Type 2 diabetes mellitus is a highly prevalent clinical condition that is frequently accompanied by an increase in blood pressure values, which are responsible for a further increase in the already elevated risk of cardiovascular events typical of this disease . The clinical relevance of the association between hypertension and diabetes was demonstrated by several intervention trials, which provided strong evidence on the important reduction in cardiovascular risk accompanying the successful treatment of high blood pressure in patients with diabetes [2–4]; a significant reduction in morbidity and mortality being reported in particular in those patients with hypertension and type 2 diabetes mellitus in whom tight blood pressure control could be achieved [2,4]. An aggressive and effective treatment of the arterial hypertension associated with diabetes is therefore strongly recommended, and, according to the 2003 European Society of Hypertension–European Society of Cardiology Guidelines for the management of arterial hypertension , a combination of pharmacological and non-pharmacological interventions is always required in these patients, aimed at achieving the demanding goal of reducing blood pressure values below 130/80 mmHg .
In recent years, a novel approach to the non-pharmacological treatment of hypertension has been proposed, consisting of device-guided breathing exercises aimed at obtaining a respiratory frequency as low as six breaths per minute (bpm). This is achieved through the use of an electronic device, termed the ‘RESPeRATE’ , capable of driving the breathing rate by means of sounds interactively-generated as a function of the patient's spontaneous breathing activity. Such an intervention was reported to be successful in reducing blood pressure if the achieved breathing frequency was less than 10 bpm at the end of the paced breathing exercises, scheduled on a daily basis for 10–15 min [6–10]. The mechanisms responsible for the blood pressure reduction following this intervention are multifold and are still poorly understood. Certainly, an important role is played by a the modulation of autonomic cardiovascular regulation, characterized by an increased parasympathetic and a reduced sympathetic activity, as documented by an increase in the sensitivity of baroreflex heart rate modulation during and after a paced slow breathing exercise [11,12]. Given the importance of autonomic imbalance among the factors involved in the development of hypertension , these autonomic changes could at least partly explain the concomitant blood pressure reduction.
The reported blood pressure-lowering effect of slow breathing exercise may also partly depend on the concomitant psychological relaxation induced by this intervention. A number of previous papers have suggested that stress reduction through non-pharmacological means [14–18], such as yoga or meditation practice, can successfully reduce blood pressure both in normotensive and hypertensive individuals. However, such studies have often been criticized for poor methodology. Device-guided breathing was developed to focus specifically on one potentially effective part of yoga and meditation practice, namely slow breathing, which could exert its blood pressure-lowering effect through both a central relaxing effect and an improvement in the above-mentioned reflex mechanisms leading to a favourable modulation of peripheral vascular resistance . The RESPeRATE device was designed in order to make slow breathing exercise easy to perform. It includes a computer whose size is comparable to that of a common portable tape player; it is battery operated and is attached to headphones and to a thoracic belt with a breathing sensor. The device monitors the users' respiratory pattern, calculates inspiration and expiration times and synthetizes a two-tone melody, with one tone for inhalation and one for exhalation. The user synchronizes his/her breathing with the melody, and the device gradually prolongs the exhalation tone, guiding the user to a slower respiratory rate. The goal respiratory rate is less than 10 bpm, with prolonged exhalation, and the device automatically stores individuals' performance data from each session, being programmed to stop after 15 min of use.
