regulation.

Oxytocin (OT), a nonapeptide, has a variety of functions. Despite extensive studies on OT over past decades, our understanding of its neural functions and their regulation remains incomplete. OT is mainly produced in OT neurons in the supraoptic nucleus (SON), paraventricular nucleus (PVN) and accessory nuclei between the SON and PVN. OT exerts neuromodulatory effects in the brain and spinal cord. While magnocellular OT neurons in the SON and PVN mainly innervate the pituitary and forebrain regions, and parvocellular OT neurons in the PVN innervate brainstem and spinal cord, the two sets of OT neurons have close interactions histologically and functionally. OT expression occurs at early life to promote mental and physical development, while its subsequent decrease in expression in later life stage accompanies aging and diseases. Adaptive changes in this OT system, however, take place under different conditions and upon the maturation of OT release machinery. OT can modulate social recognition and behaviors, learning and memory, emotion, reward, and other higher brain functions. OT also regulates eating and drinking, sleep and wakefulness, nociception and analgesia, sexual behavior, parturition, lactation and other instinctive behaviors. OT regulates the autonomic nervous system, and somatic and specialized senses. Notably, OT can have different modulatory effects on the same function under different conditions. Such divergence may derive from different neural connections, OT receptor gene dimorphism and methylation, and complex interactions with other hormones. In this review, brain functions of OT and their underlying neural mechanisms as well as the perspectives of their clinical usage are presented.

Severe cardiomyopathy associated with the VCP p.R155C and c.177_187del MYBPC3 gene variants.

Inclusion Body Myopathy, Paget's Disease of Bone, with Frontotemporal Dementia is a progressive autosomal dominant disease that affects the ubiquitin-proteasome complex, that is caused by variants in the Valosin Containing Protein (VCP) gene. We report the first case of concurrent pathogenic variants in both MYBPC3 and VCP that led to earlier onset of congestive heart failure with features of dilated cardiomyopathy. Cardiomyopathy has previously been associated with VCP inclusion body myopathy mostly at an advanced stage of the disease. Due to acute onset of cardiomyopathy in a previous asymptomatic individual, a cardiomyopathy gene panel was obtained which revealed an additional c.177_187del variant of the MYBPC3 gene. We report a first case of concurrent pathogenic variants in both c.177_187del gene of MYBPC3 and p.R155C VCP that led to earlier onset and a more severe form of the cardiomyopathy.

Shone's complex and aortic dissection: case report and review of a rare, underdiagnosed congenital heart disease.

BACKGROUND: Shone's complex is a rare congenital heart disease consisting of a variety of left ventricular inflow and outflow tract lesions. Patients typically present in childhood requiring early surgical intervention; however, with improved surgical techniques, these patients are surviving later into adulthood. This increased survival comes with a new set of medical complications that providers need to be aware of. CASE PRESENTATION: A 27 year old man with a complex cardiac history including an incomplete Shone's complex and persistent symptomatic atrial flutter presented with sharp chest pain radiating to his back. He was found to have type A aortic dissection on imaging in the setting of severe patient-prosthesis mismatch. He had multiple valvular surgeries in childhood. The patient was being followed-up as an outpatient for an enlarging chronic aortic aneurysm and was non-compliant with his medications. He was taken emergently to the operating room for a skirted Bentall procedure, aortic valve replacement, and right sided MAZE. CONCLUSIONS: Shone's complex is a rare congenital heart disease associated with significant morbidities including atrial flutter, patient-prosthesis mismatch, and aortic dissection. As patients continue to live longer into adulthood with this disease, it is important to raise awareness of this rare syndrome for providers and highlight its potential complications. Further research is needed to determine appropriate guidelines for when to intervene on aortopathy-associated CHD.

Implementation of Cholesterol-Lowering Therapy to Reduce Cardiovascular Risk in Persons Living with HIV.

