Cardiometabolic syndrome and chronic kidney disease: what is the link?

The term metabolic syndrome or cardiometabolic syndrome describes the clustering of several cardiovascular and renal risk factors, including type 2 diabetes mellitus, central obesity, hypertension, and dyslipidemia. Over the past 15 years, several studies have examined the association between the metabolic/cardiometabolic syndrome or its central component, insulin resistance, with the presence of elevated urine albumin excretion. Intrarenal changes associated with the cardiometabolic syndrome result in elevated glomerular filtration rate, impaired pressure natriuresis, endothelial dysfunction related to changes in nitric oxide and, hence, impaired renal autoregulation and enhanced chronic inflammation. The aforementioned changes that occur in the cardiometabolic syndrome all contribute to the development of renal injury. While this review focuses on the epidemiology and mechanisms associated with vascular/renal injury, it must be remembered that prevention and treatment of kidney disease require a multifactorial approach. Weight loss through diet and exercise can reverse many of these pathophysiologic adaptations. Pharmacologic intervention should be aimed at achieving guideline goals and include insulin sensitizers to aid in tight glycemic control, lipid control, blockade of the renin-angiotensin-aldosterone system for blood pressure reduction, and anti-inflammatory therapies.     

Myocardial myocyte remodeling and fibrosis in the cardiometabolic syndrome

Myocardial cellular and extracellular matrix remodeling are important in the development of left ventricular hypertrophy and are essential for the adaptive and maladaptive changes associated with the cardiometabolic syndrome. This brief review of myocyte remodeling also presents preliminary observational findings regarding myocardial adaptive hypertrophy remodeling, including an increase in mitochondria and capillaries, convolutions and lengthening of intercalated discs, the addition of sarcomeres, thickened Z lines, and the novel presence of pericapillary fibrosis (in addition to perivascular arteriolar fibrosis). The 11-week-old TG(mREN-2)27 transgene rat model of tissue angiotensin II overexpression, which develops hypertension and insulin resistance, was chosen to examine both myocyte hypertrophy and extracellular matrix fibrosis. This review and the preliminary observational findings may provide the clinician and researcher a better understanding of remodeling changes in the myocardium and ultimately foster earlier recognition and therapeutic interventions.     

Nebivolol in Obese and Non-Obese Hypertensive Patients

Use of β-blockers in hypertensive obese patients remains controversial because of concerns about potential influences on weight, lipids, and glucose metabolism. The authors examined a pooled analysis of 3 multicenter randomized placebo-controlled trials. Patients were randomized to placebo or an increasing dose of nebivolol for 12 weeks. Primary outcome was the mean baseline to end point change in trough mean sitting diastolic blood pressure (SiDBP). Secondary outcomes were baseline to end point changes in trough sitting systolic blood pressure (SiSBP); trough standing and peak supine diastolic blood pressure and systolic blood pressure. Nebivolol reduced SiDBP significantly compared with placebo at all doses ≥2.5 mg in obese and non-obese patients. Reductions in SiSBP with nebivolol were higher than controls at all studied doses ≥5 mg in non-obese and ≥2.5 mg in obese patients. These findings and nebivolol's neutral effects on lipid and carbohydrate metabolism suggest that it is one option for blood pressure control in the moderately obese population.     

Circulating bioactive androgens in midlife women

CONTEXT: It is important to characterize the biological activity of circulating androgenic steroid hormones during the menopausal transition because these appear to impact the metabolic and cardiovascular health risk factors of women. OBJECTIVE: The objective of the study was to develop and characterize a cell-based bioassay that measures the androgen receptor-mediated signal transduction in serum. DESIGN: This was a clinically relevant experimental study nested in a sample population of a longitudinal cohort study. SETTING: The study was conducted at a university laboratory. METHODS: A receptor-mediated luciferase expression bioassay based on HEK 293 cells that were stably cotransfected with plasmids containing the human androgen receptor and luciferase gene was developed. In 49 samples from menstruating women aged 42-52 yr, total testosterone (T) and SHBG concentrations were measured by immunoassay; free T concentrations were calculated from the total T and SHBG concentrations. RESULTS: Mean total T concentration of the sample was 1.15 nm (sd 0.46, range 0.57-3.86 nm). The mean bioactive androgen detected was 1.00 nm (sd 0.24, range 0.53-1.60 nm). Calculated free T (mean 0.0156 nm) was significantly lower than the levels of bioactive androgens measured by receptor-mediated bioassay. There was significant positive correlation between bioactive androgen levels and total T values in young women and polycystic ovarian disorder patients, whereas no correlation was found between the two values in middle-aged women. CONCLUSIONS: An androgen receptor-mediated bioassay can provide additional information in the evaluation of total bioactive androgens in midlife women. Our data suggest that levels of circulating SHBG may have a significant impact on the levels of total circulating bioavailable androgens.     