The ability of the RESPeRATE device to lower blood pressure in hypertensive patients was addressed by a few studies over the past 10 years. Such studies have been identified by a search carried out on the Medline database, the Cochrane clinical trials database, the Cochrane reviews database and the Database of Abstracts of Reviews of Effects (DARE), using the key words ‘device-guided breathing’, cross-referenced with the keywords ‘hypertension’ and ‘cardiovascular disease’. The search was performed for the period from 1966 to August 2006. Seven published papers on device-guided breathing using the RESPeRATE device were found to date (Table 1). All studies provided evidence in favour of a blood pressure-lowering effect of slow breathing exercise, although to a different extent. One is a recent review of the topic, which used a single case report to illustrate the use of the device in practice . Two are small sample studies with a pre and postobservational design [7,9]. Two are larger prospective investigations, with a design similar to that of prospective matched case–control studies [6,10]. The final two studies are relatively large prospective randomized controlled trials [8,21]. Those studies had either no active control group or a control group that listened to music through a Walkman. Although one small observational trial found good results in patients with resistant hypertension, the above randomized clinical trials and case–control studies only enrolled uncomplicated and otherwise healthy individuals with treated or untreated blood pressures in the stages I and II range. No information on the ethnicity or the literacy levels of patients participating in the trials is available, because these variables are not reported in the publications, thus limiting the generalizability of the results. Despite these limitations, it appears that device-guided breathing is useful for some patients either as a primary treatment in stage I hypertension or as adjunctive treatment for those already taking antihypertensive medications with treated blood pressure values persisting in the stages I and II range. It remains unclear from the studies whether device-guided breathing has a major effect on systolic or on diastolic blood pressure. There is also no evidence that lowering blood pressure by this method improves health outcomes, although such an inference might be safely made, given that reducing elevated blood pressure levels implies reducing a major risk factor for adverse health outcomes. Finally, no information is yet available on the possible usefulness of device-guided breathing as an adjunctive treatment in hypertensive patients at high cardiovascular risk, such as those with known ischaemic heart disease, previous stroke, and chronic obstructive pulmonary disease. In particular, the effectiveness of this non-pharmacological treatment has never been specifically addressed in patients with high blood pressure and diabetes.
In this issue of the Journal of Hypertension, the paper by Logtenberg et al.  provides information aimed at filling this gap, by comparing the effects of slow breathing exercise on blood pressure and on quality of life with the effects of a ‘placebo’ (i.e. listening to various kinds of random music with a discman) in a group of 30 patients with type 2 diabetes mellitus and hypertension under antihypertensive drug treatment. This was performed according to a randomized, single blind, controlled trial design, over a period of 8 weeks. The control group listened to music and used no other therapeutic device. During the study, blood pressure was repeatedly measured in the clinic and at home, always using the same oscillometric automated blood pressure measuring device. The results are surprisingly negative, compared with those of the other studies published on the effectiveness of slow breathing exercise in a general hypertensive population. There was no significant difference in the systolic/diastolic blood pressure changes over time between groups, the office blood pressure reduction being on average −7.5/−1.0 mmHg in the intervention group and −12.2/−5.5 mmHg in the control group. No between-group differences were observed even when considering changes in home blood pressure values. Whether or not the target breathing frequency of 10 bpm was reached did not affect the blood pressure changes. There were also no significant changes in quality of life scores. The conclusions drawn by Logtenberg et al.  are that the effects of RESPeRATE on blood pressure and on quality of life were not significantly different from those found in the control group. In other words, breathing exercises guided by an electronic device do not seem to be able to reduce blood pressure in patients with type 2 diabetes mellitus, as measured both in the clinic and at home, to a greater extent than listening to music with a discman. The choice of listening to music with a discman as a placebo intervention in the control group was based on the reports by previous studies that listening to music can lower blood pressure, although this was in most cases shown in a perioperative setting or in patients undergoing endoscopic procedures [23–26]. Using music as a placebo in the control group thus enabled the study to differentiate between the blood pressure effects of listening to music itself (the RESPeRATE also produces musical tones) and the effects of reducing breathing frequency.
Overall, the authors' general conclusion was that this device appeared to be poorly suitable for clinical management of patients with hypertension associated with type 2 diabetes mellitus.
The results provided by Logtenberg et al.  are certainly of interest. However, the quite different conclusions reached in previous studies on a similar issue raise the question of what the reason for the negative results obtained in this paper might be. Certainly, use of music as a placebo makes the results of the present paper more convincing than those obtained in other studies that did not include a control group. Another possible reason for the discrepancy with the positive results obtained in previous papers is likely to be the focus on hypertensive patients with type 2 diabetes mellitus. Given the multifactorial nature of hypertension, it might well be that in type 2 diabetes mellitus patients other factors might be involved in explaining the blood pressure elevation compared with non-diabetic hypertensive individuals. This may be even more likely in the case of a longstanding association between diabetes and hypertension, which may affect the severity of hypertension as well as of its target organ damage, and might reduce the probability of its correction by non-pharmacological treatment.
