Asif Anwar

Aging, Atherosclerosis, and IGF-1

Insulin-like growth factor 1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that circulates at high levels in the plasma and is expressed in most cell types. IGF-1 has major effects on development, cell growth and differentiation, and tissue repair. Recent evidence indicates that IGF-1 reduces atherosclerosis burden and improves features of atherosclerotic plaque stability in animal models. Potential mechanisms for this atheroprotective effect include IGF-1-induced reduction in oxidative stress, cell apoptosis, proinflammatory signaling, and endothelial dysfunction. Aging is associated with increased vascular oxidative stress and vascular disease, suggesting that IGF-1 may exert salutary effects on vascular aging processes. In this review, we will provide a comprehensive update on IGF-1s ability to modulate vascular oxidative stress and to limit atherogenesis and the vascular complications of aging.

IGF-1, oxidative stress, and atheroprotection

Atherosclerosis is a chronic inflammatory disease in which early endothelial dysfunction and subintimal modified lipoprotein deposition progress to complex, advanced lesions that are predisposed to erosion, rupture and thrombosis. Oxidative stress plays a crucial role not only in initial lesion formation but also in lesion progression and destabilization. Although most growth factors are thought to promote vascular smooth muscle cell proliferation and migration, thereby increasing neointima, recent animal studies indicate that insulin-like growth factor (IGF)-1 exerts both pleiotropic anti-oxidant effects and anti-inflammatory effects, which together reduce atherosclerotic burden. This review discusses the effects of IGF-1 in models of vascular injury and atherosclerosis, emphasizing the relationship between oxidative stress and potential atheroprotective actions of IGF-1.

Elevation of cardiovascular risk by non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently used medications. NSAIDs profoundly modify prostaglandin homeostasis through inhibition of the enzyme, cyclooxygenase (COX), especially COX-2. COX-2 inhibition is associated with adverse cardiovascular outcomes as demonstrated by recent trials using this type of drug. This review explores the latest available data, including recent, randomized, clinical trials, controversies, and pathophysiology of the adverse effects of COX-inhibition.

C-reactive protein is an independent predictor for carotid artery intima-media thickness progression in asymptomatic younger adults (from the Bogalusa Heart Study)

BackgroundConflicting information exists regarding the association between hsCRP and the progression of early stages of atherosclerosis. The purpose of the study was to investigate the association of high sensitiviy c-reactive protein (hsCRP) along with major cardiovascular (CV) risk factors on early carotid atherosclerosis progression in a large, population-based cohort study.MethodsThe study cohort included 839 young adults (aged 24 to 43 years, 70% white, 42% men) enrolled in Bogalusa Heart Study, who in 2001-2002 attended baseline examination with measurements of CV risk factors. Progression of carotid artery intima-media thickness (IMT) was assessed during a mean follow-up of 2.4 years.ResultsCarotid artery IMT progression rates were as follows: composite carotid artery = 9.2 ± 52 μm/y, common carotid artery = 0.0 ± 51 μm/y, carotid bulb = 8.8 ± 103 μm/y, and internal carotid artery = 18.9 ± 81 μm/y. Elevated baseline hsCRP, reflecting an inflammatory state, showed independent association with composite carotid artery IMT progression. Increased age, systolic blood pressure, fasting glucose, LDL cholesterol, and current smoking were other risk associates of carotid artery IMT progression in young adults, indicating an underlying burden on the CV system by multiple risk factors.ConclusionIn this population-based study, we observed independent categorical association of increased hsCRP with carotid artery IMT progression in young adults. This study underlines the importance of assesssing hsCRP levels along with smoking and traditional CV risk factor profiles in asymptomatic young adults.

AQ-13, an investigational antimalarial, versus artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria: a randomised, phase 2, non-inferiority clinical trial