The widespread availability of highly effective antiretroviral therapies has reduced mortality from opportunistic infections in persons living with HIV (PLHIV), resulting in an increase in atherosclerotic cardiovascular disease (ASCVD) and other chronic illnesses (Samji et al. 2013). Although there has been a decline in morbidity and mortality from ASCVD in the past several decades, contemporary studies continue to report higher rates of cardiovascular events (Rosenson et al. 2020). HIV has been identified as a risk enhancer for ASCVD by multiple professional guideline writing committees (Grundy Scott et al. 2019, Mach et al. 2020); however, the utilization of cholesterol-lowering therapies in PLHIV remains low (Rosenson et al. 2018). Moreover, the use of statin therapy in PLHIV is complicated by drug-drug interactions that may either elevate or lower the blood statin concentrations resulting in increased toxicity or reduced efficacy respectively. Other comorbidities commonly associated with HIV present other challenges for the use of cholesterol-lowering therapies. This review will summarize the data on lipoprotein-associated ASCVD risk in PLHIV and discuss the challenges with effective treatment. Finally, we present a clinical algorithm to optimize cardiovascular risk reduction in this high-risk population.

Regional Strain Pattern and Correlation with Cardiac Magnetic Resonance Imaging in Fabry Disease.

BACKGROUND: Cardiovascular disease is the most common cause of death among Fabry disease patients, who carry significantly increased risk for heart failure and sudden cardiac death. Echocardiographic strain imaging and cardiac MRI are important clinical tools for early detection of cardiomyopathy before onset of systolic or diastolic dysfunction. However, studies on these imaging modalities are limited among Fabry patients. AIM AND OBJECTIVE: To evaluate echocardiographic strain pattern and correlation with cardiac MRI in Fabry disease. MATERIALS AND METHODS: We performed a detailed analysis of global longitudinal strain and correlation with cardiac MRI finding in 9 patients diagnosed with Fabry disease. RESULTS: Despite normal left ventricular ejection fraction, basal and mid inferior segments are more likely to demonstrate strain abnormalities compared to other regions. Additionally, increased interventricular septal and left ventricular posterior wall thickness are correlated with greater strain abnormalities. Finally, MRI evidence of fibrosis and infiltration are detected among most patients with strain abnormalities, but in some cases, strain imaging were able to detect early evidence of cardiomyopathy even before MRI was fully able to detect the change. Basal and mid inferoseptal segment strain abnormalities are early signs of developing cardiomyopathy among patients with Fabry disease. CONCLUSION: Though cardiac MRIs are critical tools for detection of myocardial infiltration and scarring, these findings may not always be detectable in early phases of the disease. Multiple imaging modalities maybe considered in monitoring and evaluation of cardiomyopathy in Fabry disease.

Prevalence of cerebral small vessel disease in a Fabry disease cohort.

OBJECTIVE: To characterize the prevalence of brain ischemia and cerebral small vessel disease in a cohort of patients with Fabry disease (FD) seen at an academic medical center. BACKGROUND: FD is an inherited X-linked lysosomal storage disorder with central nervous system involvement. Limited data are available in the literature on the cerebrovascular neuroimaging findings in FD, and the reported prevalence of stroke symptoms and cerebral small vessel disease has varied widely. DESIGN/METHODS: Brain MRI was performed in 21 patients with FD followed at University of California Irvine Medical Center. Stroke symptoms were assessed and quantification of cerebral microvascular disease was performed using small vessel disease (SVD) score. Lacunes and deep white matter hyperintensities were scored on a four-point scale of 0 (absent) and 1-3 to account for increasing severity; microbleeds were scored 0 (absent) or 1 (present). The total SVD score is the sum of the three components and ranges from 0 to 7. RESULTS: Nearly 43% (9/21) of our FD cohort (aged 32-81 years, mean = 50) had a SVD score of one or higher, all of whom were aged 50 or more years. The most common MRI-defined SVD was white matter hyperintensities (9/9, 100%), followed by microbleeds (6/9, 66%), and lacunes (3/9, 33%). The three patients with previous strokes had some of the highest SVD scores reported in the cohort (scores 3-5). CONCLUSIONS: In this cohort, the prevalence of SVD (43%) was three times higher than prevalence of stroke symptoms. SVD score was highest in the those who had experienced a stroke. These findings emphasize the importance of routine MRI screening of patients with FD in order to identify and treat high risk patients.

