Differential Effects of Sound Intervention and Rest on Cardiovascular Parameters in Cancer Patients: A Randomized Cross-over Trial

Abstract

Background:

Music therapy or sound interventions were shown to confer beneficial effects in patients with cancer for instance in terms of pain or fear relief and improvement of other patient reported outcomes. Cardiovascular parameters, especially heart rate variability (HRV) were found to have prognostic implications in cancer patients. In this trial we aimed to investigate the effects of a sound intervention on cardiovascular parameters compared to rest in patients with cancer.

Methods and results:

Using a randomized cross-over design, 52 patients (male 13, female 39) with cancer were recruited to receive both a 15-minute sound intervention and a 15-minute rest intervention within 4 weeks with at least a one-week blanking period. Cardiovascular parameters (among others HRV, aortic pulse wave velocity [PWV], augmentation index [Aix], aortic blood pressure [BP], heart rate [HR]) were assessed immediately before (pre) and after (post) the intervention had taken place. HRV (Root mean square of successive RR interval differences [RMSSD, ms]) significantly increased, during sound intervention (median RMSSD pre 24 [range 5-112] vs post 22 [range 9-141], P = .03). Likewise, median PWV, as a direct marker of arterial stiffness, was significantly reduced by sound intervention ([m/s] pre 8.5 [range 5.6-19.6] vs post 8.3 [range 5.6-15.6], P = .04). For both parameters no statistically significant change during rest was observed. HR was lowered by both, rest (P < .0001) and sound intervention (P = .02), with a more pronounced effect by rest. A significant increase in systolic aortic blood pressure was shown by rest ([mmHg] median 101 [range 78-150] vs post median 103 [range 71-152], P = .04) but not during sound intervention (P = .59), while rest intervention led to a decrease in resistance index (pre median 33 [range 13-92] vs post median 32 [11-84], P = .02).

Conclusion:

In comparison with rest, a single sound intervention in patients with cancer improved cardiovascular parameters commonly associated with increased stress levels. Studies with longer follow-up and multiple interventions are warranted.

Trial Registration:

ISRCTN registry 70947363.

Keywords

cancer sound intervention rest heart rate variability aortic pulse wave velocity

Introduction

Music therapy is a practically based scientific discipline which interacts with various scientific fields, especially medicine, social sciences, psychology, musicology, and education.¹ The term “music therapy” describes the therapeutic use of music and sound addressing different aspects, such as physical (eg, pain, unpleasant sensations),² emotional (eg, depression, anxiety),^3,4 cognitive (eg, neurological impairments, confusion),^5,6 and social needs (eg, isolation, loneliness)^7,8 of patients. Due to beneficial effects on quality of life and patient reported outcomes, music therapy has gained importance in the field of palliative care.⁹ However, there is also a growing interest of music therapy as part of supportive care in cancer patients in general.^10,11

The diagnosis of cancer represents a challenging situation that is accompanied by a high degree of stress and fear. For this reason, the treatment focus is nowadays placed not only on cancer alone, but also on the emotional health of the patient as part of a holistic approach.¹² Stress is a major complaint in cancer patients. It affects the patient’s quality of life, and directly influences cardiovascular parameters through an increased sympathetic tone that can be objectively measured. This autonomic imbalance is associated with reduced heart rate variability (HRV) and increased arterial stiffness.^13,14 Positive effects of music therapy on HRV have been demonstrated in healthy individuals and patients with cancer.^15,16 However, it is unclear (i) to what extent music therapy or sound interventions influence other cardiovascular parameters as an expression of arterial stiffness and increased vascular tone and (ii) how this compares to structured rest periods. Thus, the present randomized cross-over trial study sought to investigate effects of sound intervention on different cardiovascular parameters compared to rest in patients with cancer.

