Peroxisome proliferator-activated receptors (PPARs) and their agonists for hypertension and heart failure: are the reagents beneficial or harmful?

Peroxisome proliferator-activated receptors (PPARs) alpha and gamma regulate nearly every step in cellular fatty acid uptake, utilization, oxidation, and storage pathways. They also control cell growth and migration, oxidative stress, and inflammation in the cardiovascular system. Recent studies have shown that PPARs have paradoxical effects on cardiovascular diseases, especially hypertension and heart failure. It is still unclear whether the blood pressure increases or decreases after treatment with a PPAR alpha agonist; it is also uncertain whether PPAR agonists are beneficial or harmful for heart failure. In order to clarify these issues, the literature on PPAR alpha and gamma and their agonists, as well as their effect on hypertension and heart failure not only in humans but also in experimental animals, was reviewed.     

A critical evaluation of the role of Lp(a) in cardiovascular disease: can Lp(a) be useful in risk assessment?

Lp(a) is a structurally complex particle which resembles LDL, but which also contains the distinctive glycoprotein apo(a). Apo(a) is characterized by a variable number of repeated kringle domains, which gives rise to differently-sized Lp(a) isoforms in the population. Although epidemiological studies indicate that elevated Lp(a) concentration and/or small apo(a) isoform sizes increase the risk of coronary heart disease (CHD), a causal role for Lp(a) in CHD remains unproven. This is largely due to the difficulty in establishing a relevant animal model to probe Lp(a) function, and the lack of intervention studies in which Lp(a) concentrations are lowered and outcomes followed. The accumulation of apo(a)/Lp(a) in arterial lesions has provided the rationale for numerous in vitro studies aimed at dissecting its function in this milieu. These studies have resulted in the proposal of numerous proatherogenic, prothrombotic and antifibrinolytic roles for both native and modified apo(a)/Lp(a). Although characterization of Lp(a) in the general population is not presently justified, Lp(a) analysis in patients at risk for CHD may be warranted.     

The role of IGF-I in the development of cardiovascular disease in type 2 diabetes mellitus: is prevention possible?

The incidence of peripheral, cerebro- and cardiovascular disease (CVD) in patients with type 2 diabetes mellitus is approximately twice as high as in the non-diabetic population. Conventional cardiovascular risk factors such as plasma lipids, lipoproteins and hypertension only partially explain this excessive risk of developing atherosclerosis and CVD. Meta-analysis of studies performed in non-diabetic populations indicates that the risk of CVD increases continuously with glucose levels above 4.2 mmol/l. The glucose hypothesis suggests that treatment which normalizes glucose levels prevents or delays the long-term complications of diabetes mellitus. However, the outcome of the UK Prospective Diabetes Study demonstrates that glucose control does not completely prevent CVD.In healthy subjects, serum IGF-I levels peak in early adulthood, after which they gradually decrease with increasing age. Several observations suggest that there is a premature and progressive age-related decline in serum IGF-I bioactivity in type 2 diabetics, which eventually results in a (relative) IGF-I deficiency. In type 2 diabetics, close relationships have been demonstrated between glycaemic control and serum IGF-I levels, with worse control being associated with lower IGF-I levels. Several studies (in non-diabetics) suggest that lowered circulating IGF-I levels account for a poor outcome of CVD. We previously observed in a population-based study that a genetically determined lowered IGF-I expression increases the risk of myocardial infarction with type 2 diabetes.This genetic approach overcomes the problem that cross-sectional studies cannot distinguish whether changes in IGF-I levels are a cause or a consequence of a disease. IGF-I is an important metabolic regulatory hormone. In addition, IGF-I suppresses myocardial apoptosis and improves myocardial function in various models of experimental cardiomyopathy. Compared with other growth factors, the 'survival' effect of IGF-I on myocardium seems rather unique.Therefore, we hypothesize that the premature and progressive decline in serum IGF-I bioactivity in ageing patients with type 2 diabetics is an important pathophysiological abnormality. It contributes not only to elevated glucose and lipid levels, but also to the progression and the poor outcome of CVD. If this hypothesis is proven to be right, treatment with IGF-I as an adjunct to insulin offers great potential and might not only improve metabolic control but also reduce the incidence and prevalence of CVD in type 2 diabetes patients. However, there is as yet no experimental evidence that long-term (replacement) treatment with IGF-I prevents, delays or reduces CVD in type 2 diabetes patients. Clinical trials are necessary to prove that long-term IGF-I treatment, preferably in the form of a better-tolerated IGF-I/IGF-binding protein-3 complex, improves the overall cardiovascular risk in type 2 diabetes.     

What is the role of angiotensin-receptor blockade in cardiovascular protection?

The role of angiotensin II, the key mediator of the renin-angiotensin-aldosterone system, in the pathophysiology of cardiovascular disease is well known. Pharmacologic interruption of the activity of angiotensin II, either through blockade of the angiotensin receptor or inhibition of angiotensin-converting enzyme, is associated with a reduction in cardiovascular disease morbidity and mortality, as evidenced by accumulated data from large-scale, well-controlled clinical trials in high-risk populations. As the underlying mechanisms of vascular disease and the effects of blockade of the renin-angiotensin-aldosterone system on these processes have been further defined, the therapeutic focus has begun to shift toward prevention of disease progression at earlier stages. Continued research has identified early signs of vascular disease, such as endothelial dysfunction and vascular and cardiac remodeling, which occur long before clinical manifestations of cardiovascular disease become evident. Diagnostic tests are now available to assess otherwise healthy individuals for these signs. A preliminary trial is under way to evaluate the role of angiotensin receptor blockade as preventive treatment of individuals with early signs of vascular or cardiac disease.     