Summary Background Chloroquine was used for malaria treatment until resistant Plasmodium falciparum was identified. Because 4-aminoquinolines with modified side chains, such as AQ-13, are active against resistant parasites, we compared AQ-13 against artemether plus lumefantrine for treatment of uncomplicated P falciparum malaria. Methods We did a randomised, non-inferiority trial. We screened men (≥18 years) with uncomplicated malaria in Missira (northeast Mali) and Bamako (capital of Mali) for eligibility (≥2000 asexual P falciparum parasites per μL of blood). Eligible participants were randomly assigned to either the artemether plus lumefantrine group or AQ-13 group by permuting blocks of four with a random number generator. Physicians and others caring for the participants were masked, except for participants who received treatment and the research pharmacist who implemented the randomisation and provided treatment. Participants received either 80 mg of oral artemether and 480 mg of oral lumefantrine twice daily for 3 days or 638·50 mg of AQ-13 base (two oral capsules) on days 1 and 2, and 319·25 mg base (one oral capsule) on day 3. Participants were monitored for parasite clearance (50 μL blood samples twice daily at 12 h intervals until two consecutive negative samples were obtained) and interviewed for adverse events (once every day) as inpatients during week 1. During the 5-week outpatient follow-up, participants were examined for adverse events and recurrent infection twice per week. All participants were included in the intention-to-treat analysis and per-protocol analysis, except for those who dropped out in the per-protocol analysis. The composite primary outcome was clearance of asexual parasites and fever by day 7, and absence of recrudescent infection by parasites with the same molecular markers from days 8 to 42 (defined as cure). Non-inferiority was considered established if the proportion of patients who were cured was higher for artemether plus lumefantrine than for AQ-13 and the upper limit of the 95% CI was less than the non-inferiority margin of 15%. This trial is registered at ClinicalTrials.gov, number NCT01614964. Findings Between Aug 6 and Nov 18, 2013, and between Sept 18 and Nov 20, 2015, 66 Malian men with uncomplicated malaria were enrolled. 33 participants were randomly assigned to each group. There were no serious adverse events (grade 2–4) and asexual parasites were cleared by day 7 in both groups. 453 less-severe adverse events (≤grade 1) were reported: 214 in the combination group and 239 in the AQ-13 group. Two participants withdrew from the AQ-13 group after parasite clearance and three were lost to follow-up. In the artemether plus lumefantrine group, two participants had late treatment failures (same markers as original isolates). On the basis of the per-protocol analysis, the AQ-13 and artemether plus lumefantrine groups had similar proportions cured (28 [100%] of 28 vs 31 [93·9%] of 33; p=0·50) and AQ-13 was not inferior to artemether plus lumefantrine (difference −6·1%, 95% CI −14·7 to 2·4). Proportions cured were also similar between the groups in the intention-to-treat analysis (28 of 33, 84·8% for AQ-13 vs 31 of 33, 93·9% for artemether and lumefantrine; p=0·43) but the upper bound of the 95% CI exceeded the 15% non-inferiority margin (difference 9·1%, 95% CI −5·6 to 23·8). Interpretation The per-protocol analysis suggested non-inferiority of AQ-13 to artemether plus lumefantrine. By contrast, the intention-to-treat analysis, which included two participants who withdrew and three who were lost to follow-up from the AQ-13 group, did not meet the criterion for non-inferiority of AQ-13, although there were no AQ-13 treatment failures. Studies with more participants (and non-immune participants) are needed to decide whether widespread use of modified 4-aminoquinolones should be recommended. Funding US Food and Drug Administration Orphan Product Development, National Institutes of Health, US Centers for Disease Control and Prevention, Burroughs-Wellcome Fund, US State Department, and WHO.

Vitamin C and percutaneous coronary intervention.

Percutaneous coronary intervention (PCI) is associated with a 15% to 35% incidence of periprocedural myocardial injury (PMI). Its spectrum ranges from obvious clinical myocardial infarction to subtle myocardial injury manifested by mild rises in cardiac enzymes. Even in the latter case, the

Management of Advanced Heart Failure Patients

The incidence of heart failure (HF) patients in the USA is estimated to be around six million, with half a million new cases adding each year) [1, 2]. It is associated with high symptom burden, frequent hospital admissions, diminished quality of life, high costs, and remains the leading cause of death in the USA [3, 4]. It is expected that 70–80 % of patients younger than age 65 will die within 8 years of their HF diagnosis, despite the availability of new medical and surgical options [2]. The evolution of HF in patients is typically characterized by acute crises or exacerbations followed by periods of stability lasting for months or even years. However, these patients are 6–9 times more likely to die of sudden cardiac death than the general population [2]. Several tools are available to help assess the prognosis in advanced HF patients: some are single-item predictors (such as the B-type natriuretic peptide [5], maximal oxygen consumption [6], creatinine level [7], other multivariable models (such as the Seattle Heart Failure Score [7] and the Acute Decompensated Heart Failure National Registry (ADHERE)) [8]. Similarly multiple prognostic factors are associated with increased likelihood of death in advanced HF, especially when coexistent: frequent emergency department visits or hospitalizations, symptoms at rest, dependency in activities of daily living, weight loss ≥ 10 %, albumin 2.5 g/dL, ejection fraction < 20 %, symptomatic arrhythmia, prior cardiopulmonary resuscitation, prior syncope, and embolic stroke. However, even while using these algorithms and other tools, life expectancy remains difficult to predict in advanced HF [3], and this is probably one of the reasons why less than 12 % of these patients benefit from hospice care [4].