An incidental danger: Left ventricular thrombus in takotsubo syndrome.

Takotsubo cardiomyopathy is a potentially lethal condition characterized by transient regional systolic dysfunction in the absence of coronary artery ischemia. This syndrome predominantly affects postmenopausal women and is often preceded by physical or emotional stress and often presents with symptoms of acute coronary syndrome, chest pain, and shortness of breath. Although the effects can be transient, takotsubo cardiomyopathy still results in an 8-12% rate of in-hospital mortality, with cardiogenic shock being the most common cause of death. There are known risk factors that increase the likelihood of a patient developing a left ventricular thrombus during the clinical course. The management of these cases is discussed in this report.

Infective Endocarditis After Transcatheter Aortic Valve Implantation: A Systematic Review.

Infective endocarditis (IE) after transcatheter aortic valve implantation (TAVI) is a rare but potentially fatal event. In this systematic review, we searched PubMed and Embase for large TAVI studies and registries to identify the incidence, presentation, microbiology, risk factors, and outcomes of IE in this population. After application of the selection criteria and quality assessment, 8 studies representing 255,310 TAVR cases and 4218 cases of IE qualified for this review. IE following TAVI is uncommon with an incidence of 0.87 to 1.7 events per 100 person-years. Most events occur in the first year following valve implantation. Staphylococcus , Enterococcus , and Streptococcus species are the most common pathogens. Risk factors include age, sex, concomitant comorbidities, and procedural factors. Outcomes are dismal, and surgical intervention is rare in this population.

Association of Thiazide Diuretics With Diabetes Progression, Kidney Disease Progression, Cardiovascular Outcomes, and Death Among Patients With Diabetes Who Initiate Statins.

Statins have been associated with diabetes mellitus (DM) progression but their cardiovascular benefit in patients with DM outweigh the harm. However, the effects of concurrent use of other medications that similarly increase blood glucose level, such as thiazide diuretics, are not well studied. This study aimed to evaluate the association of concurrent use of thiazide diuretics and statins on DM progression, cardiovascular and renal outcomes, and death in patients with DM. This is a retrospective cohort study of Veterans with DM who initiated statins between 2003 and 2015. The cohort comprised thiazide users (concomitantly used thiazides and statins for ≥6 months) and active comparators (concomitantly used calciun channel blockers [CCB] but not thiazides and statins for ≥6 months). We excluded patients who were <18 years old, with chronic kidney disease stage 4 or worse, or used loop diuretics. We propensity-score-matched comparison groups on 99 baseline characteristics including demographics, healthcare utilization, co-morbidities, cardiovascular and co-morbidity scores, vital signs, laboratory data, and medication class usage. Outcomes were: (1) DM progression (new insulin initiation, increase in the number of glucose-lowering medication classes, and hyperglycemic episodes); (2) kidney disease progression (doubling of serum creatinine, incidence of chronic kidney disease stage 5, initiation of renal replacement therapy, and incidence of diabetic nephropathy); (3) cardiovascular outcomes (acute myocardial infarction, stroke, cardiac arrest); and (4) total mortality. From 297,967 statin users (228,509 Thiazide-statin users and 69,458 active comparators), we successfully matched 67,614 pairs. In comparison to active comparators, thiazide-statin users had increased risk of DM progression (65.6% in CCB group vs 68.1% in thiazide group; odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.09 to 1.15), decreased risk of kidney progression (16.9% in CCB group vs 16.5 in thiazide group; OR: 0.97, 95% CI: 0.94 to 0.99), decreased risk of cardiovascular outcomes (15.7% in CCB group vs 14.6% in thiazide group; OR: 0.92, 95% CI: 0.89 to 0.95), and similar risk of total mortality (19.7% in each group; OR: 1.00, 95% CI: 0.98 to 1.03). This study attempted to answer an important clinical question whether thiazide diuretics should be discontinued or substituted upon statin initiation. Our results showed that concurrent use of statin and thiazides in patients with DM was associated with DM progression but with less kidney progression and cardiovascular outcomes and no difference in mortality. Clinicians should closely monitor DM control when thiazides and statins are used concurrently.

