Cardiac Health in Women With Metabolic Syndrome: Clinical Aspects and Pathophysiology

Although the classical cardiovascular risk factors (e.g., smoking and hypertension) are becoming more effectively managed, a continuous increase of the so‐called “cardiometabolic risk” is noted. Starting from this century, the nomenclature “metabolic syndrome” has become more popular to identify a cluster of disorders including obesity, dyslipidemia, hypertension, and insulin resistance. It is a primary risk factor for diabetes and cardiovascular disease in both genders. Interestingly, the metabolic diseases display a distinct gender disparity with an apparent “female advantage” in the premenopausal women compared with age‐matched men. However, women usually lose such “sex protection” following menopause or affliction of metabolic syndrome especially insulin resistance. A controversy exists in the medical literature concerning whether metabolic syndrome is a real syndrome or simply a cluster of risk factors. Several scenarios are speculated to contribute to the gender dimorphism in the cardiovascular sequelae in patients with metabolic syndrome including sex hormones, intrinsic organ function, and the risk factor profile (e.g., hypertension, dyslipidemia, obesity, sedentary lifestyle, and atherogenic diet). With the alarming rise of obesity prevalence, heart problems in metabolic syndrome continue to rise with a distinct gender dimorphism. Although female hearts seem to better tolerate the stress insults compared with the male counterparts, the female sex hormones such as estrogen can interact with certain risk factors to precipitate myopathic changes in the hearts. This synthetic review of recent literature suggests a role of gender disparity in myopathic factors and risk attributable to each metabolic component in the different prevalence of metabolic syndrome.     

老年高血压合并高脂血症并发缺血性心脏病患者的相关危险因素分析

摘要目的：探究老年高血压合并高脂血症并发缺血性心脏病患者的相关危险因素。方法：对我院2008年5月一2011年11月收治的老年高血压患者进行回顾分析,将合并高脂血症及缺血性心脏病患者纳入观察组,其余患者纳入对照组,对年龄、家族史等临床资料进行危险因素回归分析,总结其相关危险因素。结果：单因素分析发现,年龄、家族史、肥胖、糖尿病等9项因素存在统计学差异,将其纳入多因素COX模型分析,发现年龄、吸烟史、高甘油三酯血症、高胆固醇血症、高水平C反应蛋白及高尿酸血症是影响老年高血压合并高脂血症并发缺血性心脏病的独立危险因素。结论：年龄、吸烟史、高甘油三酯血症、高胆固醇血症、高水平C反应蛋白及高尿酸血症是影响老年高血压合并高脂血症并发缺血性心脏病的独立危险因素,对于存在危险因素的患者应及时进行早期干预,防止严重并发疾病的出现。     

Endoplasmic reticulum stress-induced hepatic stellate cell apoptosis through calcium-mediated JNK/P38 MAPK and Calpain/Caspase-12 pathways

Since ischemic heart disease (IHD) is a major cause of mortality and heart failure, novel therapeutic strategies are expected to improve the clinical outcomes of patients with acute myocardial infarction. Brief episodes of ischemia/reperfusion performed at the onset of reperfusion can reduce infarct size; a phenomenon termed “ischemic postconditioning.” Extensive research has determined that different autacoids (e.g., adenosine, bradykinin, opioid, etc.) and cytokines, their respective receptors, kinase signaling pathways, and mitochondrial modulation are involved in ischemic conditioning. Modification of these factors by pharmacological agents mimics the cardioprotection by ischemic postconditioning. Here, the potential mechanisms of ischemic postconditioning, the presence of comorbidities, and the possible extrapolation to the clinical setting are reviewed. In the near future, large, multicentered, randomized, placebo-controlled, clinical trials will be required to determine whether pharmacological and/or ischemic postconditioning can improve the clinical outcomes of patients with IHD.     