Characteristics of VCP mutation-associated cardiomyopathy.

VCP associated inclusion body myopathy, Paget's disease of bone, and Frontotemporal Dementia (IBMPFD, VCP disease, or multisystem proteinopathy type 1 (MSP1)) is an autosomal dominant disease caused by missense mutations in the VCP gene, which plays a crucial role in ubiquitin-proteasome dependent degradation of cytosolic proteins. Those diagnosed with the disorder often suffer from cardiovascular complications in the advanced stages. We conducted an observational cross-section study to investigate echocardiographic features of asymptomatic carriers and those affected by the disease to determine the differences and potential early features of the VCP-associated cardiomyopathy. The study cohort constituted of 32 patients with VCP mutations including 23 affected individuals diagnosed with myopathy +/- Paget disease of bone, and 9 asymptomatic carriers. Among the affected individuals, 95.7% had myopathy, 43.5% had Paget's disease of bone, and none had frontotemporal dementia, and the carriers were asymptomatic. Not surprisingly the carriers were younger (mean age 38.4 ±â€¯3.8 years), than the affected cohort (mean age 50.6 ±â€¯9.1 years; p < 0.001). There was a 43.5% prevalence of diastolic dysfunction on echocardiogram among patients who were symptomatic from VCP disease, whereas none of the two asymptomatic carriers manifested diastolic dysfunction (p = 0.017). Among the 5 affected individuals who had consequential echocardiograms 2-3 years apart, three affected individuals developed diastolic dysfunction, and two already had diastolic dysfunction on the initial study. The two carriers did not develop diastolic function changes. This present study represents the largest series of echocardiograms performed in patients and asymptomatic carriers with VCP myopathy, and will pave the way for future, large-scale studies that may include other imaging modalities such as cardiac MRI and strain evaluation in patients at all stages of the disease.

Pericardial Effusion After Renal Transplantation: Timing and Clinical Characteristics.

BACKGROUND: Pericardial effusion and tamponade have been recognized as potentially serious complications in patients who have undergone renal transplantation. Our study aims to analyze the association between sirolimus and the development of pericardial effusion in renal transplant recipients. METHODS: This is a single-center retrospective study of 585 consecutive patients who underwent renal transplantation between 2005 and 2016. The study included 82 patients (14%) who developed new pericardial effusion after transplantation. Baseline demographics, medical comorbidities, medication use, echocardiographic parameters, and time to occurrence of effusion were assessed. Patients were divided into 2 groups based on timing of effusion development: early onset, ≤4 years after transplantation (51%); and late onset, >4 years after transplantation (49%). We examined the likelihood of immunosuppressant use and timing of effusion development using univariate and multivariate logistic regression analysis. RESULTS: The mean age of the cohort was 55.1 ± 11.5 years, 58.5% were men, 81.7% were white, and mean time from transplantation to the development of effusion was 4 ± 3.1 years. There were no significant differences between the early and late effusion groups in the demographic characteristics and medical comorbidities. However, sirolimus therapy was more common in the late effusion group. Furthermore, after adjusting for comorbidities, sirolimus use was associated with greater risk for developing late-onset effusion, adjusted odds ratio of 3.58 (95% confidence interval 1.25-10.20, P = .017). CONCLUSION: Pericardial effusion is prevalent in renal transplant recipients. In our cohort, treatment with sirolimus was associated with late-onset pericardial effusion. Awareness of pericardial disease in this population is important, and further studies are needed to identify predisposing factors.

Sex Differences Remain Under-Reported in Cardiovascular Publications.