An additional possible reason for the negative results of the paper is the possible occurrence of autonomic dysfunction in hypertensive patients with diabetes. As mentioned above, slow breathing exercise may at least partly exert its effects through an improvement in autonomic cardiovascular regulation. This may be more difficult to obtain in patients with diabetes. Neuropathy is an important complication of diabetes , caused at least partly by damage to the blood vessels that supply nerve fibres. The autonomic nerves are also commonly involved and although patients are initially asymptomatic, clinical evidence of early neural involvement is present in the majority of patients with diabetes, and may contribute to their adverse prognosis . The early occurrence of autonomic dysfunction in diabetes [29,30], which may further worsen the altered neural regulation typical of hypertensive patients [31,32], might thus have prevented the effects of slow breathing exercise on blood pressure from becoming manifest in the hypertensive patients with diabetes investigated by Logtenberg et al. , at least over the relatively short follow-up time set in their study (8 weeks).
The paper by Logtenberg et al., however, does not provide any information on such a possibility, although a few markers of autonomic dysfunction could easily be quantified. Among them is the albumin excretion rate, which was shown to correlate with deteriorating autonomic function in diabetes, and has been proved to be a reliable index of autonomic neuropathy in several studies [33,34]. The possible presence of microalbuminuria was, however, not investigated in the study. Similarly, and unfortunately, no measure of autonomic cardiovascular regulation, such as baroreflex sensitivity, was obtained in the study, either in the laboratory through conventional autonomic tests  or through modern techniques based on a computer analysis of spontaneous cardiovascular variability [29,32,36]. Thus, a possible relationship between the features of autonomic cardiovascular control and blood pressure response to breathing exercises can only be hypothesized, and remains an important issue still to be properly addressed in future papers.
A further possibility to consider while interpreting the results of the present study is that patients with type 2 diabetes mellitus might have had some degree of pulmonary disease, clinically not evident, as recently reported in cats with diabetes mellitus . This could contribute to explaining the difficulty in reaching the respiratory endpoint, and in order to exclude this possibility it would have been important also to include a control group of non-diabetic hypertensive patients.
Finally, and most importantly, in the study by Logtenberg et al.  only nine of the 15 patients in the intervention group (60%) were successful in lowering their breathing rates to the target of less than 10 bpm, in spite of the repeated instructions. Therefore, the question remains unanswered as to whether the failure to observe any effect on blood pressure is caused by a lack of efficacy of the device, or to the inability of the patients recruited to reach sufficiently low breathing frequencies. This on one hand may contribute to make RESPeRATE therapy less attractive for use in clinical practice in patients with type 2 diabetes mellitus, but on the other hand this finding may emphasize that in order to obtain clinically relevant results with this kind of non-pharmacological treatment, more efforts are needed to optimize patients' compliance with the prescribed intervention.
Two questions arise when considering the results of the paper by Logtenberg et al. : (i) was the respiration-pacing device ineffective because it succeeded in reducing the respiratory rate only in a small number of type 2 diabetic patients with hypertension who were compliant with the breathing exercise? Or (ii) did these patients fail to experience any benefit in blood pressure reduction after the modulation of respiratory frequency because of their autonomic dysfunction or because of the concomitant presence of target organ damage?
No clear answer can be provided by the study results, and more research appears to be needed to investigate fully the effects of both music and breathing exercises on blood pressure. Based on the research questions raised by the present paper, possible areas of improvement in future studies aimed at addressing this issue again appear to be the following. First, in order to eliminate any observer or patient bias, an independent double-blind study design should be adopted, in which the intervention and the control groups should make use of the same device, with the only difference that in the intervention group the breathing frequency is paced towards lower values (< 10 bpm), whereas in the control group it does not. Second, breathing frequency before and during the follow-up should also be monitored in the control group. Third, information on patients' adherence to breathing exercises, on the minimum necessary number of sessions per week, and on the long-term effects should be collected. Fourth, some measure of autonomic cardiovascular regulation, such as arterial baroreflex sensitivity, should be obtained before and during the intervention, and, finally, data on target organ damage, such as microalbuminuria or carotid intima–media thickness, should also be collected during the follow-up. Until this information is available, caution is needed in drawing any final conclusion on the suitability and efficacy of slow breathing exercise in the clinical management of hypertensive patients with type 2 diabetes mellitus.
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