Fitness and prostate cancer screening, incidence, and mortality: Results from the Henry Ford Exercise Testing (FIT) Project.

BACKGROUND: The relation between cardiorespiratory fitness (CRF) and prostate cancer is not well established. The objective of this study was to determine whether CRF is associated with prostate cancer screening, incidence, or mortality. METHODS: The Henry Ford Exercise Testing Project is a retrospective cohort study of men aged 40 to 70 years without cancer who underwent physician-referred exercise stress testing from 1995 to 2009. CRF was quantified in metabolic equivalents of task (METs) (<6 [reference], 6-9, 10-11, and ≥12 METs), estimated from the peak workload achieved during a symptom-limited, maximal exercise stress test. Prostate-specific antigen (PSA) testing, incident prostate cancer, and all-cause mortality were analyzed with multivariable adjusted Poisson regression and Cox proportional hazard models. RESULTS: In total, 22,827 men were included, of whom 739 developed prostate cancer, with a median follow-up of 7.5 years. Men who had high fitness (≥12 METs) had an 28% higher risk of PSA screening (95% CI, 1.2-1.3) compared with those who had low fitness (<6 METs. After adjusting for PSA screening, fitness was associated with higher prostate cancer incidence (men aged <55 years, P = .02; men aged >55 years, P ≤ .01), but not with advanced prostate cancer. Among the men who were diagnosed with prostate cancer, high fitness was associated with a 60% lower risk of all-cause mortality (95% CI, 0.2-0.9). CONCLUSIONS: Although men with high fitness are more likely to undergo PSA screening, this does not fully account for the increased incidence of prostate cancer seen among these individuals. However, men with high fitness have a lower risk of death after a prostate cancer diagnosis, suggesting that the cancers identified may be low-risk with little impact on long-term outcomes.

Comprehensive Care Models for Cardiometabolic Disease.

PURPOSE OF REVIEW: The high burden of cardiovascular disease and the simultaneous obesity pandemic is placing an extraordinary strain on the health care system. In the current siloed care model, patients with cardiometabolic disease receive only fractionated care from multiple specialists, leading to insufficient treatment, higher costs, and worse outcomes. RECENT FINDINGS: The imminent need for a new care model calls for the creation of a distinct cardiometabolic specialty in conjunction with a cardiometabolic outpatient clinic dedicated to the comprehensive cardiometabolic care. The cardiometabolic clinic would consist of a diverse range of professionals relevant to comprehensive treatment. The outpatient clinic we envision here would facilitate an interdisciplinary collaboration between specialists and deliver prevention-focused treatment to patients at risk/established cardiometabolic disease.

The effects of 2-hydroxyglutarate on the tumorigenesis of gliomas.

Mutation of the isocitrate-dehydrogenase (IDH) enzymes is one of the central research topics regarding gliomagenesis. Indeed, 70% of gliomas are associated with a gain-of-function IDH mutation and consequently synthesize the oncometabolite, 2-hydroxyglutarate (2-HG). This review aims to elucidate the effects of 2-HG on gliomagenesis. 2-HG promotes tumorigenesis by impacting metabolism, vascularization and altering the epigenome of glioma cells. Glioma metabolism and vascularization is altered by 2-HG's effect on the stability of hypoxia-inducible factor (HIF) and inhibition of endostatin. However, 2-HG's impacts on epigenetic mechanisms are more profound to gliomagenesis. Through competitive inhibition of JHDMs and TET proteins, 2-HG orchestrates histone and DNA hypermethylation, which is associated with gene silencing and dedifferentiation of cells. The hypermethylator phenotype induced by 2-HG also results in alterations of the interaction of the immune system with the tumour. Additionally, this study reviews 2-HG promotion of tumorigenesis by inhibiting repair of DNA alkylation damage through competitive inhibition of AlkB proteins.

Cardiometabolic medicine: a review of the current proposed approaches to revamped training in the United States.

Cardiovascular disease (CVD) remains the leading cause of mortality in the United States, and the population of patients with cardiometabolic conditions, including obesity, metabolic syndrome and diabetes mellitus, continues to grow. There is a need for physicians with specific training in cardiometabolic medicine to provide a 'medical home' for patients with cardiometabolic disease, rather than the fractured care that currently exists in the United States. Cardiometabolic specialists will head multidisciplinary clinics, develop practice guidelines, and lead through research. Proposals for US training in cardiometabolic medicine include: maintain the current training model, a dedicated 2-3 year fellowship following internal medicine residency, a 1-year fellowship following either internal medicine residency or fellowship in cardiology or endocrinology, and certification available to any interested clinician. This review discusses the pros and cons of these approaches. The authors believe that a dedicated cardiometabolic training fellowship has significant advantages over the other options.

Danish National Trends in Cardiovascular Disease and Cancer Drug Expenditure in Relation to Trends in Cardiovascular Disease and Cancer Deaths.