A review of the postulated mechanisms concerning the association of Helicobacter pylori with ischemic heart disease

Since its discovery, Helicobacter pylori has been implicated in the pathogenesis of several diseases, both digestive and extradigestive. Interestingly, the majority of the extradigestive-related literature is focused on two vascular manifestations: stroke and ischemic heart disease. Potential mechanisms for the establishment of a H. pylori-induced ischemic heart disease have been proposed with regard to chronic inflammation, molecular mimicry, oxidative modifications, endothelial dysfunction, direct effect of the microorganism on atherosclerotic plaques as well as changes regarding traditional or novel risk factors for ischemic heart disease or even platelet-H. pylori interactions. A positive link between H. pylori infection and ischemic heart disease has been suggested by a series of studies focusing on epidemiologic evidence, dyslipidemic alterations, upregulation of inflammatory markers or homocysteine levels, induction of hypercoagulability, oxidation of low-density lipoprotein, causation of impaired endothelial function, detection of H. pylori DNA in atherosclerotic plaques, and participation of certain antigens and antibodies in a cross-reactivity model. There are studies, however, which investigated the relationship between H. pylori and ischemic heart disease with regard to the same parameters and failed to confirm the suggested positive association. Further studies in the direction of interaction between H. pylori and the host's genotype as well as a quest for evidence towards novel risk factors for ischemic heart disease such as oxidative stress, vascular remodeling, vascular calcification, or vasomotor activity, may reveal a field of great interest, thus contributing to the determination of new potential mechanisms.     

Cardiac fibrosis: Pathobiology and therapeutic targets

Cardiac fibrosis is characteristic of the end stage in nearly all forms of heart disease. Accumulation of extracellular matrix in the myocardium leads to increased risk of arrhythmia and impaired cardiac function, and ultimately progression to heart failure. Despite the critical need to slow or reverse development of cardiac fibrosis to maintain cardiac function, there are no approved therapies that directly target the extracellular matrix. Research into the underlying causes and therapeutic targets has been hampered, in part, by the lack of a clear marker for cardiac fibroblasts – the cells responsible for regulating extracellular matrix turnover. Lineage tracing studies as well as single-cell RNA sequencing studies have provided new insights into cardiac fibroblast origins and heterogeneity. Moreover, a greater understanding of pathways governing fibroblast activation during ischemic and non-ischemic cardiac remodeling and their communication with other inflammatory and cardiac cells may lead to novel therapeutic targets to slow or reverse fibrotic remodeling. The special issue of Cellular Signaling entitled “Cardiac Fibrosis: Pathobiology and Therapeutic Targets” is comprised of review articles in which these topics, as well as important open questions for future investigation, are discussed.     

Age-Related Factors Associated With The Risk of Hip Fracture

ObjectiveAdvancing age is a powerful risk factor for hip fractures. The biological mechanisms through which aging impacts the risk of hip fractures have not been well studied.MethodsBiological factors associated with “advancing age” that help to explain how aging is associated with the risk of hip fractures are reviewed. The findings are based on analyses of the Cardiovascular Health Study, an ongoing observational study of adults aged ≥65 years with 25 years of follow-up.ResultsThe following 5 age-related factors were found to be significantly associated with the risk of hip fractures: (1) microvascular disease of the kidneys (albuminuria and/or elevated urine-albumin-to-creatinine ratio) and brain (abnormal white matter disease on brain magnetic resonance imaging); (2) increased serum levels of carboxymethyl-lysine, an advanced glycation end product that reflects glycation and oxidative stress; (3) reduced parasympathetic tone, as derived from 24-hour Holter monitoring; (4) carotid artery atherosclerosis in the absence of clinical cardiovascular disease; and (5) increased transfatty acid levels in the blood. Each of these factors was associated with a 10% to 25% increased risk of fractures. These associations were independent of traditional risk factors for hip fractures.ConclusionSeveral factors associated with older age help to explain how “aging” may be associated with the risk of hip fractures. These same factors may also explain the high risk of mortality following hip fractures.     

Causal Relationship of Susceptibility Genes to Ischemic Stroke: Comparison to Ischemic Heart Disease and Biochemical Determinants