Outcomes of Transcatheter Aortic Valve Implant Among Patients With A Previous Coronary Artery Bypass Graft: A Nationwide Analysis.

There is a paucity of data regarding the temporal trends and outcomes of transcatheter aortic valve implant (TAVI) among patients with a previous coronary artery bypass graft (CABG) surgery. We queried the Nationwide Readmissions Database (2016 to 2019) for hospitalized patients who underwent TAVI using the appropriate International Classification of Diseases, Tenth Revision procedural codes. A multivariable regression analysis was used to adjust for the patients' and hospitals' characteristics in comparing the study groups. The primary outcome was in-hospital mortality. The final analysis included 237,829 patients who underwent TAVI, of whom 42,671 (17.9%) had a previous CABG. During the study period, there was a decrease in the proportion of patients with previous CABG who underwent TAVI (21.0% in 2016 vs 15.5% in 2019, ptrend = 0.01), although there was no change in their in-hospital mortality rate (1.08% in 2016 vs 1.25% in 2019, ptrend = 0.43). Patients with a previous CABG were younger and less likely to be women than those without a previous CABG. TAVI among those with a previous CABG was associated with lower in-hospital mortality (adjusted odds ratio [aOR] 0.79, 95% confidence interval [CI] 0.69 to 0.91), similar rate of ischemic stroke (aOR 0.81, 95% CI 0.71 to 0.93) and permanent pacemaker implant (aOR 1.00, 95% CI 0.93 to 1.05). Patients with a previous CABG had a lower all-cause 90-day readmission (odds ratio 0.95, 95% CI 0.94 to 1.06) but higher readmission for transient ischemic attack. Among those with a previous CABG, female gender and chronic kidney disease stage ≥3 were independently associated with a higher in-hospital mortality, whereas obesity was associated with a lower in-hospital mortality. In conclusion, there was a decrease in the proportion of patients with a previous CABG among those who underwent TAVI. TAVI among those with a previous CABG was not associated with increased in-hospital adverse events or 90-day all-cause readmissions.

Pulmonary Hypertension in Pregnancy: Challenges and Solutions.

Pulmonary hypertension (PH) is a heterogeneous disease characterized by an elevated mean pulmonary artery pressure of 20 mm Hg or above. PH is a prevalent condition among women of reproductive age and is linked with poor prognosis during pregnancy. Pregnancy is a stressful event and complicates the management and prognosis in patients with PH. In this review, we discuss the pathogenesis, clinical presentation as well as therapeutic options for PH during pregnancy. We also highlight knowledge gaps to guide future research.

Compound C Inhibits Ovarian Cancer Progression via PI3K-AKT-mTOR-NFκB Pathway.

Epithelial Ovarian cancer (OvCa) is the leading cause of death from gynecologic malignancies in the United States, with most patients diagnosed at late stages. High-grade serous cancer (HGSC) is the most common and lethal subtype. Despite aggressive surgical debulking and chemotherapy, recurrence of chemo-resistant disease occurs in ~80% of patients. Thus, developing therapeutics that not only targets OvCa cell survival, but also target their interactions within their unique peritoneal tumor microenvironment (TME) is warranted. Herein, we report therapeutic efficacy of compound C (also known as dorsomorphin) with a novel mechanism of action in OvCa. We found that CC not only inhibited OvCa growth and invasiveness, but also blunted their reciprocal crosstalk with macrophages, and mesothelial cells. Mechanistic studies indicated that compound C exerts its effects on OvCa cells through inhibition of PI3K-AKT-NFκB pathways, whereas in macrophages and mesothelial cells, CC inhibited cancer-cell-induced canonical NFκB activation. We further validated the specificity of the PI3K-AKT-NFκB as targets of compound C by overexpression of constitutively active subunits as well as computational modeling. In addition, real-time monitoring of OvCa cellular bioenergetics revealed that compound C inhibits ATP production, mitochondrial respiration, and non-mitochondrial oxygen consumption. Importantly, compound C significantly decreased tumor burden of OvCa xenografts in nude mice and increased their sensitivity to cisplatin-treatment. Moreover, compound C re-sensitized patient-derived resistant cells to cisplatin. Together, our findings highlight compound C as a potent multi-faceted therapeutic in OvCa.