BACKGROUND: Cancer and cardiovascular disease are the 2 leading causes of death in most developed countries, making up the majority of national health care expenditures. In this study, we investigated nationwide trends of cardiovascular disease and cancer drug expenditure in relation to concomitant trends in cardiovascular disease and cancer death rates. METHODS: We obtained cardiovascular and cancer drug expenditure data in Denmark through the Danish Register of Medical Product Statistics. Trends in cancer deaths and cardiovascular disease deaths were observed by linkage to the cancer statistics for the Nordic Countries and Danish Heart Foundation databases. RESULTS: Our data show that introduction and rapid uptake of generic versions of most cardiovascular disease drugs have resulted in a remarkable cost-neutral development in cardiovascular disease drug expenditure from 1995 to 2018 despite increased drug use. This development is contrasted to cancer drug expenditure, which has increased more than 15-fold in the same period. Since 2006, expenditure for cancer drugs has exceeded that for cardiovascular disease drugs and is now more than triple that cost. However, death rates for cancer have dropped a fraction as much as for cardiovascular disease. CONCLUSION: Our results point to a disproportionate high mortality-adjusted expenditure for cancer drugs compared to cardiovascular disease drugs and demonstrate an enormous potential for national health care savings when cheaper versions like biosimilars of many cancer drugs are introduced.

Cardiometabolic Medicine: Development of a New Subspecialty.

CONTEXT: The worldwide rise in the prevalence of cardiometabolic disease, and the introduction of therapeutic options for treating metabolic disease that also lower cardiovascular risk, calls for a restructuring of how we care for patients with cardiometabolic disease. We propose establishment of a new medicine subspecialty, Cardiometabolic Medicine. EVIDENCE ACQUISITION: This summary is based on a synthesis of published original and review articles identified through PubMed, professional society guidelines, and the authors' knowledge of the fields of metabolism, diabetes, and cardiology. EVIDENCE SYNTHESIS: The growing prevalence of cardiometabolic disease will continue to be perhaps the greatest challenge in the United States and throughout the world. We have entered an era where a large set of clinical tools are available that help prevent and treat cardiometabolic disease; however, our old models of clinical training and siloed care are barriers to rapid uptake and efficient healthcare delivery and are in need of change. CONCLUSIONS: Establishing the field of Cardiometabolic Medicine would be a small step in the right direction towards providing the best possible comprehensive care for those with complex cardiometabolic disease.

Cardiometabolic medicine - the US perspective on a new subspecialty.

The high prevalence of cardiovascular disease and worldwide diabetes epidemic has created an ever-increasing burden on the healthcare system. This calls for the creation of a new medicine subspecialty: cardiometabolic medicine. Using information from review articles listed on PubMed and professional society guidelines, the authors advocate for a cardiometabolic medicine specialization training program. The curriculum would integrate relevant knowledge and skills of cardiology and endocrinology as well as content of other disciplines essential to the optimal care of cardiometabolic patients, such as epidemiology, biostatistics, behavioral science and psychology. Cardiometabolic medicine should be seen as an opportunity for life-long learning, with core concepts introduced in medical school and continuing through CME courses for practicing physicians. To improve care for complex patients with multiple co-morbidities, a paradigm shift must occur, transforming siloed education, and treatment and training to interdisciplinary and collaborative work.

Association between coronary artery calcium and cardiovascular disease as a supporting cause in cancer: The CAC consortium.

BACKGROUND: Identifying cancer patients at high risk of CVD is important for targeting CVD prevention strategies and evaluating chemotherapy options in the context of cardiotoxicity. Coronary artery calcium (CAC), a strong marker of coronary atherosclerosis, is used clinically to enhance risk assessment, yet the value of CAC for assessing risk of CVD complications in cancer is poorly understood. OBJECTIVE: In cases of cancer mortality, to determine the value of CAC for predicting risk of CVD as a supporting cause of death. METHODS: The CAC Consortium is a multi-center cohort of 66,636 asymptomatic adults without CVD who underwent CAC scanning. During a follow-up of 12.5 years, 1129 patients died of cancer and were included in this analysis. The primary outcome was presence of CVD listed as a supporting cause of cancer mortality on official death certificates obtained from the National Death Index. Logistic regression models were used to assess the odds of CVD being listed as a supporting cause of death by CAC. RESULTS: CVD was listed as a supporting cause of death in 306 (27%) cancer mortality cases. Baseline CAC was significantly higher in individuals with CVD-supported mortality. Odds ratios of having CVD-supported death increased by ASCVD risk score category [1.15 (0.81, 1.65) for 5-20% 10-year risk and 1.97 (1.36, 2.89) for ≥20% risk, in reference to <5% 10-year ASCVD risk] and CAC category [1.07 (0.73, 1.57) for CAC 1-99, 1.29 (0.87, 1.93) for CAC 100-399, and 2.14 (1.48, 3.09) for CAC ≥400 relative to CAC 0]. In the CAC ≥400 group, these associations remained significantly elevated after adjustment for traditional CVD risk factors [1.66 (1.08, 2.55)]. A sensitivity analysis using a more specific ASCVD-supported mortality outcome, defined as coronary heart disease, stroke, and peripheral artery disease, demonstrated that adjusted odds of ASCVD-supported cancer mortality were significantly elevated in the CAC ≥400 group relative to CAC 0 [3.09 (1.39, 7.38)]. CONCLUSIONS: In cancer mortality cases, high antecedent CAC predicted risk of having CVD as a supporting cause of death on official death certificates, independently of ASCVD risk score and CVD risk factors. CAC may be useful for identifying cancer patients at high CVD risk who might benefit from more intense preventive cardiovascular therapies.