Interrelationships between genetic and biochemical factors underlying ischemic stroke and ischemic heart disease are poorly understood. We: 1) undertook the most comprehensive meta-analysis of genetic polymorphisms in ischemic stroke to date; 2) compared genetic determinants of ischemic stroke with those of ischemic heart disease, and 3) compared effect sizes of gene-stroke associations with those predicted from independent biochemical data using a mendelian randomization strategy. Electronic databases were searched up to January 2009. We identified: 1) 187 ischemic stroke studies (37,481 cases; 95,322 controls) interrogating 43 polymorphisms in 29 genes; 2) 13 meta-analyses testing equivalent polymorphisms in ischemic heart disease; and 3) for the top five gene-stroke associations, 146 studies (65,703 subjects) describing equivalent gene-biochemical relationships, and 28 studies (46,928 subjects) describing biochemical-stroke relationships. Meta-analyses demonstrated positive associations with ischemic stroke for factor V Leiden Gln506, ACE I/D, MTHFR C677T, prothrombin G20210A, PAI-1 5G allele and glycoprotein IIIa Leu33Pro polymorphisms (ORs: 1.11 – 1.60). Most genetic associations show congruent levels of risk comparing ischemic stroke with ischemic heart disease, but three genes—glycoprotein IIIa, PAI-1 and angiotensinogen—show significant dissociations. The magnitudes of stroke risk observed for factor V Leiden, ACE, MTHFR and prothrombin, but not PAI-1, polymorphisms, are consistent with risks associated with equivalent changes in activated protein C resistance, ACE activity, homocysteine, prothrombin, and PAI-1 levels, respectively. Our results demonstrate causal relationships for four of the most robust genes associated with stroke while also showing that PAI-1 4G/5G polymorphism influences cardiovascular risk via a mechanism not simply related to plasma levels of PAI-1 (or tPA) alone.     

On the Additive and Multiplicative Models of Relative Risk

Two popular models of absence of synergism in epidemiologic cohort studies are analyzed and compared. It is shown that the statistical concept of the union of independent events that traditionally has given rise to the “additive” model of relative risk can also generate the “multiplicative” model of relative risk. In fact, the same set of approximating conditions can be used to generate both models, which suggests a lack of identifiability under the traditional approach. An alternate approach is proposed in this paper. The new approach does not require the assumption that background risk factors are independent from causal agents of interest. The concept of “dose additivity” is discussed.     

Comparative-biochemical analysis of lipids of blood serum lipoproteins of human and some animal species

Lipid composition of blood serum and total lipids of low density lipoproteins (LDL) and high density lipoproteins (HDL₂ and HDL₃) were studied in human (donors, patients with ischemic heart disease, bronchial asthma, chronic obstructive bronchitis, as well as with a combined pathology), in mammals predisposed to atherosclerosis (pig, rabbit) and resistant to atherosclerosis (rat, mink, Arctic fox), in birds (hen, pigeon), in teleost fish (white fish, pike-perch, pike, bream, burbot) and cartilaginous fish (sturgeon, housen). It has been established that the most enriched in lipids is the blood serum of animals, particularly of cartilaginous fish. Twice lower is the lipid content in blood serum of donors than of animals. However, in the vascular, bronchopulmonary, and combined human pathologies the lipid level rises statistically significantly. In human and in animals predisposed to atherosclerosis the main mass of lipid is located in LDL, whereas in animals resistant to this disease—in HDL. The ratio of the human lipid content in LDL/HDL increases from 1.4 (in donors) to 2.7 in pathological states—in ischemic heart disease and its combination with chronic obstructive disease. In animals, a decrease of this ratio is noted from 1.0 to 0.2 in cartilaginous fish. By the example of one taxon (fish) there is established a regularity that indicates that evolution of lipoproteins occurred with an increase of the lipid amount in the “younger” LDL and with a decrease of concentration of the “older” HDL.     

Risky cultures to risky genes: The racialised discursive construction of south Asian genetic diabetes risk

Type 2 diabetes within UK South Asian populations has increasingly become the focus of health science discourse. Growing rates across the globe have been a public health concern for a number of decades. Diabetes discourse has focused on lifestyle and a generalized idea of “cultural” factors as contributory factors. These have become part of what I identify as a South Asian diabetes “risk-package.” This risk formulation is extended to an additional genetic discourse which generates new causal explanations for this heightened “risk.” South Asian groups are already the subject of discursive, racialized risk constructions, which positions them as active owners of “risky culture.” The mobilization of genetic arguments repositions them as additionally passive owners of “risky genes.” I argue that the use of racial categories in genetic diabetes science, despite the relative uncertainty and ambiguity of scientific knowledge claims, is problematic and requires critical re-situating.     

