Vascular Inflammation, Cancer, and Cardiovascular Diseases.

PURPOSE OF REVIEW: Cancer and cardiovascular disease are among the leading causes of morbidity and mortality in the USA. Cancer and cardiovascular disease have inflammatory underpinnings that have been associated with both the development and progression of these disease states. RECENT FINDINGS: Inflammatory signaling has been found to be a critical event in both cardiovascular disease and cancer formation and progression. Further, many chemotherapeutic agents potentiate inflammation exacerbating existing cardiovascular disease or leading to its presence. The exact mechanisms of these interactions remain poorly understood. The proinflammatory milieu observed in both cancer and cardiovascular disease likely plays an important role in the development and potentiation of both conditions. Further evaluation of this relationship will be critical in the development of new diagnostic and therapeutic modalities.

Comparative Safety and Effectiveness of Loading Doses of P2Y12 Inhibitors in Patients Undergoing Elective PCI: a Network Meta-analysis.

PURPOSE: Effective platelet inhibition prior to elective percutaneous coronary intervention (PCI) reduces the risk of ischemic complications. Newer P2Y12 inhibitors are preferred agents over clopidogrel for patients presenting with the acute coronary syndrome. However, the comparative efficacy and safety of them over clopidogrel in elective PCI is unclear. We performed a network meta-analysis to compare the safety and efficacy of loading strategies of P2Y12 inhibitors in patients undergoing elective PCI. METHODS: We conducted a systematic review of randomized controlled trials (RCT) up to June 2021 to compare the safety and effectiveness of different loading strategies of P2Y12 inhibitors before elective PCI. The endpoints of interest were overall mortality, rates of myocardial infarction (MI), stroke, revascularization, and major bleeding. Random effects model using the frequentist approach was used to perform a network meta-analysis using R software. RESULTS: Five trials with a total of 5194 patients were included in our analysis. For ischemic outcomes, including MI, stroke, and revascularization, prasugrel had the most favorable trend. However, clopidogrel had the highest probability of being most effective for major bleeding and all-cause mortality. None of these trends was statistically significant due to lack of power for each outcome. CONCLUSION: Although prasugrel and ticagrelor are known as more potent antiplatelet agents, their effects in preventing MI and stroke are marginal and do not translate into improved overall mortality and bleeding compared with clopidogrel.

Microtubule Inhibitors and Cardiotoxicity.

PURPOSE OF REVIEW: Cancer and heart disease are the leading causes of mortality in the USA. Advances in cancer therapies, namely, the development and use of chemotherapeutic agents alone or in combination, are becoming increasingly prevalent. RECENT FINDINGS: Many chemotherapeutic agents have been associated with adverse cardiovascular manifestations. The mechanisms of these sequelae remain incompletely understood. In particular, microtubule inhibitor (MTI) agents have been related to the development of heart failure, myocardial ischemia, and conduction abnormalities. At present, there are no guidelines for patients undergoing MTI therapy as it pertains to both preventative and mitigatory strategies for cardiovascular complications. We conducted a literature review focusing on content related to the use of MTIs and their effect on the cardiovascular system. MTIs have been associated with various forms of cardiotoxicity, and fatal cardiotoxicities are rare. The most well-described cardiotoxicities are brady- and tachyarrhythmias. The co-administration of anthracycline-based agents with MTIs can increase the risk of cardiotoxicity.

Outcomes With Ultrafiltration Among Hospitalized Patients With Acute Heart Failure (from the National Inpatient Sample).