Background: For the past two decades, there has been increased interest from medical journals and calls to action from various organizations such as the National Institutes of Health to study sex differences in cardiovascular (CV) disease. It is unknown whether this emphasis has translated to a growth in publications addressing sex differences in CV disease. Materials and Methods: We performed a bibliometric analysis of all CV publications from 2006 to 2015. The National Library of Medicine's PubMed database was searched for articles containing the phrases "cardiac," "cardiovascular" or "cardiology," in the first author affiliation field. This was followed by a subsequent search for publications containing any of the following phrases in the title and/or abstract: "woman," "women," "female," "females," "gender," or "sex." The presence of such terms defined the publication as sex-specific. Trends over time were analyzed for specified subgroups, including publication category and funding source. Results: A total of 189,543 CV publications were identified, out of which there were 24,615 (12.99%) sex-specific publications. For the 10-year period, there were no significant changes in the relative proportion of sex-specific publications. When specific publication categories were analyzed, there were significant proportional increase of sex-specific publications in general articles category, but not for reviews, clinical trials, meta-analysis, or letters. Conclusion: Despite calls for greater attention, only a small fraction of publications for the past decade have reported on sex differences. There was no significant proportional growth of sex-specific publications for a recent 10-year period, except for the general research articles.

Cardiovascular protective properties of oxytocin against COVID-19.

SARS-CoV-2 infection or COVID-19 has become a worldwide pandemic; however, effective treatment for COVID-19 remains to be established. Along with acute respiratory distress syndrome (ARDS), new and old cardiovascular injuries are important causes of significant morbidity and mortality in COVID-19. Exploring new approaches managing cardiovascular complications is essential in controlling the disease progression and preventing long-term complications. Oxytocin (OXT), an immune-regulating neuropeptide, has recently emerged as a strong candidate for treatment and prevention of COVID-19 pandemic. OXT carries special functions in immunologic defense, homeostasis and surveillance. It suppresses neutrophil infiltration and inflammatory cytokine release, activates T-lymphocytes, and antagonizes negative effects of angiotensin II and other key pathological events of COVID-19. Additionally, OXT can promote γ-interferon expression to inhibit cathepsin L and increases superoxide dismutase expression to reduce heparin and heparan sulphate fragmentation. Through these mechanisms, OXT can block viral invasion, suppress cytokine storm, reverse lymphocytopenia, and prevent progression to ARDS and multiple organ failures. Importantly, besides prevention of metabolic disorders associated with atherosclerosis and diabetes mellitus, OXT can protect the heart and vasculature through suppressing hypertension and brain-heart syndrome, and promoting regeneration of injured cardiomyocytes. Unlike other therapeutic agents, exogenous OXT can be used safely without the side-effects seen in remdesivir and corticosteroid. Importantly, OXT can be mobilized endogenously to prevent pathogenesis of COVID-19. This article summarizes our current understandings of cardiovascular pathogenesis caused by COVID-19, explores the protective potentials of OXT against COVID-19-associated cardiovascular diseases, and discusses challenges in applying OXT in treatment and prevention of COVID-19. CHEMICAL COMPOUNDS: Angiotensin-converting enzyme 2 (ACE2); atrial natriuretic peptide (ANP); cathepsin L; heparan sulphate proteoglycans (HSPGs); interferon; interleukin; oxytocin; superoxide dismutase; transmembrane serine protease isoform 2 (TMPRSS2).

Astroglial Regulation of Magnocellular Neuroendocrine Cell Activities in the Supraoptic Nucleus.

Studies on the interactions between astrocytes and neurons in the hypothalamo-neurohypophysial system have significantly facilitated our understanding of the regulation of neural activities. This has been exemplified in the interactions between astrocytes and magnocellular neuroendocrine cells (MNCs) in the supraoptic nucleus (SON), specifically during osmotic stimulation and lactation. In response to changes in neurochemical environment in the SON, astrocytic morphology and functions change significantly, which further modulates MNC activity and the secretion of vasopressin and oxytocin. In osmotic regulation, short-term dehydration or water overload causes transient retraction or expansion of astrocytic processes, which increases or decreases the activity of SON neurons, respectively. Prolonged osmotic stimulation causes adaptive change in astrocytic plasticity in the SON, which allows osmosensory neurons to reserve osmosensitivity at new levels. During lactation, changes in neurochemical environment cause retraction of astrocytic processes around oxytocin neurons, which increases MNC's ability to secrete oxytocin. During suckling by a baby/pup, astrocytic processes in the mother/dams exhibit alternative retraction and expansion around oxytocin neurons, which mirrors intermittently synchronized activation of oxytocin neurons and the post-excitation inhibition, respectively. The morphological and functional plasticities of astrocytes depend on a series of cellular events involving glial fibrillary acidic protein, aquaporin 4, volume regulated anion channels, transporters and other astrocytic functional molecules. This review further explores mechanisms underlying astroglial regulation of the neuroendocrine neuronal activities in acute processes based on the knowledge from studies on the SON.