Angiogenesis Inhibitor Bevacizumab Increases the Risk of Ischemic Heart Disease Associated with Chemotherapy: A Meta-Analysis

Concerns have arisen regarding the risk of ischemic heart disease with the novel antiangiogenic agent bevacizumab, a recombinant humanised monoclonal antibody to the vascular endothelial growth factor that is widely used in cancer treatment. Currently, the role of bevacizumab in ischemic heart disease is controversial. This meta-analysis was therefore performed to assess the overall risk of ischemic heart disease associated with the use of bevacizumab. The databases of PubMed, EMBASE and Web of Science were searched for English language studies of randomised controlled trials comparing bevacizumab with control therapy published through October 25, 2012. Summary incidence rates, relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of the included studies. A total of 4,617 patients from 7 randomised controlled trials were identified and included for analysis. Among those patients receiving bevacizumab, the summary incidence of ischemic heart disease was 1.0% (95% CI, 0.6%–1.4%). Patients treated with bevacizumab had a significantly increased risk of ischemic heart disease with an RR of 2.49 (95% CI, 1.37–4.52) compared with controls. In addition, both high doses and low doses of bevacizumab increased the risk of cardiac ischemia (low dose at 2.5 mg/kg per week: RR, 2.14 [95% CI, 1.09–4.19]; high dose at 5 mg/kg per week: RR, 4.81 [95% CI, 1.03–22.42]). Bevacizumab was also found to significantly increase the risk of cardiac ischemia in patients with colorectal cancer (RR, 2.13; 95% CI, 1.11–4.06) compared with controls. This meta-analysis shows the use of bevacizumab was associated with an increased risk of developing ischemic heart disease in colorectal cancer patients receiving this drug. Our conclusions are limited by the available data. Further evaluations of high-quality RCTs are needed.     

“Smart” Drug Carriers: PEGylated TATp-Modified pH-Sensitive Liposomes

To engineer drug carriers capable of spontaneous accumulation in tumors and ischemic areas via the enhanced permeability and retention (EPR) effect and further penetration and drug delivery inside tumor or ischemic cells via the action of the cell-penetrating peptide (CPP), we have prepared liposomes simultaneously bearing on their surface CPP (TAT peptide, TATp) moieties and protective PEG chains. PEG chains were incorporated into the liposome membrane via the PEG-attached phosphatidylethanolamine (PE) residue with PEG and PE being conjugated with the lowered pH-degradable hydrazone bond (PEG-HZ-PE). Under normal conditions, liposome-grafted PEG “shielded” liposome-attached TATp moieties since the PEG spacer for TATp attachment (PEG₁₀₀₀) was shorter than protective PEG₂₀₀₀. PEGylated liposomes are expected to accumulate in targets via the EPR effect, but inside the “acidified” tumor or ischemic tissues lose their PEG coating due to the lowered pH-induced hydrolysis of HZ and penetrate inside cells via the now-exposed TATp moieties. This concept is shown here to work in cell cultures in vitro as well as in ischemic cardiac tissues in the Langendorff perfused rat heart model and in tumors in experimental mice in vivo.     

La crise de la psychiatrie contemporaine 2ème partie: la reconquête du singulier

The first part of this article (PSN vol. 1, No 3 : 19–24) sets out to reveal the theoretical weakness and the practical constraints which burden present-day psychiatry, which is dominated by an excessive medicalization process in the absence of conceptions of normality and disease. In this second part, the authors reply to scientific reductionism purposing the development of a philosophical anthropology. A global approach to the human reality, which takes into account the biological, psychological, social and cultural dimensions, would enable a better understanding of the individual’s experience as well as of his dependence or autonomy on the environment. The individual’s different ways to experience social rules and values form the basis of “existential types” which will play different part in social and historical processes. Owing to biological and environmental factors, individuals prone to psychiatric disorders are unbendingly dominated by a single type of relationship to values: over-identification in manic-depressive disorders (“hypernomia”); weakness in schizophrenia (“hétéronomia”); under-identification in some personality disorders (“hyponomia”); and conflict in obsessive disorders (“idionomia”).     