Acute heart failure (HF) management is a complex and often involves a delicate balance of both cardiac and renal systems. Although pharmacologic diuresis is a mainstay of the pharmacologic management of decompensated HF, ultrafiltration (UF) represents a nonpharmacologic approach in the setting of diuretic resistance. We conducted a cross-sectional analysis of the 2009 through 2014 hospitalization data from the National Inpatient Sample. The study population consisted of hospitalizations with a discharge Diagnosis Related Groups of HF who were older than 18 years of age, did not have end-stage kidney disease, acute kidney injury and had not undergone hemodialysis or hemofiltration. There were 6,174 hospitalizations which included UF among the 7,799,915 hospitalizations for HF. Hospitalizations which included UF were among patients significantly younger in age (68.1 ± 1.0 vs 73.8 ± 0.1 years), male (61.9% vs 47.7%), and with higher prevalence of co-morbid conditions including chronic kidney disease (58% vs 31%), diabetes mellitus (53% vs 42%), and higher rates of co-morbidity (Charlson comorbidity score ≥2, 92% vs 80%). All-cause mortality was significantly higher among hospitalizations which included an UF (4.68% vs 2.24%). Hospitalizations with UF had a longer mean length of stay (6.2 vs 4.3 days, p <0.01) average total charges ($42,035 vs 24,867 USD, p <0.01) as compared with those without UF. Hospitalizations with UF were associated with a greater adjusted odds of all-cause mortality (odds ratio: 3.36, [95% confidence interval 1.76,6.40]), greater than DRG-level target length of stay (odds ratio, 2.46; [95 confidence interval 1.65,3.67]), and a 72% increase in the average hospital charges. In conclusion, hospitalizations which included UF identified a subgroup of HF patients with more co-morbid conditions who are at higher risk of mortality and increased resource burden in terms of length of stay and costs. These findings also highlight that the need for UF may identify patients who are most likely to benefit from a multidisciplinary cardiorenal approach to alter the trajectory of their disease.

Utilization of Emicizumab in Acquired Factor VIII Deficiency.

BACKGROUND Acquired hemophilia A (AHA) is a rare autoimmune disease caused by immunoglobulins that bind and inactive factor VIII, thereby predisposing to life-threatening bleeding. Bleeding is typically stabilized by utilizing bypassing agents, such as recombinant factor VIIa (rVIIa). Select case reports have demonstrated the success of alternative prophylaxis for clearance of factor VIII inhibitors through the use of emicizumab, a current FDA approved medication for treatment of congenital hemophilia A. In this case report we present the efficacy of utilizing emicizumab as a prophylactic agent in a patient that was unable to tolerate first-line therapy for prophylaxis. CASE REPORT A 91-year-old male presented for ongoing hematuria for 5 weeks with prior workup unrevealing. He was given a day's course of recombinant factor VIIa to stabilize his bleeding and was started on cyclophosphamide and prednisone after a revealing hematological workup including activated partial thromboplastin time (aPTT) >100 seconds and factor VIII inhibitor level of 44 BU/mL. He continued to require VIIa infusions to control his bleeding and was started on emicizumab once stabilized. His bleeding remained controlled and his inhibitor decreased after 6 months of therapy with repeat factor VIII inhibitor level of 1.9 BU/mL. CONCLUSIONS The success of utilizing emicizumab for bleeding prophylaxis in AHA is demonstrated by this patient's resolution of bleeding. The high frequency of dosing and higher risk for thrombosis with factor VIIa, in conjunction with our patient's medical history and ease of administration, make emicizumab an ideal agent for bleeding prophylaxis while awaiting clearance of factor VIII inhibitors.

Mitochondrial translocation of cyclin C stimulates intrinsic apoptosis through Bax recruitment.

Intrinsic apoptosis requires mitochondrial outer membrane disruption triggered by recruitment, activation, and oligomerization of the Bcl-2 homology protein Bax. Following oxidative stress, we demonstrated that the transcriptional regulator cyclin C is released into the cytosol where it directs mitochondrial fragmentation and efficient apoptotic induction. This study reveals that cytoplasmic cyclin C is required for both normal Bax activation and its efficient mitochondrial localization. This activity appears direct as cyclin C co-immunoprecipitates with active Bax in stressed cells and binds recombinant Bax in vitro. In addition, stable cyclin C-Bax association requires the fission complex. Pharmacologically stimulating cyclin C nuclear release is sufficient for Bax association and their mitochondrial localization in the absence of any stress signals. However, these cells do not undergo cell death as Bax fails to oligomerize. These data support a model that cyclin C association defines an initial step in Bax mitochondrial recruitment and provides a physical connection between the fission and apoptotic factors. This strategy allows the cell to discriminate stress-induced fission able to recruit Bax from other types of mitochondrial divisions.