Therapeutic Potential of Oxytocin in Atherosclerotic Cardiovascular Disease: Mechanisms and Signaling Pathways.

Coronary artery disease (CAD) is a major cardiovascular disease responsible for high morbidity and mortality worldwide. The major pathophysiological basis of CAD is atherosclerosis in association with varieties of immunometabolic disorders that can suppress oxytocin (OT) receptor (OTR) signaling in the cardiovascular system (CVS). By contrast, OT not only maintains cardiovascular integrity but also has the potential to suppress and even reverse atherosclerotic alterations and CAD. These protective effects of OT are associated with its protection of the heart and blood vessels from immunometabolic injuries and the resultant inflammation and apoptosis through both peripheral and central approaches. As a result, OT can decelerate the progression of atherosclerosis and facilitate the recovery of CVS from these injuries. At the cellular level, the protective effect of OT on CVS involves a broad array of OTR signaling events. These signals mainly belong to the reperfusion injury salvage kinase pathway that is composed of phosphatidylinositol 3-kinase-Akt-endothelial nitric oxide synthase cascades and extracellular signal-regulated protein kinase 1/2. Additionally, AMP-activated protein kinase, Ca2+/calmodulin-dependent protein kinase signaling and many others are also implicated in OTR signaling in the CVS protection. These signaling events interact coordinately at many levels to suppress the production of inflammatory cytokines and the activation of apoptotic pathways. A particular target of these signaling events is endoplasmic reticulum (ER) stress and mitochondrial oxidative stress that interact through mitochondria-associated ER membrane. In contrast to these protective effects and machineries, rare but serious cardiovascular disturbances were also reported in labor induction and animal studies including hypotension, reflexive tachycardia, coronary spasm or thrombosis and allergy. Here, we review our current understanding of the protective effect of OT against varieties of atherosclerotic etiologies as well as the approaches and underlying mechanisms of these effects. Moreover, potential cardiovascular disturbances following OT application are also discussed to avoid unwanted effects in clinical trials of OT usages.

Pericardial Effusion Associated With Sirolimus Use After Renal Transplantation: A Single-Center Case Series.

Pericardial effusion and cardiac tamponade following renal transplantation have been recognized as a potentially serious complications associated with the use of sirolimus for immunosuppression. Our study aims to analyze the development of sirolimus-associated pericardial effusion. Patients who underwent renal transplantation at our institution between 2001 and 2014 were reviewed and the correlation between sirolimus exposure and pericardial effusion was determined. Nineteen out of 792 patients who received a renal transplant over this 14-year period (incidence 2.4%) developed symptomatic pericardial effusion (determined by the need for pericardiocentesis or a pericardial window). All patients had a pre-transplantation cardiac workup, including echocardiogram, which did not reveal the presence of pericardial effusion. Our cohort of patients is mostly male (57.9%) and Caucasian (73.7%), which is consistent with the makeup of transplant recipients at our center. The mean age was 52.42 years at the time of transplantation. The development of symptomatic pericardial effusions occurred at a mean of 5.06 (.5-9.8) years after renal transplant while on sirolimus therapy. Sirolimus levels at diagnosis were 5.19-7.47 ng/mL. No significant pericardial effusion (resulting in tamponade physiology) recurred after therapeutic intervention, including cessation of sirolimus with or without pericardial drainage. This study is the largest single-center report of the possible association between pericardial effusion in renal transplant recipients who received sirolimus. Due to the widespread use of sirolimus in organ transplantation, clinicians must remain vigilant for this potential cardiac complication.