Cardiovascular Disease in Women Update: Ischemia,Diagnostic Testing,and Menopause Hormone Therapy

ObjectiveThis update will address 3 areas specifically that are essential to improving cardiovascular outcomes for women.MethodsThe current literature has been reviewed and three important areas of cardiovascular care in women are highlighted. First is that even though women and men share many traditional risk factors for ischemic heart disease, several of these risk factors affect women disproportionately when it comes to CVD risk and events. There are also unique sex-specific risk factors for women and risk factors that are more common in women than in men. Adverse outcomes of pregnancy and hypertensive disorders of pregnancy are associated with an increased long-term risk of CVD and events. At menopause, cardiovascular risks increase, and lipids become unfavorable. Second is that diagnostic testing for ischemic heart disease presents different specificities and sensitivities between men and women and testing should be determined according to what is best and safest for women. Third is that currently, menopause hormone therapy is approved by the U.S. Food and Drug Administration for the treatment of vasomotor and genitourinary symptoms, prevention of osteoporosis, and estrogen replacement in the setting of surgical menopause, hypogonadism, or premature ovarian insufficiency. It is not recommended for the primary or secondary prevention of CVD and not recommended for women with high atherosclerotic CVD risk.ResultsCardiovascular disease (CVD) remains the most common cause of death in women in the United States despite tremendous improvements in cardiovascular care for men and women. The prevention of CVD in women with early detection and implementation of preventive therapies before atherosclerotic CVD develops is critical to improving outcomes for women.     

Sex differences in ischemic heart disease and heart failure biomarkers

Since 1984, each year, more women than men die of ischemic heart disease (IHD) and heart failure (HF), yet more men are diagnosed. Because biomarker assessment is often the first diagnostic employed in such patients, understanding biomarker differences in men vs. women may improve female morbidity and mortality rates.Some key examples of cardiac biomarker utility based on sex include contemporary use of “unisex” troponin reference intervals under-diagnosing myocardial necrosis in women; greater use of hsCRP in the setting of acute coronary syndrome (ACS) could lead to better stratification in women; and greater use of BNP with sex-specific thresholds in ACS could also lead to more timely risk stratification in women.Accurate diagnosis, appropriate risk management, and monitoring are key in the prevention and treatment of cardiovascular diseases; however, the assessment tools used must also be useful or at least assessed for utility in both sexes. In other words, going forward, we need to evaluate sex-specific reference intervals or cutoffs for laboratory tests used to assess cardiovascular disease to help close the diagnostic gap between men and women.     

Prevalencia de obesidad y riesgo cardiovascular asociado en la población general de un área de salud de Extremadura. Estudio Hermex

Introduction and objectivesTo estimate the prevalence of obesity and its associated cardiovascular risk in the general population of a health area in Extremadura.Materials and methodsA cross-sectional study on a random population sample aged 25-79 years from the Don Benito-Villanueva (Badajoz) health area. Risk factors and cardiovascular disease were examined. Anthropometric and blood pressure measurements were collected, and a blood sample was taken. Obese subjects were categorized into different risk levels as proposed by the Spanish Society for the Study of Obesity, and the influence of obesity on estimation of the risk of ischemic heart disease was studied using the Framingham function, as adapted for Spain.ResultsA total of 2833 of the 3521 subjects screened (80.5%) participated in the study. Mean age was 51.2 years (SD 14.7), and 46.5% were males. Male subjects had a greater prevalence of overweight and obesity (46.2% and 37.7% respectively) as compared to females (37.7% and 32.6%) (p<0.005 and p<0.05 respectively). Only 10% of obese subjects had no increased cardiovascular risk. Obesity was associated to an 8-fold increase in the presence of a high risk for ischemic heart disease in females (p<0.001), as compared to a 1.4-fold increase in males (p=0.095).ConclusionsObesity is highly prevalent and affects, together with overweight, 74.1% of the population in an Extremadura health area. A vast majority of obese subjects have an increased cardiovascular risk, which is very marked for ischemic heart disease in females.     

<Emphasis Type="Bold">Personal Genomic Testing,Genetic Inheritance,and Uncertainty</Emphasis>

The case outlined below is the basis for the In That Case section of the “Ethics and Epistemology of Big Data” symposium. Jordan receives reports from two separate personal genomic tests that provide intriguing data about ancestry and worrying but ambiguous data about the potential risk of developing Alzheimer’s disease. What began as a personal curiosity about genetic inheritance turns into an alarming situation of medical uncertainty. Questions about Jordan’s family tree are overshadowed by even more questions about Alzheimer’s disease and healthy ageing. As a parent, Jordan is unsure whether to share these results and what it would mean for their children to learn about their genetic inheritance and potential future health. Furthermore, Jordan is unsure how to make sense of these reports in light of current knowledge of the risk factors for Alzheimer’s disease and in the absence of effective treatments or robust preventative guidelines.     