A Silent Killer: Left Main Coronary Artery Disease in Gastrointestinal Bleed.

Left main coronary artery disease (LMCAD) is defined as more than 50% angiographic arterial narrowing and has been demonstrated in nearly 5% of all patients undergoing coronary angiography. It carries an extremely high risk for cardiovascular morbidity and mortality as it impacts more than two-thirds of the left ventricle. Prediction of LMCAD in the right clinical setting is important for the selection of the proper treatment strategies. Typical ECG characteristics are ST elevation (STE) in lead augmented vector right (aVR-STE) of more than 0.5 mV accompanied by ST depression (STD) notably in leads I, II, and V4-6 or STE in aVR ≥ V1. Furthermore, the presence of aVR-STE is associated with worse outcomes and careful evaluation and close monitoring are warranted. However, not every aVR-STE is an acute occlusion of the left main coronary artery (LMCA), as acute occlusion is a catastrophic event. aVR-STE can also be associated with severe triple-vessel disease or diffuse subendocardial ischemia.

An Unusual Presentation of Left Ventricular Non-compaction Cardiomyopathy in an Elderly Patient.

Left ventricular non-compaction cardiomyopathy (LVNC) is a rare cardiomyopathy. The true prevalence of LVNC is unclear. The clinical presentation of LVNC varies widely from asymptomatic to end-stage heart failure or sudden cardiac death, and the diagnostic criteria are not standardized. Moreover, there is an increased risk for thromboembolic events with LVNC. We present an unusual case of LVNC first diagnosed in a septuagenarian.

Metabolomic credentialing of murine carcinogen-induced urothelial cancer.

Bladder cancer (BCa) is the most common malignancy of the urinary system with increasing incidence, mortality, and limited treatment options. Therefore, it is imperative to validate preclinical models that faithfully represent BCa cellular, molecular, and metabolic heterogeneity to develop new therapeutics. We performed metabolomic profiling of premalignant and non-muscle invasive bladder cancer (NMIBC) that ensued in the chemical carcinogenesis N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model. We identified the enriched metabolic signatures that associate with premalignant and NMIBC. We found that enrichment of lipid metabolism is the forerunner of carcinogen-induced premalignant and NMIBC lesions. Cross-species analysis revealed the prognostic value of the enzymes associated with carcinogen-induced enriched metabolic in human disease. To date, this is the first study describing the global metabolomic profiles associated with early premalignant and NMIBC and provide evidence that these metabolomic signatures can be used for prognostication of human disease.

Prognostic significance of body mass index-adjusted criteria for left ventricular hypertrophy.

