| 1 IntroductionAlthough the.etiology and pathogenesis of hypertension has not been elucidated,there are a variety of defined risk factors,including genetics,high sodium and low potassium diet,overweight and obesity,and long-term mental stress,etc.However,psychological pressure can not be analyzed quantitatively,which is different from high sodium and low potassium diet,overweight and obesity.And these methodological problems preclude the assessment of the causal relationship between mental stress and hypertension in epidemiology and prospective clinical study;it also results in the absence of mental stress treatment in the hypertension treatment guidelines.The therapy of hypertension includes non-and pharmacological treat?ments to control blood pressure.Both home and abroad hypertension treat-ment guidelines suggest that all of the hypertensive patients should start with non-drug therapy,except acute severe hypertensive patients.In our 2009 Edi-tion primary hypertension treatment guidelines,recommendations about non-drug treatments to alleviate mental stress including:keeping optimistic,reducing the psychological burden,overcoming suspicious psychology,cor-recting unhealthy personality,resisting adverse social factors,seeking psy-chological counseling,and receiving music therapy and self-training or qigong and so on.This is the first mention of music therapy in the world's,but there is no specific advice on music therapy.Recent studies have shown that music therapy can decrease the inci-dence of anxiety and depression,relieve the clinical symptoms of Parkinson disease,epilepsy and Alzheimer's disease,alleviate pain,pressure and anxi-ety during pregnancy and promote the repairation of cerebral injury.Systolic and diastolic blood pressure has been decreased significantly after 2 months of music therapy for patients over 50 years of age who have suffered from stage 1 hypertension.Our recent studies show that music therapy can improve the symptoms of anxiety in mice that suffer from the brain-derived neurotrophic factor(BDNF)gene mutations.BDNF mRNA and protein levels increased in multiple brain regions,and its molecular mechanism was that music therapy increased the expression level of mRNAof TrkB,the receptor of BDNF.Studies of the above suggest that music therapy for hypertension has theoretical and experimental evidence,but the mechanisms underlying its antihypertensive and protective effects on target organ damage remain unknown.Massive experimental and clinical evidence suggests that sympathetic excitability and RAS system activation play a central role in the pathogenesis of hypertension.Sympathetic nerve excitement can increase the release of catecholamines(adrenaline and norepinephrine),which work on the a receptor in the blood vessels,resulting in small arteries and small vein contraction,in-creasing the peripheral circulation resistance.While the release of catecholamines also act on the ?1 receptor in the heart,increasing the heart rate,myocardial contractility,blood volume,and blood pressure.The cardiomyocyte adrenergic receptor is a class of G protein-coupled receptors,including ?1,?2 and ?1 three subtypes.Although it is theoretically speculated that music therapy may play a role through the inhibition of sympathetic acti-vation,the effect of music therapy for the cardiomyocyte adrenergic receptors has not been reported.In summary,compared with the drug therapy of hypertension,music therapy is simple and economical,with no side effects and high compliance,so there is a potential clinical application prospects.However,there are still some major scientific questions that need to be solved urgently in this field:(1)Lack of evidence from large scale randomized clinical trials regarding the antihy-pertensive effects of music therapy;(2)Lack of standard in music therapy:Western classical music,such as Mozart's,was used in previous studies,but the compare of effects of different types of Western music is few.And the an?tihypertensive effects of Chinese and Western traditional music therapy are unknown;(3)The relative antihypertensive effect of music and drug therapy is unknown.(4)It is unclear that if music therapy and drugs have synergistic ef-fect on blood pressure;(5)Previous studies have only evaluated the antihy-pertensive effect of music therapy,but whether music therapy can improve the target organ damage of hypertension is unknown;(6)There's still no report for music therapy's effect on sympathetic nerve activity,the expression of adren-ergic a1,?1 and ?2 receptor subunits,the expression of Gq,GS and Gi,and intracellular PKC,PKA and PI3K signaling pathways so far,2 Objectives(1)To provide robust evidence of anti-hypertensive effects of music ther-apy in large sample patients by meta-analysis;(2)To study the effect of different types of music on reducing high blood pressure and attenuating myocardial hypertrophy;(2)To compare the relative and synergistic values of music therapy and drug therapy in SHR rats;(3)To investigate the molecular mechanisms underlying antihypertensive effects of music therapy in SHR rats.3 Methods3.1 Literature search and analysisAll literatures ragrading the relation between music and blood pressure were searched from Pubmed.Embase.Medline,Cochrane Central and Web of Science database.The inclusion criteria of selected papers were:(1)randomized clinical trials from 1985 to 2017;(2)study subjects were aged more than 18 years,and sample size ?30 cases;(3)systolic and/or diastolic blood pressure data available before and after music therapy;(4)definite history and blood pressure recording in patients with hypertension,who were taking or not taking anti-hypertensive drugs.A total of 397 literatures werefirst enrolled and finally only 13 papers satisfied all inclusion criteria and were used for meta-analysis.3.2 Animal modelsAnimal experiments in the present study were divided into three parts:Part I(n=60)Based on the different treatment,fifty male SHR rats aged 8 weeks were randomly divided into 5 groups(n=10 per group).The five groups were treated with no sound,noise,rock roll,Western classical music and Chinese classical music respectively.Ten male Wistar rats aged 8 weeks were needed as normal control group.Part II(n=50)Forty male SHR rats aged 8 weeks were randomly divided into 4 groups(n=10 per group)with the ten Wistar male rats were used as normal control group.Highly selective ?1 blocker bisoprolol was used for oral treatment.The control group received no drug,the low-dose bisoprolol group received bisoprolol(2.5mg/kg),the medium-dose bisoprolol group received bisoprolol(5mg/kg),and the high-dose bisoprolol group received bisoprolol(10mg/kg).All the rats were given normal diet during treatment.Part?