LETTER TO THE EDITOR Chronotherapy beyond blood pressure reduction? To the Editor Although hypertension is one of the most highly studied topics of recent decades, the number of well-controlled hypertensive drugs is unacceptably low worldwide. The fact that up to 90% of the elderly develops high blood pressure (BP) challenges cardiologists to search for new drugs and approaches to improve the prognosis of this undesirable cardiovascular condition. The meta-analysis of large trials of antihypertensive treatments indicate that the Ôbeyond BP reductionÕ philosophy, considering the specific classes of drug therapy which offer benefits for cardiovascular disease prevention beyond BP reduction per se, was not justified, or at least, was not of such importance as expected [1]. Instead of tailoring the particular drug to particular patient, the precise BP control seems to be the principal therapeutic target. However, the potential benefit from achieving of optimal BP values does not exclude the possibility that treatment in addition to BP reduction could be of value. Several cardioprotectives were proved to be useful beyond their influence on the hemodynamic profile in the hyperten- sive population. The application of acetylsalicylic acid to standard antihypertensive treatments was shown to reduce morbidity when added to patients with diastolic hyperten- sion in the Hypertension Optimal Treatment study [2]. The Anglo-Scandinavian Cardiac Outcomes Trial indicated that the addition of a small dose of statin to hypertensive patients with increased cardiovascular risk provided additional therapeutic benefits independently of serum lipid level [3]. Furthermore, evidence is emerging that the circadian rhythmicity of the cardiovascular system plays an impor- tant role in several pathological conditions including hypertension [4]. The endogenous circadian pacemaker, located in the suprachiasmatic nuclei, imposes 24-hr rhythm on endocrine and autonomic mechanisms, influ- encing the normal daily rhythmicity of BP (e.g., higher BP during the daytime and a reduction during the night). It is known that nondippers are at a higher risk of cardiovas- cular events than the common population. Moreover, recently a published follow-up of almost 7500 patients for 10 yr indicated that increased nighttime BP is a better indicator of poor prognosis than daytime BP. Accordingly, recording the ambulatory BP during the entire 24-hr period seems to be necessary and the night BP/day BP ratio is important for both hypertension diagnosis and prognosis [5]. The aim is not only to normalize the mean 24-hr systolic and diastolic BP values, but to mimic the physiological 24- hr BP profile. It is reasonable to suppose that shifting from a nondipper to dipper pattern may improve the outcome of patients with an abnormal pattern of BP variability. There are two potential approaches which could indicate whether this consideration is correct. First, the time regimen of well-established antihypertensives could be modified according to physiological circadian variability of BP. An exciting and perhaps revolutionary trial, the Ambulatory Blood Pressure Monitoring and Cardiovascular Events (MAPEC) study, in 3000 adult hypertonics investigates whether chronotherapy influences the prognosis beyond the reduction of clinic-determined daytime or ambulatory BP monitoring-determined 24-hr mean BP levels [6]. The results achieved in 250 patients with resistant hypertension suggest that the precise timing of treatment for the achievement of desirable BP values and circadian BP pattern may be more important than just changing the drug combination [7]. Melatonin also should be considered for the treatment of elevated nocturnal BP. An evening rise in melatonin is an important part in suprachiasmatic nucleus-induced adap- tation to the rest and activity period. Nighttime melatonin secretion is decreased [8] and a lower ratio of night/day melatonin concentration is observed in nondippers [9]. Moreover, nighttime melatonin supplementation reduce nighttime BP in untreated hypertensive men [10], in nondipping women [11], in patients with nocturnal hyper- tension [12], and in adolescents with type 1 diabetes mellitus [13]. Along with melatonins reduction in BP per se, the strong antioxidant and scavenging effects of melatonin determined by receptor-dependent and -independent actions in both outside and inside the cell [14, 15] might attenuate the development of target organ damage associ- ated with an increased hemodynamic load. In addition to the MAPEC study, a large trial with melatonin in patients with an insufficient decline or even rise of nocturnal BP could help clarify the role of the restoration of the normal circadian BP pattern. The outcomes of these trials could substantially modify the daily schedule of hypertension treatment and might support the view that the 24-hr BP monitoring should become a method of choice for the diagnosis and control of hypertension treatment. Fedor Simko and Ludovit Paulis E-mail: fedor.simko@fmed.uniba.sk, ludo@lfuk.sk References 1. Williams B. Recent hypertension trials. Implications and controversies. J Am Coll Cardiol 2005; 45:813–827. 2. Hansson L, Zanchetti A, Carruthers SG et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hyperten- sion Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351:1755–1762. J. Pineal Res. 2008; 45:227–228 Doi:10.1111/j.1600-079X.2008.00575.x Ó 2008 The Authors Journal compilation Ó 2008 Blackwell Munksgaard Journal of Pineal Research 227