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Peroxisome proliferator activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. The PPAR subfamily consists of three members: PPARα, PPARγ, and PPARβ/δ. Fibrates are acting via PPARα, and they are used as lipid-lowering agents. PPARγ agonists reduce insulin resistance and have been used in the treatment of type 2 diabetes. As the knowledge of the pleiotropic effects of these agents advances, further potential indications are being revealed, including a novel role in the management of cardiovascular disorders (CVD). PPARα/γ dual agonists are currently under development and hold considerable promise in the management of type 2 diabetes and provide an effective therapeutic option for treating the multifactorial components of CVD. Several experimental and clinical evidences elucidated the beneficial effects of PPAR ligands in prevention and treatment of various CVD. However, PPARα and PPARγ agonists have been shown to be proinflammatory and proatherogenic in a few studies. Further, PPARγ ligands have been noted to be involved in the pathogenesis of congestive heart failure. These controversial results obtained from a few studies created further complication in understanding the role of PPARs. The function of PPARδ and its potential as a cardiovascular therapeutic target are currently under investigation. The present review focuses on the merits and limitations of PPAR agonists with regard to their use in CVD.

The present study has been designed to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor (PPAR)α agonist, rosiglitazone, a PPARγ agonist and the combination of both fenofibrate and rosiglitazone in partial abdominal aortic constriction (PAAC)-induced pathological cardiac hypertrophy in rats. Rats were subjected to PAAC for 4 weeks to produce pathological cardiac hypertrophy. The fenofibrate (3 mg/kg day^–1, p.o.), rosiglitazone (3 mg/kg day^–1, p.o.) and the combination of both fenofibrate (3 mg/kg day^–1, p.o.) and rosiglitazone (3 mg/kg day^–1, p.o.) were administered 3 days before PAAC and continued for 4 weeks after PAAC. The development of cardiac hypertrophy was assessed in terms of measuring ratio of left ventricular (LV) weight to body weight (LVW/BW), LV wall thickness (LVWT), LV protein content and LV collagen content. Further, the collagen accumulation in left ventricle was analyzed using picrosirius red staining. Moreover, the cross-sectional area (CSA) of cardiomyocytes was assessed using hematoxylin and eosin staining and measured using a NIH Scion image analyzer. The PAAC produced cardiac hypertrophy by increasing LVW/BW, LVWT, LV protein content, LV collagen content and mean CSA of cardiomyocytes. However, treatment with fenofibrate and rosiglitazone either alone or in combination significantly attenuated PAAC-induced increase in LVW/BW, LVWT, LV protein content, LV collagen content and mean CSA of cardiomyocytes. The combination of fenofibrate and rosiglitazone was more effective in attenuating the PAAC-induced cardiac hypertrophy than either drug alone. Thus, it may be concluded that dual activation of PPARα and PPARγ may provide synergistic benefits in preventing the development of pathological cardiac hypertrophy.

Milrinone is a bipyridine phosphodiesterase inhibitor with positive inotropic and vasodilatory effects. As interest in longer term use of intravenous therapy increases, it becomes essential to monitor its plasma concentration owing to a narrow therapeutic range, an increased half-life in renal failure and toxicity associated with high levels. A high-performance liquid chromatography (HPLC) method with mass (MS) detection using a triple quadrupole mass spectrometer is presented. The method was compared with the UV/HPLC method and validated according to current international guidelines. Coefficients of variation of less than 7.5% were obtained across the therapeutic range and 18.3% at 2.4 ng/mL, the lower limit of quantitation. Plasma from 13 cardiac surgery patients receiving standard intravenous doses of milrinone were measured. Eight patients achieved therapeutic milrinone levels within 3-4 h post start of infusion, one was borderline sub-therapeutic and four patients achieved levels that were above the upper limit of the therapeutic range and potentially toxic. This method offers high sensitivity, is rapid, easy to use and requires minimal amount of sample. We believe this method could become the reference procedure for clinical monitoring of milrinone and help to improve the safety of the use of this drug in patients with cardiac failure.

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