Methods

Study Design and Setting

This randomized cross-over study was conducted at the Interdisciplinary Tumour Center, University Medical Centre Mannheim, University of Heidelberg, Germany. It was designed as a head-to-head comparison of music and rest intervention in patients with cancer. Recruitment started in November 2019 and ended in May 2020. Patients were not followed up (Figure 1, flow chart).

Figure 1.

Flow chart depicting the different phases of the randomized controlled trial.

The study was conducted according to the principles of the declaration of Helsinki and was approved by the local ethical committee, Medical Ethics Commission II, Faculty of Medicine Mannheim, University of Heidelberg, Germany (2019-736N). Data protection was in accordance with the EU Data Protection Directive.

Study Population

Patients with histologically confirmed cancer aged >18 years were included in the study. Exclusion criteria comprised acute myocardial infarction or stroke (within the past 30 days), cardiogenic shock, indication for aortocoronary bypass operation, known minimal heart rate at rest below 50 bpm, need for pacemaker stimulation, hypotension with systolic blood pressure <80 mmHg or uncontrolled hypertension with systolic blood pressure ≥180 mmHg, bilateral axilla dissection, Parkinson’s disease or tremor of other origin, and atrial fibrillation. Treatment with cholinergic agonists/ antagonists or autonomic modulators (eg, betablockers) was not an exclusion criterion.

Variables

Patients characteristics

Baseline demographic and clinical characteristics were acquired using clinical charts, and patients were asked to fill in a questionnaire, which collected information about the emotional state, legal stimulants and especially about the musical experience. Patients were asked whether they liked listening to music and whether they played an instrument.

The use of concomitant medication with possible influence on vascular function, such as betablocker, antihypertensive drugs (angiotensin converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB], calcium channel blocker) or statins was also documented, as well as treatment with analgesics or antidepressants.

Intervention

All patients received both, a 15-minute sound intervention and a 15-minute rest intervention as part of a cross-over design. Interventions were performed in lying position after a 10-minute resting period. In order to rule out a systematic bias, the sequence of intervention was randomized. The 2 interventions took place within 4 weeks with at least a one-week blanking period between the 2 interventions.

The sound intervention was performed with a body monochord called “Heaven and Earth” (http://klangkoerper.de/himmel-und-erde.html).¹⁷ This instrument consists of a semi-open resonance body with 29 strings (24 of those in C₁sharp, 2 in C₂sharp, 2 C₃sharp, and 1 in G₃sharp) and is an established method in everyday clinical practice for music therapy.^18,19 The monochord was placed on the chest during the intervention to ensure optimal transmission of the vibrations (Figure 2). The instrument was played for 15 minutes by one of the investigators in all patients (CR). Similarly, rest intervention was done in a lying position for 15 minutes after the 10-minute resting phase.

Figure 2.

Demonstration of a music intervention with the body monochord “Heaven & Earth.” The proband (DW) is examined in a supine position with the instrument placed on the lower chest/abdomen. The strings are stroked with fingers by the examiner (CR). Written consent was obtained from the persons in the photo (DW and CR).

Cardiovascular parameters

Cardiovascular parameters were assessed non-invasively using the VascAssist 2 device (inmediQ GmbH, Butzbach, Germany) after a 10 minute resting phase before and after each (music or rest) intervention. The duration of VascAssist measurement is about 10 minutes. VascAssist is an established oscillometric medical device for determining arterial stiffness, with good correlation to invasively measured values.^20-22 Four pneumatic cuffs were applied to both upper and lower arms. In addition to conventional vital parameters (heart rate [HR], blood pressure [BP]), the VascAssist provides aortic parameters, such as aortic pulse wave velocity (PWV) and aortic BP (both reflecting increased arterial stiffness up to end organ damage), and the augmentation index (Aix). Moreover, model-based parameters, such as resistance indices and systolic parameters are also calculated. An additional module provides HRV metrics (Root mean square of successive RR interval differences [RMSSD, ms]). HRV was also recorded in supine position over 10 minutes.