Electrocardiographic left ventricular hypertrophy (ECG-LVH) is associated with both cardiovascular and all-cause mortality. Obesity attenuates the sensitivity of several ECG-LVH criteria, so body mass index (BMI) adjusted criteria have been developed. However, the prognostic significance of BMI-adjusted ECG-LVH criteria is not known. This analysis included 7812 participants (59.8 ± 13.4 years, 53% women, 50% non-Hispanic-whites) from the Third National Health and Nutrition Examination Survey. The Cornell criteria (R in aVL + S in V3 ≥ 2800 µV in men or ≥2200 µV in women) and Sokolow-Lyon criteria (S in V1 + R in V5 or R in V6 ≥ 3500 µV) criteria were used for LVH. To account for the effects of obesity, the BMI-adjusted Cornell criteria (product of R in aVL + S in V3 and BMI > 60 400 µV kg m-2 ) and the BMI-adjusted Sokolow-Lyon criteria (add 400 µV if overweight, add 800 µV if obese) were used. Compared to traditional ECG-LVH criteria, more participants met criteria for ECG-LVH with BMI-adjusted Cornell voltage (9.9% vs 2.9%) and BMI-adjusted Sokolow-Lyon (13.1% vs 6.4%) criteria. In multivariable-adjusted Cox proportional hazards models, the BMI-adjusted Sokolow-Lyon criteria performed no better than traditional criteria (HR 1.18, 95% CI 1.06-1.32 for all-cause, HR 1.38, 95% CI 1.17-1.62 for cardiovascular mortality) and the BMI-adjusted Cornell voltage criteria attenuated the association with all-cause (HR 1.16, 95% CI 1.03-1.32) and cardiovascular mortality (HR 1.34, 95% CI 1.13-1.60). Despite potential improvements in the detection of LVH using BMI-adjusted ECG-LVH criteria, adjusting for BMI may result in the loss of prognostic information.

Mesenchymal Stem Cell Therapy for Doxorubicin-Induced Cardiomyopathy: Potential Mechanisms, Governing Factors, and Implications of the Heart Stem Cell Debate.

Over the past decades, researchers have reported several mechanisms for doxorubicin (DOX)-induced cardiomyopathy, including oxidative stress, inflammation, and apoptosis. Another mechanism that has been suggested is that DOX interferes with the cell cycle and induces oxidative stress in C-kit+ cells (commonly known as cardiac progenitor cells), reducing their regenerative capacity. Cardiac regeneration through enhancing the regenerative capacity of these cells or administration of other stem cells types has been the axis of several studies over the past 20 years. Several experiments revealed that local or systemic injections with mesenchymal stem cells (MSCs) were associated with significantly improved cardiac function, ameliorated inflammatory response, and reduced myocardial fibrosis. They also showed that several factors can affect the outcome of MSC treatment for DOX cardiomyopathy, including the MSC type, dose, route, and timing of administration. However, there is growing evidence that the C-kit+ cells do not have a cardiac regenerative potential in the adult mammalian heart. Similarly, the protective mechanisms of MSCs against DOX-induced cardiomyopathy are not likely to include direct differentiation into cardiomyocytes and probably occur through paracrine secretion, antioxidant and anti-inflammatory effects. Better understanding of the involved mechanisms and the factors governing the outcomes of MSCs therapy are essential before moving to clinical application in patients with DOX-induced cardiomyopathy.

Role of tumor microenvironment in the pathobiology of ovarian cancer: Insights and therapeutic opportunities.

Ovarian cancer is the fifth most common cancer affecting women and at present, stands as the most lethal gynecologic malignancy. The poor disease outcome is due to the nonspecific symptoms and the lack of effective treatment at advanced stages. Thus, it is of utmost importance to understand ovarian carcinoma through several lenses and to dissect the role that the unique peritoneal tumor microenvironment plays in ovarian cancer progression and metastasis. This review seeks to highlight several determinants of this unique tumor microenvironment, their influence on disease outcome and ongoing clinical trials targeting these determinants.

Role of tumor microenvironment in ovarian cancer pathobiology.

Ovarian cancer is the fifth most common cancer affecting the female population and at present, stands as the most lethal gynecologic malignancy. Poor prognosis and low five-year survival rate are attributed to nonspecific symptoms and below par diagnostic criteria at early phases along with a lack of effective treatment at advanced stages. It is thus of utmost importance to understand ovarian carcinoma through several lenses including its molecular pathogenesis, epidemiology, histological subtypes, hereditary factors, diagnostic approaches and methods of treatment. Above all, it is crucial to dissect the role that the unique peritoneal tumor microenvironment plays in ovarian cancer progression and metastasis. This review seeks to highlight several important aspects of ovarian cancer pathobiology as a means to provide the necessary background to approach ovarian malignancies in the future.