Disease modification and cardiovascular risk reduction: two sides of the same coin?

Inflammatory rheumatic diseases are associated with a substantial increase in accelerated atherosclerosis, with complex interactions between traditional and disease-related risk factors. Therefore, cardiovascular risk reduction should be considered as integral to the control of disease activity in the care plans of patients with RA, SLE and, arguably any chronic inflammatory disease. Shared care structures, already established for the monitoring of DMARDs, could be adapted to communicate and monitor cardiovascular risk reduction objectives. We review the evidence for the efficacy of a range of therapeutic strategies, the majority of which impact on both disease activity and cardiovascular risk. The algorithm proposed here attempts to distil the latest advice from specialist panels at the National Cholesterol Education Program and the British Hypertension Society, as well as incorporating the existing data on SLE and RA patients. The algorithm is structured to minimize clinic time and resources necessary to stratify patients into groups for ROUTINE, SUBSTANTIAL or INTENSIVE risk management; the associated table summarizes optimal therapeutic objectives in each of these groups. The implication of this algorithm is that management of cardiovascular risk should be much more aggressive than is currently the norm in patients with chronic inflammatory diseases, such as RA and SLE. Long-term studies of such interventions are needed to further clarify the benefits of intensive cardiovascular risk management in these patients.     

A possible role of osteocalcin in the regulation of insulin secretion: human in vivo evidence?

Recent studies have indicated a novel function for skeleton unraveling its importance in the control of energy metabolism. In the present commentary, we speculate on the meaning for bone to act as a 'rheostat' modulating glucose metabolism, and how the primitive way of communication between bone and energy metabolism through switch on/off genes (like Ptprv) evolved to a more complicated 'talking' via gain/loss of hormones activity (like osteocalcin) by carboxylation/decarboxylation process.     

Coronary microvascular dysfunction due to essential thrombocythemia and policythemia vera: The missing piece in the puzzle of their increased cardiovascular risk?

Myeloproliferative neoplasms are most commonly associated with venous thrombosis. Up to 60% of patients experience a thrombotic event in their lifetimes, including stroke or myocardial infarction. It is unclear whether pathogenetic factors linking essential thrombocythemia (ET) and polycythemia vera (PV) to thrombotic complications do play a role in the risk of coronary artery disease (CAD). We aimed to assess coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic patients with ET and PV. Fifty‐two patients with ET (M/F 13/39, age 61 ± 7 years) and 22 patients with PV (M/F 13/9, age 60.4 ± 13 years) without clinical evidence of heart disease, and 50 controls matched for age and gender were studied. None had CAD. All control subjects were asymptomatic with no history of heart disease. CFR in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. In patients with ET and PV, CFR was lower than in controls (2.9 ± 0.94 and 2.2 ± 0.7 vs. 3.8 ± 0.7, P < 0.004 and P < 0.0001 respectively). The prevalence of CFR ≤ 2.5 was higher in patients with ET (20 cases, 38.5%) and PV (15 cases, 68.2%) compared with controls (4.1%) (P < 0.0001). Severe CFR (CFR < 2) impairment was found in eight patients with ET (15.4%), in nine patients with PV (40.9%), and in none of control subjects. The mutation of JAK2 gene was associated with abnormal CFR. Asymptomatic patients with ET and PV have coronary microvascular dysfunction in the absence of clinical conditions suggesting CAD. Am. J. Hematol. 90:109–113, 2015. © 2014 Wiley Periodicals, Inc.     

Defective mitochondrial biogenesis: a hallmark of the high cardiovascular risk in the metabolic syndrome?

The metabolic syndrome is a group of risk factors of metabolic origin that are accompanied by increased risk for type 2 diabetes mellitus and cardiovascular disease. These risk factors include atherogenic dyslipidemia, elevated blood pressure and plasma glucose, and a prothrombotic and proinflammatory state. The condition is progressive and is exacerbated by physical inactivity, advancing age, hormonal imbalance, and genetic predisposition. The metabolic syndrome is a particularly challenging clinical condition because its complex molecular basis is still largely undefined. Impaired cell metabolism has, however, been suggested as a relevant pathophysiological process underlying several clinical features of the syndrome. In particular, defective oxidative metabolism seems to be involved in visceral fat gain and in the development of insulin resistance in skeletal muscle. This suggests that mitochondrial function may be impaired in the metabolic syndrome and, thus, in the consequent cardiovascular disease. We have recently found that mitochondrial biogenesis and function are enhanced by nitric oxide in various cell types and tissues, including cardiac muscle. Increasing evidence suggests that this mediator acts as a metabolic sensor in cardiomyocytes. This implies that a defective production of nitric oxide might be linked to dysfunction of the cardiomyocyte metabolism. Here we summarize some recent findings and propose a hypothesis for the high cardiovascular risk linked to the metabolic syndrome.     

Microalbuminuria and C-reactive protein: Similar messengers of cardiovascular risk?

C-reactive protein (CRP) and urinary albumin excretion are both determinants of cardiovascular risk. The first is closely related to systemic and vascular low-grade inflammation, the latter is considered to be a marker of endothelial dysfunction. Because of these properties, one might presume them to be closely interrelated. In this article, we review the available evidence concerning the relationships of CRP and urinary albumin excretion, with each other and with other cardiovascular risk markers and factors. Should they be considered as dependent or independent risk markers, and which risk markers might be present in the cardiovascular risk estimation formula of the near future? The reasons that this formula might or should include CRP and urinary albumin excretion, rather than diabetes mellitus and the metabolic syndrome, are discussed.