Analyses were performed offline with the VascViewer 2 software for Windows (iSYMED GmbH, Butzbach, Germany).

Of the described parameters, PWV and HRV are best established by substantiating data. PWV is a direct measure of arterial stiffness, whereby a value of >10 m/s is associated with an increased risk for cardiovascular events.^23,24 RMSSD as measure of HRV shows a large age-dependent range.^25-27 Higher values indicate increased HRV with better adaptability of the heart, whereby a value <20 ms is considered pathological.

Table 1 gives an overview of the cardiovascular parameters with an explanation of the characteristics that are measured.

Table 1.

Cardiovascular Parameters.

Parameter	Explanation	Normal values
Vitals
Heart rate (bpm)	Number of heartbeats per minute. Simple measure of cardiac function.	60-80 bpm
Brachial BP (mmHG)	Elevated values are associated with an increased risk of cardiovascular diseases.	120/80 mmHg
Heart rate variability
RMSSD (ms)	An increased HRV indicates a better adaptability of the heart	Large, age-dependent range.
RMSSD (ms)		A value <20 ms is considered pathological.
Resistance indices
Compliance index	Total elasticity of the conduction arteries.	0,1 (very stiff) to 0,8 (very elastic)
Resistance index	Total resistance in the conduction arteries, reflects permeability of the vessels.	Not available
Aortic impedance index	Model-based parameter, corresponds to cardiac afterload, measure of LV hypertrophy	100 (low afterload)-500 (high afterload)
Aortic parameters
Aortic BP (mmHg)	Central (aortic) BP (systolic/diastolic). Calibrated by brachial BP.	Under physiological conditions central BP should be lower than brachial BP.
Aix@75 (%)	Augmentation index, normalized to 75 beats per minute, non-specific marker for arterial stiffness.	Higher positive values indicate increased stiffness.
Aortic PWV (m/s)	Calculated from time difference between the first and second peak of the brachial pulse wave.	5 (elastic)-15 (stiff).
Aortic PWV (m/s)		A value of >10 m/s indicates probable end organ damage.
Systolic parameters
LVET (ms)	Left ventricular ejection time. Duration of systole.	200-380
LVPT (ms)	Left ventricular plateau time, model-based parameter, probably increased in LV hypertrophy. Often also conspicuous in aortic stenosis.	Not validated.
		0 (inconspicuous)-300 (conspicuous).
		A value >100 ms indicates increased preload
PRT (ms)	Radial pulse raise time.	80 (normal)-200 (very conspicuous)
PRT (ms)	Time between start of systole and first systolic peak. Increased values may indicate aortic stenosis (bilateral) or stenosis between aorta and wrist (unilateral).	80 (normal)-200 (very conspicuous)

Outcomes

Improvement of HRV and reduction of PWV as an expression of direct stress reduction served as primary outcome measure. The secondary outcome was any change in vital signs (heart rate, blood pressure). All cardiovascular parameters were assessed non-invasively using the VascAssist 2 device at baseline and after the rest and sound interventions. Analyses are conducted as pooled analysis between the 2 groups (sound and rest) and as intra-individual analysis for each individual study participant.

Statistical Analysis

Analyses were performed using SAS 9.4. (SAS Institute Inc., North Carolina) by a statistician blinded to patient identity (IB). Demographic variables and computed variables are summarized by descriptive statistics (median and range). Categorical variables are analyzed using absolute frequencies and percentages. All patients received 4 measurements of cardiovascular parameters at 2 different times, 1 before and after rest intervention and 1 before and after sound intervention. Descriptive analyses of cardiovascular parameters were performed by measurement time point (pre and post) and by intervention (rest and sound). In addition, grouped boxplots were generated for illustration. Intraindividual differences between both measurement time points as well as between both interventions were compared using Wilcoxon signed rank test. P < .05 was considered statistically significant. All analyses are of explorative nature. A sample size calculation was therefore not performed in advance.

