In 1993, Roman et al.  showed that the peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist clofibrate reduced blood pressure in Dahl salt-sensitive rats on an 8% salt diet. Importantly, cessation of clofibrate caused a rebound of arterial pressure to baseline values, stressing that this was a direct and reversible effect. Subsequently, the same group and others have shown that in various models of salt-sensitive hypertension, both clofibrate and fenofibrate can prevent the development of a positive sodium balance or even reverse the sodium balance from positive to negative at a later stage [2–4]. There is also evidence that fenofibrate can reduce salt-sensitive hypertension in humans . The signalling route from PPARalpha via Cyp4a induces the production of the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (HETE), which appears to be required for this natriuresis . Salt-sensitive rodent models are listed in Table 1.
Moreover, rodent models of hypertension depending on activation of the renin–angiotensin system at normal salt intake such as angiotensin II infusion , reduced renal perfusion in the two-kidney one-clip model  or in abdominal aorta constriction between the left and right renal arteries  also show a fall in arterial pressure with fibrate treatment. Antihypertensive effects have also been reported at normal salt intake in the high-fat diet model of the metabolic syndrome wherever salt retention is also reversed . Similar observations have often been reported in the deoxycorticosterone acetate-salt model  and at normal salt intake in spontaneously hypertensive rats (SHR) . An overview of rodent studies with hypertension at normal salt intake is provided in Table 2.
So far so good; however, there are a number of observations, mostly to be found in Table 2, that do not fit easily into this picture. Fenofibrate would be expected to be ineffective whenever hypertension is induced in transgenic mice lacking PPARalpha. Alarmingly, however, PPARalpha-deficient mice show adverse effects of fenofibrate. This was first reported in 2007 in the thoracic aorta constriction (TAC) model of chronic pressure overload cardiac hypertrophy, diastolic heart failure and cardiac fibrosis . Actually, the authors were expecting beneficial effects because of pleiotropic effects of fenofibrate, but in the PPARalpha-deficient mice, fenofibrate aggravated myocardial fibrosis and lung edema and decreased survival without any effect on blood pressure. Soon after, another group reported that in double transgenic renin and angiotensinogen Tsukuba hypertensive mice (THM), fenofibrate further increased blood pressure, whereas PPARalpha-deficient THM mice (obtained by double crossing the two strains) were in fact protected against hypertension, myocardial fibrosis and atherosclerosis . Fenofibrate was also found to induce cardiac hypertrophy in mice lacking muscle ring finger-1 (MuRF1), an ubiquitin ligase and inhibitor of PPARalpha  that is essential in the setting of HETE, therapeutic regression of cardiac hypertrophy . In SHR, two more recent reports document adverse cardiac remodelling and hypertrophy, as well as fibrosis and oxidative stress even though arterial pressure was reduced [12,17]. Although there remains substantial unexplained heterogeneity in response to fibrates, it appears that setting of preexistent or stimulated left ventricular hypertrophy, fenofibrate can have unfavourable pleiotropic effects.
Studies with fibrates in humans show inconsistent results on blood pressure. A few smaller studies show a reduction in BP in dyslipidemic patients [18–20]. Larger and controlled studies failed to replicate this effect, however [21–25]. A study by Subramanian et al.  even showed an increase in BP after fenofibrate administration in healthy controls. Although many of the smaller, positive studies may suffer from confounding because of a lack of control group, an elegant cross-over study by Gilbert et al.  showed that there may only be a responsive subgroup in patients with salt-sensitive hypertension.
Clinical results in the primary and secondary prevention of cardiovascular events using fibrates show modest and heterogeneous, but overall positive results . It must be noted, however, that a substantial part of the evidence for clinical efficacy is from studies with clofibrate, which has been discontinued because of safety concerns . In accordance with animal studies, primary prevention – where there is little end-organ damage – has also been explored with positive results, though numbers-needed-to-treat are large .
It is not inconceivable that, similar to animals, there is only a subgroup of patients that will respond favourably to fibrates. More alarmingly, the above-mentioned preclinical results suggest that fibrates may be actually harmful in certain conditions. For these reasons, it is of great importance that exact indications and the nature of pleiotropic effects of fibrates are further specified.
In the current issue of the Journal of Hypertension, Castiglioni et al.  administered fenofibrate to stroke-prone SHR (SHRSP) on the so-called Japanese high-salt diet (1% NaCl in drinking water). Interestingly, in young SHRSP treated from 2 to 4 months of age, they found beneficial antifibrotic cardiac and renal effects with improved systolic and diastolic function and prevention of proteinuria of concomitant fenofibrate treatment. However, no experiments were performed in older SHRSP. As previously reported by this group, survival in male SHRSP on this high-salt diet is poor [31,32]. However, female SHRSP appears to have a longer survival and thus more opportunity to develop chronic cardiac and renal injury . In the context of the potential adverse effects of fibrates in the setting of preexistent target-organ damage, it would be interesting to start the high-salt diet at 6 weeks of age, but to delay initiation of fibrates to a later age in female SHRSP, for example, to 3 months of age, to probe whether the beneficial effects of fenofibrate on preexistent target-organ damage are then still present.
The authors are supported by the Netherlands Cardiovascular Research Initiative: an initiative supported by the Dutch Heart Foundation (CVON2014-11 RECONNECT).
Conflicts of interest
There are no conflicts of interest.
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