Prediction and classification of cardiovascular disease risk in older adults with diabetes.

AIMS/HYPOTHESIS: We sought to derive and validate a cardiovascular disease (CVD) prediction algorithm for older adults with diabetes, and evaluate the incremental benefit of adding novel circulating biomarkers and measures of subclinical atherosclerosis. METHODS: As part of the Cardiovascular Health Study (CHS), a population-based cohort of adults aged ≥65 years, we examined the 10 year risk of myocardial infarction, stroke and cardiovascular death in 782 older adults with diabetes, in whom 265 events occurred. We validated predictive models in 843 adults with diabetes, who were followed for 7 years in a second cohort, the Multi-Ethnic Study of Atherosclerosis (MESA); here 71 events occurred. RESULTS: The best fitting standard model included age, smoking, systolic blood pressure, total and HDL-cholesterol, creatinine and the use of glucose-lowering agents; however, this model had a C statistic of 0.64 and poorly classified risk in men. Novel biomarkers did not improve discrimination or classification. The addition of ankle-brachial index, electrocardiographic left ventricular hypertrophy and internal carotid intima-media thickness modestly improved discrimination (C statistic 0.68; p = 0.002) and classification (net reclassification improvement [NRI] 0.12; p = 0.01), mainly in those remaining free of CVD. Results were qualitatively similar in the MESA, with a change in C statistic from 0.65 to 0.68 and an NRI of 0.09 upon inclusion of subclinical disease measures. CONCLUSIONS/INTERPRETATION: Standard clinical risk factors and novel biomarkers poorly discriminate and classify CVD risk in older adults with diabetes. The inclusion of subclinical atherosclerotic measures modestly improves these features, but to develop more robust risk prediction, a better understanding of the pathophysiology and determinants of CVD in this patient group is needed.

Augmented age-associated innate immune responses contribute to negative inotropic and lusitropic effects of lipopolysaccharide and interferon gamma.

Innate immunity not only mediates early host defenses to infection, but also contributes to septic hemodynamic compromise through nitric oxide synthase (NOS2) induction and inhibition of cardiovascular adrenergic responses. Because of increased age-related susceptibility to sepsis, we hypothesized that hearts from old (28-29 months) adult rats would exhibit greater beta-adrenergic hyporesponsiveness than young (6-8 months) following lipopolysaccharide (LPS, 6 mg/kg) with and without interferon gamma (INF-gamma, 5000 units). LPS/INF-gamma depressed baseline +dP/dt and isoproterenol-stimulated inotropy in both old and young hearts. beta-adrenergic inotropic (+dP/dt) and lusitropic responses were more depressed in old v young LPS/INF-gamma hearts. Additionally isoproterenol-stimulated cAMP elaboration was less in old (1950+/-160 fmol/min/g) v young (2440+/-170 fmol/min/g, P=0.05) LPS/INF-gamma hearts. LPS alone also depressed basal +dP/dt and prolonged myocardial relaxation in old and young hearts, but suppressed isoproterenol +dP/dt responses only in old hearts. Depressed beta-adrenergic inotropic responses were augmented with the selective NOS2 inhibitor N-iminoethyl-L-lysine. To establish biochemical mechanisms for this, we tested whether induction of NOS2 and innate immune system receptors (CD14 and Toll-like receptor 4, TLR4) were enhanced in old v young hearts. Induction of myocardial NOS2 and CD14 (not present in control) by LPS/INF-gamma was approximately 2-3-fold greater in old compared to young animals. TLR4 was constitutively expressed in old and young hearts and was unaffected by LPS/INF-gamma. These findings indicate that advanced age is associated with augmented cardiac beta-adrenergic depression and enhanced CD14-NOS2 signaling in response to cytokines. Upregulation of cardiovascular innate immunity may have clinical implications for increased mortality in older individuals with systemic inflammatory response syndromes.

Upregulation of the nitric oxide-cGMP pathway in aged myocardium: physiological response to l-arginine.

Cardiovascular aging is associated with decreased endothelial vasoreactivity and prolonged diastolic relaxation. As diminished NO signaling contributes to age-associated endothelial dysfunction, we tested the hypothesis that impaired NO signaling or bioactivity also contributes to slowed ventricular relaxation with age. Accordingly, we measured myocardial NO synthase (NOS) enzyme activity, protein abundance, and cGMP production in old (22 to 25 months) and young adult (4 to 7 months) male Wistar rats. Both NOS3 protein abundance and calcium-dependent NOS activity were elevated in old compared with young adult hearts (7.2+/-1.1 versus 4.2+/-0.6 pmol/mg protein, respectively, P=0.03). However, NOS activity and protein abundance were similar in isolated myocytes, indicating that endothelial NOS likely explains the age difference. Cardiac effluent cGMP (enzyme immunoassay) was 4.8-fold higher (1794+/-373 fmol/min per mg heart tissue) in older versus younger hearts (P=0.003). To assess NO pathway responsiveness, we administered the NOS substrate l-arginine (100 micrometer) to isolated perfused rat hearts. Baseline isovolumic relaxation (tau) was prolonged in old (42.9+/-2.5 ms, n=16) versus young hearts (36.0+/-1.9 ms, n=11, P=0.03). l-Arginine decreased tau (P<0.001) and left ventricular end-diastolic pressure in both old and young hearts. Supporting an NO/cGMP-mediating mechanism, the NO donor sodium nitroprusside reduced tau (maximal effect, -14+/-2%, n=5, P<0.001), and this lusitropic effect was attenuated by the soluble guanylyl cyclase inhibitor 1H:-[1,2,4]oxadiazolo-[4,3,-a]quinoxalin-1-one (n=7, P<0.001). Thus, the NO-cGMP pathway is upregulated in the endothelial cells of aged hearts. l-Arginine, the NOS precursor, enhances ventricular relaxation in old and young hearts, indicating that the NOS pathway may be exploited to modulate diastolic function in aged myocardium.

Hypertrophic and restrictive cardiomyopathies in the elderly.

Congestive heart failure (CHF) increases with age, but most CHF in the elderly is due to diastolic dysfunction with preserved systolic function. The etiology, pathophysiology, diagnosis, natural history, and treatment of hypertrophic and restrictive cardiomyopathies in the elderly are discussed as a paradigm for CHF with normal systolic function. Hypertrophic obstructive and hypertensive hypertrophic cardiomyopathies are compared and contrasted. As an example of a restrictive cardiomyopathy, the various types of amyloidosis and their clinical import in older patients are covered.