(n=50)Forty male SHR rats aged 8 weeks were randomly divided into no treat-ment group(n=10),standard music treatment group(n=10),standard drug treatment group(n=10),standard music with drug treatment group(n=10).Ten male Wistar rats aged 8 weeks were used as normal control group with no treatment.3.2 EchocaardiographyA high resolution ultrasound imaging system for small animals(Vevo2100)was used.The left atrium,left ventricle,aorta and mitral valve leaflet were imaged from the parasternal long-axis view.The end-diastolic interventricular septal thickness and the left ventricular posterior wall thickness were meas-ured and the mean of the two measurements were taken as the mean left ventricular thickness by M-mode echocardiography.3.3 Systolic blood pressure measurementA noninvasive tail-cuff system was used for the measurement of systolic blood pressure before the experiment and at 0,3,5,8 and 10 weeks.Blood pressure was reported as a mean of 3 consecutive measurements.3.4 Musical selectionThe noise group was treated with 50-100 Hz irregular noise generated by high frequency noise generator.The rock group was treated with music that has been played since 1980s with a combination of loud and loud electroa?coustic instruments.Classical Chinese music group was treated with classical music from Qin,Han,Sui and Tang dynasties.Western classical music group was treated with Baroque music from classical and romantic period of the classical works of composers3.5 Music therapyThe rats were placed in five quiet,soundproof rooms,with music,noise,and no sound treatments after the basal blood pressure and weight were measured,The sound or noise generator was one meters away from the mouse cage and the volume was controlled at 50-60 decibels during the treatment.We broadcasted music or noise continuously during the period from 7:00pm to 7:00am per day(relative active time for rats)for 10 weeks.3.6 HistopathologyThe left ventricular myocardium tissue was collected and perfused with 4%paraformaldehyde solution to prepare the tissue for subsequent paraf-fin-embedded sections.HE and immunohistochemical staining was performed to study the mechanism underlying the therapeutic effects of music treatment on hypertension.4 Statistical analysisSPSS 16.0 software was used for Statistical analysis.The measurement data is expressed as mean ± standard error,and the count data is expressed as numerical value and percentage.One way ANOVA or LSD post-hoc analy-sis is used for comparison between multiple sets of variables.P<0,05 was considered to be statistically significant.5 Results5.1 Music therapy lowered blood pressure in a large sample of patients with hypertensionIn the 13 studies included in our meta-analysis,a total of 1063 patients were enrolled and the results showed that compared with control group without music treatment,music treatment significantly lowered both systolic blood pressure and diastolic blood pressure.5.2 Chinese classical music reduces,blood pressure in SHR ratsAfter 10 weeks treatment of no sound stimulation,noise,Chinese classi-cal music,Western classical music and rock music,it was found that noise and Western classical music basically had no effect on blood pressure in SHR rats,however,Chinese classical music and rock music significantly lowered both systolic and diastolic blood pressure,with Chinese classical music having the best effect.5.3 The antihypertensive effect of Chinese classical music was similar to medium dose bisoprololThe anti-hypertensive effects of Chinese classical music and medium dose bisoprolol were compared in SHR and it was found that both treatments had similar efficacy in lowering blood pressure in SHR.In addition,the combined use of Chinese classical music and medium dose bisoprolol showed a better effect on blood pressure reduction than either music or drug treatment alone,suggesting that there exists a synergistic effect between Chinese classical music and medium dose bisoprolol,and Chinese classical music therapy might be used as adjuvant therapy for drug treatment for hypertension.5.4 Chinese classical music inhibited left ventricular hypertrophy in SHR Our study showed that in comparison with SHR control group,Chinese classical music significantly reduced the thickness of left ventricular wall.Furthermore,the combined use of Chinese classical music and medium dose of bisoprolol significantly reduced the thickness of left ventricular wall than music or drug treatment alone,again suggesting a synergistic effect between Chinese classical music and medium dose bisoprolol in attenuating left ventricular hypertrophy.5.5 Chinese classical music therapy down-regulated the expressionlevels of ?1/cAMP/PKA and a1/PLC/PKC signaling pathway We measured the expression of ?1/cAMP/PKA signaling pathway,and found that the expression level of ?1/cAMP/PKA and a1/PLC/PKC signaling,but not ?2/PI3K/Akt signaling,was down-regulated significantly after Chinese classical music therapy.Furthermore,the combined use of Chinese classical music and medium dose of bisoprolol significantly down-regulated the expres-sion level of ?1/cAMP/PKA and a1/PLC/PKC signaling than music or drug treatment alone.6 Conclusion1.Our meta-analysis of 13 randomized clinical studies demonstrated a significant reduction systolic and diastolic blood pressure in patients with hy-pertension and anxiety;2.Chinese classical music and rock music remarkably lowered blood pressure in SHR with the Chinese classical music having the best effect among all types of music studied;3.The efficacy of Chinese classical music in lowering blood pressure in SHR was similar to medium dose bisoprolol and the two therapies had a syn-ergistic effect in this aspect.4.Chinese classical music inhibited hypertension-induced left ventricular hypertrophy and showed a synergistic effect with medium dose bisoprolol in attenuating left ventricular remodeling.5.Chinese classical music played an anti-hypertensive effect via down-regulating ?1/cAMP/PKA and a1/PLC/PKCsignaling pathways. |
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