Coronary artery disease: Are men and women created equal?

Background: Ischemic heart disease in women is a difficult issue in cardiovascular medicine, mainly because of our lack of understanding of the early-stage mechanisms and symptoms. A better and earlier understanding of the pathophysiology of coronary artery disease (CAD) in women will enable us to detect ischemic heart disease earlier and prevent adverse clinical outcomes.Objectives: The aims of this article were to describe the phenomenon of ischemic heart disease in women, increase awareness of the difference between men and women in relation to ischemic heart disease, improve our understanding of the mechanisms that cause this difference, and identify new approaches for better and earlier detection and treatment of CAD in women.Methods: We conducted a search of the PubMed database for double-blind studies on the mechanistic pathways of CAD in women published in English within the past 10 years and epidemiologic studies published since 1970. Search terms included women and coronary artery disease and ischemic heart disease in women.Results: The literature search revealed 30 peer-reviewed articles pertaining to this issue. The incidence of CAD was markedly lower in women <60 years of age than in older women. After 60 years of age, the rate of CAD increased and reached the rate seen among men by the 8th decade of life. The gender difference in atherosclerosis in the coronary tree was particularly large in patients <55 years of age and remained large at older ages. The gender difference in the coronary bed was strikingly larger than in other vascular beds. Intensive risk-factor modification had a similar effect on plaque progression in both men and women. Coronary endothelial dysfunction appeared to be related to cardiovascular morbidity and mortality in women as well as in men, and because endothelial dysfunction could be modified, it appeared that the prognosis could be improved by appropriate management. A strong association was found between body mass index (BMI) and metabolic status, but only the metabolic syndrome was associated with CAD. Physical activity was independently associated with fewer risk factors, less CAD, and fewer adverse events in women; however, obesity was not associated with these outcomes.Conclusions: Results of the identified studies suggest that reduction of risk factors is a common approach to fighting heart disease in both sexes. It appears that for women, weight and BMI are not as important as previously thought, but physical exercise and fitness are very important and can change risk factors and clinical outcomes more than any other known intervention. Data suggest that global inflammation may play an important role in women and may predict cardiovascular outcome in women much better than the traditional risk factors that have been used and proved for men.     

Role of missense mutation (M235T) in the angiotensinogen gene in development of cerebral ischemia

Possible correlation of M/T polymorphism of angiotensinogen gene with risk of ischemic stroke and basic risk factors of cerebral pathology (levels of arterial pressure and blood cholesterol; presence of diabetes mellitus, coronary heart disease, or myocardial infarction in anamnesis; and stenosis of major cerebral arteries) was studied. It was shown that M/T polymorphic variants of angiotensinogen gene were factors determining neither clinical variant of cerebral ischemia development (acute ischemic stroke or chronic brain ischemia) nor formation of main risk factors of stroke.     

Pulmonary aspergillosis and endophthalmitis: complications of Cushing's syndrome.

Ischemic heart disease continues to be the leading cause of death among middle-aged people in industrialized countries. However, in North America the rates of death and disability from coronary artery disease (CAD) have declined, mostly because of a reduction of the main modifiable risk factors (high serum cholesterol levels, smoking and hypertension). Intervention trials have consistently shown that the lowering of the severity of risk factors decreases the incidence of CAD. These studies have introduced the goals of preventive cardiology to clinicians but have not provided the necessary knowledge and skills to achieve them. Unfortunately, with the exception of hypertension, the risk factors for CAD are infrequently assessed and managed in ambulatory patients. Incorporation of detection and intervention strategies derived from recent epidemiologic, behavioural and biomedical research into the existing primary health care system may be the most efficient and effective approach to further reducing the impact of CAD. The family physician''s office is the ideal location to implement behavioural change strategies. However, primary care intervention to decrease the risk of ischemic heart disease among people at high risk has yet to be studied. In addition, whether the same clinicians who render primary care can assume the responsibility for surveillance and preventive care has to be demonstrated.