Cardiogeriatrics: the current state of the art.

It is estimated that by 2050, 17% of the world's population will be greater than 85 years old, which, combined with cardiovascular disease (CVD) being the leading cause of death and disability, sets an unprecedented burden on our health and care systems. This perfect storm will be accompanied by a rise in the prevalence of CVD due to increased survival of patients with pre-existing CVD and the incidence of CVD that is associated with the process of ageing. In this review, we will focus on the diagnosis and management of common CVD conditions in old age, namely: heart failure (HF), coronary artery disease (CAD), atrial fibrillation (AF) and valvular heart disease (VHD). Despite limited evidence, clinical guidelines are increasingly considering the complexity of management of these conditions in the older person, which often coexist, for example, AF and HF or CAD and VHD. Furthermore, they, in turn, need specific consideration in the context of comorbidities, polypharmacy, frailty and impaired cognition found in this age group. Hence, the emerging role of the geriatric cardiologist is therefore vital in performing comprehensive geriatric assessment, attending multidisciplinary team meetings and ultimately considering the patient and the sum of their diseases in their totality. There have been recent advances in CVD management but how we apply these to deliver integrated care to the elderly population is key. This review article aims to bring together emerging studies and guidelines on assessment and management of CVD in the elderly, summarising latest definitions, diagnostics, therapeutics and future challenges.

CYP2C8 and SLCO1B1 Variants and Therapeutic Response to Thiazolidinediones in Patients With Type 2 Diabetes.

OBJECTIVE: Thiazolidinediones (TZDs) are putatively transported into the liver by OATP1B1 (encoded by SLCO1B1) and metabolized by CYP450 2C8 enzyme (encoded by CYP2C8). While CYP2C8*3 has been shown to alter TZD pharmacokinetics, it has not been shown to alter efficacy. RESEARCH DESIGN AND METHODS: We genotyped 833 Scottish patients with type 2 diabetes treated with pioglitazone or rosiglitazone and jointly investigated association of variants in these two genes with therapeutic outcome. RESULTS: The CYP2C8*3 variant was associated with reduced glycemic response to rosiglitazone (P = 0.01) and less weight gain (P = 0.02). The SLCO1B1 521T>C variant was associated with enhanced glycemic response to rosiglitazone (P = 0.04). The super responders defined by combined genotypes at CYP2C8 and SLCO1B1 had a 0.39% (4 mmol/mol) greater HbA1c reduction (P = 0.006) than the poor responders. Neither of the variants had a significant impact on pioglitazone response. CONCLUSIONS: These results show that variants in CYP2C8 and SLCO1B1 have a large clinical impact on the therapeutic response to rosiglitazone and highlight the importance of studying transporter and metabolizing genes together in pharmacogenetics.

Nucleus accumbens-specific interventions in RGS9-2 activity modulate responses to morphine.

Regulator of G protein signalling 9-2 (Rgs9-2) modulates the actions of a wide range of CNS-acting drugs by controlling signal transduction of several GPCRs in the striatum. RGS9-2 acts via a complex mechanism that involves interactions with Gα subunits, the Gß5 protein, and the adaptor protein R7BP. Our recent work identified Rgs9-2 complexes in the striatum associated with acute or chronic exposures to mu opioid receptor (MOR) agonists. In this study we use several new genetic tools that allow manipulations of Rgs9-2 activity in particular brain regions of adult mice in order to better understand the mechanism via which this protein modulates opiate addiction and analgesia. We used adeno-associated viruses (AAVs) to express forms of Rgs9-2 in the dorsal and ventral striatum (nucleus accumbens, NAc) in order to examine the influence of this protein in morphine actions. Consistent with earlier behavioural findings from constitutive Rgs9 knockout mice, we show that Rgs9-2 actions in the NAc modulate morphine reward and dependence. Notably, Rgs9-2 in the NAc affects the analgesic actions of morphine as well as the development of analgesic tolerance. Using optogenetics we demonstrate that activation of Channelrhodopsin2 in Rgs9-2-expressing neurons, or in D1 dopamine receptor (Drd1)-enriched medium spiny neurons, accelerates the development of morphine tolerance, whereas activation of D2 dopamine receptor (Drd2)-enriched neurons does not significantly affect the development of tolerance. Together, these data provide new information on the signal transduction mechanisms underlying opiate actions in the NAc.

Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes.

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

Genetic and gender determinants of cerebrovascular disease.

This article reviews genetic studies of stroke, bearing insight into human evidence by using studies on twins as well as on monogenic forms of stroke. Focus will be given to inbred animal models that have been used to improve genetic homogeneity and to control environmental influences. Such animal studies have lead to the identification of quantitative trait loci harboring putative genes for stroke susceptibility and sensitivity. The major strategies for gene identification are discussed. Experimental animal models of stroke have also revealed a sexual dimorphism in stroke susceptibility and sensitivity and this article reviews 2 possible candidates, namely, the Y chromosome and estrogens.