Mechanisms and Treatment of Dyslipidemia in Diabetes.

PURPOSE OF REVIEW: Type 2 diabetes mellitus is widespread throughout the world and is a powerful risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). This manuscript explored the mechanisms underlying dyslipidemia in type 2 diabetes as well as currently available treatment options and guideline recommendations. RECENT FINDINGS: Type 2 diabetes is associated with a characteristic pattern of dyslipidemia, often termed diabetic dyslipidemia. Patients with type 2 diabetes often present with low HDL levels, elevated levels of small dense LDL particles, and elevated triglyceride levels. LDL lowering is the cornerstone of managing diabetic dyslipidemia, and statins are the mainstay of therapy. The cholesterol absorption inhibitor ezetimibe and PCSK9 inhibitors have also been shown to lower risk in patients with diabetes. Recently, the eicosapentaenoic (EPA) only n-3 fatty acid, icosapent ethyl, has also shown benefit for cardiovascular risk reduction in patients with diabetes. To date, no agents targeting HDL increase have shown cardiovascular benefit in patients on background statin therapy. Diabetic dyslipidemia is significant cardiovascular disease risk factor, and LDL-lowering therapy with statins, PCSK9 inhibitors, and ezetimibe continues to be mainstay therapy to reduce cardiovascular risk. Future studies targeting low HDL and high triglycerides levels associated with type 2 diabetes could provide additional novel therapies to manage diabetic dyslipidemia.

Neprilysin Inhibition as a PARADIGM Shift in Heart Failure Therapy.

Heart failure is a growing global public health problem. With the aging population, increased risk factors for heart failure development, and better survival after myocardial infarction, the prevalence is only expected to increase in the coming years. Although existing therapies have improved the clinical course of heart failure patients, new approaches are urgently needed to enhance quality of life and reduce morbidity and mortality. However, there has been little progress in the treatment of chronic heart failure in the past decade with only two new drugs approved by the US FDA over this time. Better understanding of the neurohormonal axis of heart failure has lead to the development of LCZ696, a first-in-class novel agent that acts as an angiotensin receptor blocker and neprilysin inhibitor. In the PARADIGM-HF study, LCZ696 was superior to an angiotensin-converting enzyme inhibitor in reducing mortality and HF hospitalizations and improving quality of life across a broad spectrum of symptomatic patients with heart failure with reduced ejection fraction. While evaluation of long-term effects is still needed, the completed trials on LCZ696 demonstrate that the drug is generally well-tolerated with a safe side effect profile. LCZ696 should be strongly considered as a favorable alternative to angiotensin converting enzyme inhibitors and angiotensin receptor blockers in appropriate heart failure patients.

Taken to heart-arrhythmic potential of heart-leaf sida, a banned ephedrine alkaloid: a case report.

BACKGROUND: Ephedra and ephedrine alkaloids were commonly used in herbal supplements before being prohibited by the European Commission and US Food and Drug Administration. However, ongoing, unknowing use by consumers can lead to potential adverse cardiovascular effects, such as arrhythmias. CASE SUMMARY: A 65-year-old-man with a history of idiopathic pulmonary fibrosis status post-right single lung transplant was admitted for dizziness and resting tachycardia. Electrocardiogram showed a narrow complex, long R-P tachycardia with upright P-waves in lead V 1. An initial workup suggested an arrhythmia associated with the consumption of an herbal supplement containing heart-leaf sida, a banned botanical ephedrine alkaloid. After the supplement was discontinued, the patient's heart rate abruptly decreased without other intervention. Electrocardiogram showed a change in P-wave morphology in lead V 1 from upright to biphasic (+/-) after conversion to normal sinus rhythm. Thus, a diagnosis of atrial tachycardia originating at or near the donor right superior pulmonary vein was favoured. DISCUSSION: Atrial tachycardia can be precipitated by the proarrhythmic effects of ephedrine alkaloids, especially in patients with underlying risk factors and susceptible atrial anatomical substrate post-lung transplantation. Despite being banned by the European Union and the USA, ephedrine alkaloids continue to be used in over-the-counter herbal supplements and may go undetected by consumers. Ongoing vigilance for ephedrine alkaloids, more rigorous regulation, and active patient education can help reduce potential cardiovascular adverse events.

Women in Cardiology Twitter Network: An Analysis of a Global Professional Virtual Community From 2016 to 2019.

Background Social media is an effective channel for the advancement of women physicians; however, its use by women in cardiology has not been systematically studied. Our study seeks to characterize the current Women in Cardiology Twitter network. Methods and Results Six women-specific cardiology Twitter hashtags were analyzed: #ACCWIC (American College of Cardiology Women in Cardiology), #AHAWIC (American Heart Association Women in Cardiology), #ilooklikeacardiologist, #SCAIWIN (Society for Cardiovascular Angiography and Interventions Women in Innovations), #WomeninCardiology, and #WomeninEP (Women in Electrophysiology). Twitter data from 2016 to 2019 were obtained from Symplur Signals. Quantitative and descriptive content analyses were performed. The Women in Cardiology Twitter network generated 48 236 tweets, 266 180 903 impressions, and 12 485 users. Tweets increased by 706% (from 2083 to 16 780), impressions by 207% (from 26 755 476 to 82 080 472), and users by 440% (from 796 to 4300), including a 471% user increase internationally. The network generated 6530 (13%) original tweets and 43 103 (86%) amplification tweets. Most original and amplification tweets were authored by women (81% and 62%, respectively) and women physicians (76% and 52%, respectively), with an increase in original and amplification tweets authored by academic women physicians (98% and 109%, respectively) and trainees (390% and 249%, respectively) over time. Community building, professional development, and gender advocacy were the most common tweet contents over the study period. Community building was the most common tweet category for #ACCWIC, #AHAWIC, #ilooklikeacardiologist, #SCAIWIN, and #WomeninCardiology, whereas professional development was most common for #WomeninEP. Conclusions The Women in Cardiology Twitter network has grown immensely from 2016 to 2019, with women physicians as the driving contributors. This network has become an important channel for community building, professional development, and gender advocacy discussions in an effort to advance women in cardiology.