Stroke prevention in diabetes and obesity

Stroke is an important cause of morbidity and mortality, and is an economic burden. Diabetes and obesity are two important modifiable risk factors for stroke. Patients with diabetes have a higher incidence of stroke and a poorer prognosis after stroke. Risk-factor modification is the most important aspect of prevention of stroke in diabetes and obesity. This includes lifestyle modifications and different therapeutic modalities to control conditions, such as diabetes, hypertension, dyslipidemia and arrhythmia. Recent landmark studies have shown the beneficial effects of statins in diabetic patients even with close to normal or normal low-density lipoprotein cholesterol. Obesity, which is a risk factor for diabetes, hypertension and hyperlipidemia has been shown to be an independent risk factor for stroke. Increased leptin, dysregulation of adipocyte proteins, increased insulin resistance and C-reactive protein may be factors involved in the increased incidence of cardiovascular morbidity and mortality directly related to obesity. Visceral fat is a much bigger health risk than subcutaneous fat. Lifestyle interventions and pharmacotherapeutic agents have been used to manage obesity. In morbidly obese patients, surgical intervention seems to be the best method of treatment with a long-lasting favorable metabolic outcome. In the 21st Century, with the advanced medical knowledge and the therapeutic modalities available, it should be possible to reduce the incidence of stroke associated with diabetes and obesity.     

Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation

Transforming growth factor-beta (TGF-beta) plays a central role in the pathogenesis of inflammatory and fibrotic diseases, including radiation-induced fibrosis. We previously reported that mice null for Smad3, a key downstream mediator of TGF-beta, show accelerated healing of cutaneous incisional wounds with reduced inflammation and accumulation of matrix. To determine if loss of Smad3 decreases radiation-induced injury, skin of Smad3+/+ [wild-type (WT)] and -/- [knockout (KO)] mice was exposed to a single dose of 30 to 50 Gy of gamma-irradiation. Six weeks later, skin from KO mice showed significantly less epidermal acanthosis and dermal influx of mast cells, macrophages, and neutrophils than skin from WT littermates. Skin from irradiated KO mice exhibited less immunoreactive TGF-beta and fewer myofibroblasts, suggesting that these mice will have a significantly reduced fibrotic response. Although irradiation induced no change in the immunohistochemical expression of the TGF-beta type I receptor, the epidermal expression of the type II receptor was lost after irradiation whereas its dermal expression remained high. Primary keratinocytes and dermal fibroblasts prepared from WT and KO mice showed similar survival when irradiated, as did mice exposed to whole-body irradiation. These results suggest that inhibition of Smad3 might decrease tissue damage and reduce fibrosis after exposure to ionizing irradiation.     

C-reactive protein as a biomarker of emergent osteoarthritis

OBJECTIVE: We evaluated C-reactive protein (C-RP), a quantitative marker of the acute phase response, as a potential biomarker of prevalent and incident osteoarthritis of the knee (OAK). METHODS: Serum C-reactive protein concentrations were characterized with ultrasensitive rate nephelometry in a population-based sample of 1025 women (318 African-American and 707 Caucasian) who are enrollees in a study of musculoskeletal conditions at the mid-life. Assignment of OAK was based on Kellgren-Lawrence (K-L) scores of 2 or more on radiographs. Prevalent OAK was based on the baseline (1996) score while the classification of incident OAK was based on a score of 2 or greater at the follow-up examination 2.5 years later amongst those with a baseline K-L scores of 0 or 1. RESULTS: At baseline, the prevalence of radiographic OAK was 12% in participants who were aged 27-53 years and 18% in the subgroup of women aged 40-53 years. The mean C-RP value was 2.31 mg/L, with values ranging from below detection (0.3 mg/L) to 47.4 mg/L. Higher C-RP concentrations were associated with both prevalent and incident OAK (P < 0.0001, and P < 0.0001, respectively). For each K-L score increase from 0 to 3, there was a significantly higher mean C-RP value. Compared to women without incident OAK, women who developed OAK in the 2.5-year follow-up had significantly higher baseline C-RP concentrations. Women with bilateral OAK had higher C-RP concentrations than women with unilateral OAK (6.65 mg/L +/- 0.56 vs 3.63 mg/L +/- 0.42, P < 0.007). BMI was highly correlated with C-RP (r = 0.58) and obesity was an effect modifier with respect to OAK and C-RP concentrations. When stratified according presence or absence of OAK and obesity (BMI > 30 kg/m2), mean C-RP values were: obesity and OAK, 6.3 +/- 0.4 mg/L; obesity but not OAK, 4.3 mg/L +/- 0.2; no obesity but OAK, 1.7 mg/L +/- 0.8; and neither obesity nor OAK, 1.3 mg/L +/- 0.2 mg/L. These stratum means were significantly different from each other, indicating a higher C-RP with OAK after accounting for obesity. CONCLUSION: C-RP, as a measure of an acute phase response and inflammation, is highly associated with OAK; however, its high correlation with obesity limits its utility as an exclusive marker for OAK.     

Redox control of renal function and hypertension

Loss of redox homeostasis and formation of excessive free radicals play an important role in the pathogenesis of kidney disease and hypertension. Free radicals such as reactive oxygen species (ROS) are necessary in physiologic processes. However, loss of redox homeostasis contributes to proinflammatory and profibrotic pathways in the kidney, which in turn lead to reduced vascular compliance and proteinuria. The kidney is susceptible to the influence of various extracellular and intracellular cues, including the renin-angiotensin-aldosterone system (RAAS), hyperglycemia, lipid peroxidation, inflammatory cytokines, and growth factors. Redox control of kidney function is a dynamic process with reversible pro- and anti-free radical processes. The imbalance of redox homeostasis within the kidney is integral in hypertension and the progression of kidney disease. An emerging paradigm exists for renal redox contribution to hypertension.