Results

The study group consisted of 52 patients (pts) with a median age of 59 years (range, 28-83). Thirty-nine (75%) of the patients were female. The most common tumor types were breast cancer (18 pts, 35%), gastrointestinal tumors (8 pts [15%] colorectal cancer, 4 pts [8%] gastric cancer), and lung cancer (6 pts [12%]). Forty-six patients (89%) were receiving chemotherapy and 1 pt (2%) radiochemotherapy during the investigations. Twenty-three percent (12 pts) were treated with curative intention and 75% (39 pts) received palliative treatment. Four patients (8%) received no treatment during the study period. Concomitant medication included analgesics (13 pts, 25%) and antidepressants (7 pts, 14%). Six patients (12%) received betablocker, 9 pts (17%) ACE inhibitor/ARB while calcium channel blocker or statins were used in 5 pts (10%).

Twelve patients (23%) indicated to be actual smokers, 15 pts (29%) regularly drank alcohol and 46 pts (89%) had daily intake of caffeine either with coffee or black tea. Fifty-one of 52 patients (98%) reported that they enjoyed listening to music, with 19 (37%) of them very often consciously listening to music, 22 (42%) occasionally and 11 (21%) rather seldom. Twelve patients (23%) reported to actively play an instrument.

Baseline characteristics are displayed in Table 2.

Table 2.

Baseline Characteristics.

	Total n = 52	Rest-Sound (n = 26)	Sound-Rest (n = 26)
Sex, female (%)	39 (75.0)	18 (69.2)	21 (80.8)
Age (years)	59 (28-83)	63 (33-80)	57 (28-83)
Weight (kg)	68 (43-107)	68 (43-88)	68 (52-107)
Height (cm)	166 (152-189)	166 (152-189)	166 (155-186)
BMI (kg/m²)	24 (18-37)	23 (18-37)	24 (18-35)
Tumor type/ localization, n (%)
Breast cancer	18 (34.6)	7 (26.9)	11 (42.3)
Lung cancer	6 (11.5)	3 (11.5)	3 (11.5)
Stomach cancer	4 (7.7)	2 (7.7)	2 (7.7)
Colorectal cancer	8 (15.4)	5 (19.2)	3 (11.5)
Lymphoma	3 (5.8)	1 (3.8)	2 (7.7)
Sarcoma	2 (3.8)	1 (3.8)	1 (3.8)
Plasmocytoma	2 (3.8)	1 (3.8)	1 (3.8)
Ovarian cancer	2 (3.8)	2 (7.7)	—
Others	5 (9.6)	2 (7.7)	3 (11.5)
Oncological treatment, n (%)
Chemotherapy	46 (88.5)	21 (80.8)	25 (96.2)
Radiochemotherapy	1 (1.9)	1 (3.8)	—
None	4 (7.7)	3 (11.5)	1 (3.8)
Curative intention	12 (23.1)	5 (19.2)	2 (26.9)
Palliative treatment	39 (75.0)	20 (76.9)	19 (73.1)
Musical background, n (%)
Do you like listening to music? (yes)	51 (98.1)	26 (100)	25 (96.2)
How often do you listen consciously to music?
Very often	19 (36.5)	12 (46.2)	7 (26.9)
Occasionally	22 (42.3)	13 (50.0)	9 (34.6)
Seldom	11 (21.2)	1 (3.8)	10 (38.5)
Are you playing an instrument? (yes)	12 (23.1)	5 (19.2)	7 (26.9)
Legal stimulants, n (%)
Nicotine	12 (23.1)	5 (19.2)	7 (26.9)
Caffeine	46 (88.5)	24 (92.3)	22 (84.6)
Alcohol	15 (28.8)	8 (30.8)	7 (26.9)
Concomitant medication, n (%)
Betablocker	6 (11.5)	3 (11.5)	3 (11.5)
ACE inhibitor/ARB	9 (17.3)	6 (23.1)	3 (11.5)
Calcium channel blocker	5 (9.6)	4 (15.4)	1 (3.8)
Statin	5 (9.6)	4 (15.4)	1 (3.8)
Analgesics	13 (25.0)	10 (38.5)	3 (11.5)
Antidepressants	7 (13.5)	4 (15.4)	3 (11.5)
Change of concomitant medication during study, n (%)	8 (15.4)	4 (15.4)	4 (15.4)

Data are presented as median (range) or number (%).

Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; n, number.

Cardiovascular Parameters

All parameters assessed are depicted in Table 3.

Table 3.

Cardiovascular Parameters.

	Rest	Sound	P-value (Wilcoxon signed rank test)
Heart rate (bpm)
Pre	72 (45 to 99)	73 (52 to 98)	.47
Post	69 (47 to 96)	73 (49 to 98)	.79
Difference post-pre	−2 (−9 to 6)	−2 (−12 to 25)	.48
P-value	.0001	.02
Brachial systolic BP (mmHg)
Pre	116 (92 to 169)	117 (79 to 175)	.50
Post	116 (83 to 160)	117 (83 to 168)	.49
Difference post-pre	0 (−12 to 19)	−1 (−32 to 14)	.10
P-value	.58	.46
Brachial diastolic BP (mmHg)
Pre	70 (33 to 95)	69 (40 to 101)	.83
Post	69 (34 to 99)	70 (34 to 97)	.63
Difference post-pre	0.8 (−18 to 21)	0 (−13 to 20)	.86
P-value	.25	.88
RMSSD (ms)
Pre	22 (4 to 103)	24 (5 to 112)	.58
Post	25 (6 to 133)	22 (9 to 141)	.62
Difference post-pre	1 (−17 to 40)	3 (−14 to 29)	.20
P-value	.44	.03
Compliance index
Pre	0.4 (0.3 to 0.7)	0.4 (0.2 to 0.7)	.84
Post	0.4 (0.2 to 0.7)	0.5 (0.2 to 0.6)	.36
Difference post-pre	0 (−0.2 to 0.2)	0 (−0.2 to 0.2)	.49
P-value	.79	.22
Resistance index
Pre	33 (13 to 92)	35 (16 to 62)	.25
Post	32 (11 to 84)	32 (13 to 80)	.35
Difference post-pre	−2 (−28 to 26)	−0.3 (−15 to 28)	.33
P-value	.02	.20
Aortic impedance index
Pre	222 (149 to 361)	227 (159 to 518)	.44
Post	230 (141 to 514)	217 (158 to 440)	.43
Difference post-pre	−2.5 (−102 to 111)	−1.9 (−118 to 123)	.68
P-value	.83	.38
Aortic systolic BP (mmHg)
Pre	101 (78 to 150)	98 (68 to 162)	.50
Post	103 (71 to 152)	101 (68 to 159)	.58
Difference post-pre	1.5 (−11 to 24)	0 (−26 to 19)	.19
P-value	.04	.59
Aortic diastolic BP (mmHg)
Pre	71 (34 to 97)	70 (41 to 104)	.88
Post	71 (35 to 102)	71 (35 to 99)	.54
Difference post-pre	1 (−14 to 20)	−0.2 (−14 to 21)	.85
P-value	.30	.79
Aix@75 (%)
Pre	13.6 (−20.0 to 46.1)	10.5 (−17.8 to 47.7)	.68
Post	17.9 (−18.2 to 47.3)	12.7 (−14.8 to 45.5)	.73
Difference post-pre	1.2 (−8.3 to 13.7)	1.2 (−9.1 to 11.9)	.68
P-value	.003	.04
Aortic PWV (m/s)
Pre	8.2 (5.5 to 17.5)	8.5 (5.6 to 19.6)	.85
Post	8.2 (5.6 to 20.5)	8.3 (5.6 to 15.2)	.33
Difference post-pre	−0.1 (−1.3 to 3.0)	−0.2 (−4.5 to 1.8)	.55
P-value	.06	.04
LVET (ms)
Pre	254 (203 to 332)	252 (193 to 328)	.42
Post	261 (190 to 326)	258 (191 to 324)	.86
Difference post-pre	11 (−54 to 56)	7 (−18 to 54)	.82
P-value	<.0001	.0002
LVPT (ms)
Pre	35 (1 to 179)	34 (0 to 207)	.39
Post	56 (3 to 185)	41 (1 to 169)	.37
Difference post-pre	6 (−32 to 122)	3 (−120 to 89)	.14
P-value	.007	.32
PRT (ms)
Pre	0.1 (0.1 to 0.2)	0.1 (0.1 to 0.2)	.93
Post	0.1 (0.1 to 0.2)	0.1 (0.1 to 0.2)	.00
Difference post-pre	0	0	.56
P-value	.82	.70