ACC/AHA lipid guidelines: Personalized care to prevent cardiovascular disease.

The 2018 and 2019 guidelines from the American College of Cardiology and American Heart Association reflect the complexity of individualized cholesterol management. The documents address more detailed risk assessment, newer nonstatin cholesterol-lowering drugs, special attention to patient subgroups, and consideration of the value of therapy, all with the aim of creating personalized treatment plans for each patient. Overall, the guidelines recommend shared decision-making to meet the individual needs of each patient.

BRCA1 and Breast Cancer: a Review of the Underlying Mechanisms Resulting in the Tissue-Specific Tumorigenesis in Mutation Carriers.

Since the first cloning of BRCA1 in 1994, many of its cellular interactions have been elucidated. However, its highly specific role in tumorigenesis in the breast tissue-carriers of BRCA1 mutations are predisposed to life-time risks of up to 80%-relative to many other tissues that remain unaffected, has not yet been fully enlightened. In this article, we have applied a universal model of tissue-specificity of cancer genes to BRCA1 and present a systematic review of proposed concepts classified into 4 categories. Firstly, tissue-specific differences in levels of BRCA1 expression and secondly differences in expression of proteins with redundant functions are outlined. Thirdly, cell-type specific interactions of BRCA1 are presented: its regulation of aromatase, its interaction with Progesterone- and receptor activator of nuclear factor-κB ligand-signaling that controls proliferation of luminal progenitor cells, and its influence on cell differentiation via modulation of the key regulators jagged 1-NOTCH and snail family transcriptional repressor 2. Fourthly, factors specific to the cell-type as well as the environment of the breast tissue are elucidated: distinct frequency of losses of heterozygosity, interaction with X inactivation specific transcript RNA, estrogen-dependent induction of genotoxic metabolites and nuclear factor (erythroid-derived 2)-like 2, and regulation of sirtuin 1. In conclusion, the impact of these concepts on the formation of hormone-sensitive and -insensitive breast tumors is outlined.

The Evolving View of Coronary Artery Calcium: A Personalized Shared Decision-Making Tool in Primary Prevention.

The 2018 American Heart Association and American College of Cardiology (AHA/ACC) cholesterol management guideline considers current evidence on coronary artery calcium (CAC) testing while incorporating learnings from previous guidelines. More than any previous guideline update, this set encourages CAC testing to facilitate shared decision making and to individualize treatment plans. An important novelty is further separation of risk groups. Specifically, the current prevention guideline recommends CAC testing for primary atherosclerotic cardiovascular disease (ASCVD) prevention among asymptomatic patients in borderline and intermediate risk groups (5-7.5% and 7.5-20% 10-year ASCVD risk). This additional sub-classification reflects the uncertainty of treatment strategies for patients broadly considered to be "intermediate risk," as treatment recommendations for high and low risk groups are well established. The 2018 guidelines, for the first time, clearly recognize the significance of a CAC score of zero, where intensive statin therapy is likely not beneficial and not routinely recommended in selected patients. Lifestyle modification should be the focus in patients with CAC = 0. In this article, we review the recent AHA/ACC cholesterol management guideline and contextualize the transition of CAC testing to a guideline-endorsed decision aid for borderline-to-intermediate risk patients who seek more definitive risk assessment as part of a clinician-patient discussion. CAC testing can reduce low-value treatment and focus primary prevention therapy on those most likely to benefit.

Coronary artery calcium scoring for individualized cardiovascular risk estimation in important patient subpopulations after the 2019 AHA/ACC primary prevention guidelines.

The 2018 and 2019 American Heart Association and American College of Cardiology (AHA/ACC) guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD) recommend consideration of so-called "risk-enhancing factors" in borderline to intermediate risk individuals. These include high-risk race/ethnicity (e.g. South Asian origin), chronic kidney disease, a family history of premature ASCVD, the metabolic syndrome, chronic inflammatory disorders (e.g. rheumatoid arthritis [RA], psoriasis, or chronic human immunodeficiency virus [HIV]), and conditions specific to women, among others. Studies suggest, however, that risk may be highly heterogeneous within these subgroups. The AHA/ACC guidelines also recommend consideration of coronary artery calcium (CAC) scoring for further risk assessment in borderline to intermediate risk individuals in whom management is uncertain. Although the combination of risk enhancing factors and CAC burden (together with Pooled Cohort estimates) may lead to more accurate ASCVD risk assessment, few publications have closely examined the interplay between risk enhancing factors and CAC scoring for personalized risk estimation. Our aim is to review the relevant literature in this area. Although further research is clearly needed, CAC assessment seems a highly valuable option to inform individualized ASCVD risk management in these important, often highly heterogeneous patient subgroups.