Peguero Electrocardiographic Left Ventricular Hypertrophy Criteria and Risk of Mortality.

Background: Peguero electrocardiographic left ventricular hypertrophy (ECG-LVH) criteria are newly developed criteria that have shown better diagnostic performance than the traditional Cornell-voltage and Sokolow-Lyon criteria. However, prediction of poor outcomes rather than detection of increased left ventricular mass is becoming the primary use for ECG-LVH criteria which requires investigating any new ECG-LVH criteria in terms of prediction. Aims: To examine the prognostic significance of the newly developed Peguero ECG-LVH criteria. Methods: We compared the prognostic significance of Peguero ECG-LVH with Cornell-voltage and Sokolow-Lyon ECG-LVH criteria in 7,825 participants (age 59.8 ± 13.4 years; 52.7% women) from the third National Health and Nutrition Examination Survey who were free of major intraventricular conduction defects. ECG-LVH criteria were derived from digital ECG tracings processed at a central core laboratory. Results: At baseline, ECG-LVH was detected in 11.8% by Peguero; in 4.3% by Cornell voltage and in 6.4% by Sokolow-Lyon. During a median follow up of 13.8 years, 2,796 all-cause mortality events occurred. In multivariable models adjusted for demographics and cardiovascular risk factors, presence of Peguero ECG-LVH was associated with increased risk of all-cause mortality [HR (95% CI): 1.29 (1.16, 1.44)]. This association was not significantly different from the associations of Cornell voltage-LVH or Sokolow-Lyon LVH with all-cause mortality [HR (95%CI): 1.32 (1.12, 1.55) and 1.24 (1.07, 1.43), respectively; p-values for comparisons of these HRs with the HR of Peguero ECG-LVH 0.817 and 0.667, respectively]. Similar patterns of associations were observed with cardiovascular, ischemic heart disease and heart failure mortalities. Conclusion: Peguero ECG-LVH is predictive of increased risk of death similar to the traditional ECG-LVH criteria.

SPARC Inhibits Metabolic Plasticity in Ovarian Cancer.

The tropism of ovarian cancer (OvCa) to the peritoneal cavity is implicated in widespread dissemination, suboptimal surgery, and poor prognosis. This tropism is influenced by stromal factors that are not only critical for the oncogenic and metastatic cascades, but also in the modulation of cancer cell metabolic plasticity to fulfill their high energy demands. In this respect, we investigated the role of Secreted Protein Acidic and Rich in Cysteine (SPARC) in metabolic plasticity of OvCa. We used a syngeneic model of OvCa in Sparc-deficient and proficient mice to gain comprehensive insight into the paracrine effect of stromal-SPARC in metabolic programming of OvCa in the peritoneal milieu. Metabolomic and transcriptomic profiling of micro-dissected syngeneic peritoneal tumors revealed that the absence of stromal-Sparc led to significant upregulation of the enzymes involved in glycolysis, TCA cycle, and mitochondrial electron transport chain (ETC), and their metabolic intermediates. Absence of stromal-Sparc increased reactive oxygen species and perturbed redox homeostasis. Recombinant SPARC exerted a dose-dependent inhibitory effect on glycolysis, mitochondrial respiration, ATP production and ROS generation. Comparative analysis with human tumors revealed that SPARC-regulated ETC-signature inversely correlated with SPARC transcripts. Targeting mitochondrial ETC by phenformin treatment of tumor-bearing Sparc-deficient and proficient mice mitigated the effect of SPARC-deficiency and significantly reduced tumor burden, ROS, and oxidative tissue damage in syngeneic tumors. In summary, our findings provide novel insights into the role of SPARC in regulating metabolic plasticity and bioenergetics in OvCa, and shines light on its potential therapeutic efficacy.