Data are presented as median (range). Bold values mark statistical significance.

Aix@75, augmentation index standardized to a heart rate of 75 bpm (beats per minute).

Abbreviations: BP, blood pressure; LVET, left ventricular ejection time; LVPT, left ventricular plateau time; PRT, pulse raise time; PWV, pulse wave velocity; RMSSD, root mean square of successive difference.

Vitals

Neither rest nor sound intervention led to a change in brachial BP. A reduction in HR was observed, more pronounced for rest (P < .0001), but also for sound there was a median reduction of 2 beats per minute (P = .02).

HRV

In terms of HRV, we found that RMSSD was significantly increased during the sound intervention (P = .03). HRV remained unchanged during rest (P = .44).

Differences of RMSSD between rest and sound intervention for both total groups (a) and single individuals (b) are depicted in Figure 3.

Figure 3.

Graphical illustration of RMSSD (ms): (a) for both rest and sound intervention (grouped analysis) with boxplots for pre and post intervention, as well as the difference (post-pre) and (b) individual values for rest and sound intervention marked as line with change from pre to post.

Resistance indices

Neither aortic impedance nor compliance index were affected by rest or sound intervention. Resistance index on the other hand decreased only during rest (P = .02), but not during sound intervention.

Aortic parameters

Aortic BP remained unchanged during the sound intervention, while there was a median increase in systolic BP of 1.5 mmHg during the rest intervention (P = .04). Aix (normalized to a HR of 75 bpm) was increased by both rest (P = .003) and sound intervention (P = .04). The aortic PWV on the other hand was only influenced by sound. Here, a significant median reduction of 0.2 m/s was observed after only 1 intervention (P = .04). Changes of the PWV are shown in Figure 4.

Figure 4.

Graphical illustration of PWV (m/s): (a) for both rest and sound intervention (grouped analysis) with boxplots for pre and post intervention, as well as the difference (post-pre) and (b) individual values for rest and sound intervention marked as line with change from pre to post.

Systolic parameters

LVET as a measure of the systolic duration was extended by both rest (P < .0001) and sound (P = .0002), while extension of the LVPT was only observed during rest intervention (P = .007). Neither rest nor sound led to a change of the PRT.

Discussion

The present study investigated effects of sound intervention on cardiovascular parameters compared to rest in patients with cancer. Our main findings are:

1) Heart rate variability (HRV) metrics improved during sound intervention but not during rest periods.

2) Aortic pulse wave velocity (PWV) as a direct marker of arterial stiffness, was reduced only during sound intervention.

3) Heart rate (HR) was reduced by both rest and sound, with a greater effect during rest.

4) Rest intervention led to an increase in aortic BP and reduction of the resistance index.