Contemporary Treatment of Acute Heart Failure.

Heart failure (HF) is a rapidly growing global pandemic. A consequence of the increased prevalence of HF has been an increase in hospitalizations due to acute HF (AHF) in the United States and in many other countries around the world. Despite advances in treatment, morbidity and mortality rates in the post-discharge period after an AHF admission remain unacceptably high. The occurrence of an AHF episode poses a major clinical challenge since current therapeutic options are limited to providing mostly short-term symptomatic relief. Diuretics to relieve congestion, inotropic agents to maintain tissue perfusion and vasodilators to reduce the load on the heart are the primary drug approaches for treating AHF. Determining the most effective way of using these agents has been the focus of several recently completed studies, but success in altering outcomes has proved to be elusive. Results from studies using new experimental agents such as ularitide and serelaxin, however, have been promising and ongoing. Phase 3 clinical trials will determine their role in the therapeutic regimen. This manuscript reviews aspects of medical therapy of AHF for which new insights are available and describes pathophysiologic abnormalities that appear to be amenable to treatment with both currently available therapies and novel agents that are being developed.

Destabilization of MYC/MYCN by the mitochondrial inhibitors, metaiodobenzylguanidine, metformin and phenformin.

In the present study, we investigated the anticancer effects of the mitochondrial inhibitors, metaiodobenzylguanidine (MIBG), metformin and phenformin. 131I-MIBG has been used for scintigraphic detection and the targeted radiotherapy of neuroblastoma (NB), a pediatric malignancy. Non-radiolabeled MIBG has been reported to be cytotoxic to NB cells in vitro and in vivo. However, the mechanisms behind its growth suppressive effects have not yet been fully elucidated. Metformin and phenformin are diabetes medications that are being considered in anticancer therapeutics. We investigated the anticancer mechanisms of action of MIBG and metformin in NB. Our data revealed that both drugs suppressed NB cell growth and that the combination drug treatment was more potent. MIBG reduced MYCN and MYC expression in MYCN-amplified and non-MYCN-amplified NB cells in a dose- and time-dependent manner. Metformin was less effective than MIBG in destabilizing MYC/MYCN. The treatment of NB cells with metformin or MIBG resulted in an increased expression of genes encoding biomarkers for favorable outcome in NB [(ephrin (EFN)B2, EFNB3, EPH receptor B6 (EPHB6), neurotrophic tyrosine kinase, receptor, type 1 (NTRK1), CD44 and Myc-interacting zinc finger protein (MIZ-1)] and tumor suppressor genes [(early growth response 1 (EGR1), EPH receptor A2 (EPHA2), growth arrest and DNA-damage-inducible, beta (GADD45B), neuregulin 1 (NRG1), TP53 apoptosis effector (PERP) and sel-1 suppressor of lin-12-like (C. elegans) (SEL1L)]. Accordingly, metformin and MIBG augmented histone H3 acetylation in these cells. Phenformin also exhibited histone modification and was more effective than metformin in destabilizing MYC/MYCN in NB cells. Our data suggest that the destabilization of MYC/MYCN by MIBG, metformin and phenformin and their effects on histone modification are important mechanisms underlying their anticancer effects.

Rab5 mediates caspase-8-promoted cell motility and metastasis.

Caspase-8 is a key apical sensory protein that governs cell responses to environmental cues, alternatively promoting apoptosis, proliferation, and cell migration. The proteins responsible for integration of these pathways, however, have remained elusive. Here, we reveal that Rab5 regulates caspase-8-dependent signaling from integrins. Integrin ligation leads to Rab5 activation, association with integrins, and activation of Rac, in a caspase-8-dependent manner. Rab5 activation promotes colocalization and coprecipitation of integrins with caspase-8, concomitant with Rab5 recruitment to integrin-rich regions such as focal adhesions and membrane ruffles. Moreover, caspase-8 expression promotes Rab5-mediated internalization and the recycling of beta1 integrins, increasing cell migration independently of caspase catalytic activity. Conversely, Rab5 knockdown prevented caspase-8-mediated integrin signaling for Rac activation, cell migration, and apoptotic signaling, respectively. Similarly, Rab5 was critical for caspase-8-driven cell migration in vivo, because knockdown of Rab5 compromised the ability of caspase-8 to promote metastasis under nonapoptotic conditions. These studies identify Rab5 as a key integrator of caspase-8-mediated signal transduction downstream of integrins, regulating cell survival and migration in vivo and in vitro.