The autonomic nervous system plays an important role, not only in a physiological setting, but also in various pathological settings, such as in cancer.^28,29 HRV has become widely used to quantify cardiac autonomic regulation,³⁰ with different methods used for this purpose. The root mean square of successive differences (RMSSD) is used to quantify short-term HRV and reflects the vagal-mediated autonomic control of the heart,³¹ while the low frequency-to-high frequency (LF/HF) ratio has been long considered as measure of cardiac sympatho-vagal balance, whereby an increase in LF/HF was assumed to reflect a shift to “sympathetic dominance” and a decrease corresponding to a “parasympathetic dominance.”³² However, this assumption had to be put into perspective, which is why the RMSSD is primarily used to assess HRV as a more robust parameter.³³

The RMSSD reflects the normal rhythmic fluctuations of the heart and is an indicator of the ability of an organism to adapt the HR to physical and mental demands. A high RMSSD value reflects a good adaptability, with a balanced regulation by the autonomic nervous system, while a rigid frequency and low RMSSD value indicate an enhanced sympathetic tone in response to a higher stress level.³⁴ A reduced HRV was associated with a shorter survival time in an analysis of over 600 cancer patients.³⁵ Furthermore, a meta-analysis found a prognostic impact of HRV in terms of survival in cancer patients.³⁶ Thus, the determination of HRV in cancer patients is not only of scientific interest but may have prognostic implications. A single 15-minute sound intervention led to a HRV increase of a median 3 ms in our study. This is in line with other study results, which also showed an increase in HRV with a decrease in sympathetic nervous system activity.^15,16,37 Since rest or a lying position could also influence the activation of the parasympathetic nervous system and thus HRV, all patients received both a rest intervention and a sound intervention, to rule out a systematic error. Although the rest intervention led to a more pronounced reduction in HR, no change in HRV was observed.

Whereas the stimulatory effect of the sympathetic nervous system on cancer initiation and progression has been well documented, the role of the parasympathetic tone is less well elucidated.³⁸ A possible protective effect of the parasympathetic nervous system was initially deduced from the reduced incidence of cancer in patients who received a vagotomy.³⁹ On the contrary, stimulatory effects have also been described, promoted by the cholinergic pathway.⁴⁰ However, the relationship between the sympathetic and parasympathetic nervous system is much more complex than previously supposed. The unidirectional idea that these are 2 antagonists has been largely abandoned. Instead, the ambiguity reflects the complex interplay.⁴¹ HRV measurement is thus a simplified approach to translate this complex system into a single value, which can be easily obtained.

In addition, both rest intervention and sound intervention led to an increase in Aix in our cohort, which is physiological due to the reduction in HR and therefore no indication of increased arterial stiffness.⁴² For the other parameters (LVET, LVPT) no clear trend was observed, whereas aortic BP was slightly increased by rest, while the resistance index declined. Whether this is actually an expression of increased tension (eg, due to ruminating thoughts in patients with cancer that could arise at rest) or a random observation cannot be answered on the basis of the available data. The median increase in blood pressure during rest therapy was only 1.5 mmHg in our cohort and is therefore not of clinical relevance. Whether this is a reproducible effect ought to be verified in a larger cohort.

In summary, a rest intervention does not seem to exert the same positive effects as a sound intervention does. This becomes particularly obvious when considering the PWV, which could be significantly reduced by the sound intervention exclusively. In cardiology, PWV is an important parameter in prevention and risk estimation.⁴³ A median reduction of 0.2 m/s, as achieved in our cohort, is therefore of clear relevance. An association between (emotional) stress and PWV as a cardiovascular risk factor and marker of arterial stiffness has been proven in several studies,^14,44,45 as well as a reduction in PWV in healthy individuals by listening to music.⁴⁶ Interestingly, this effect was as strong for listening to classical music as it was for rock music, while the sham procedure (no music) showed no effects.⁴⁶

Above all, the observed significant changes in HRV and PWV seem to be of scientific interest. However, as this study is an exploratory investigation with no correlation of the results to actual physical and psychological outcomes of the patients, we can only speculate about the clinical implications. Therefore, further studies are needed to substantiate and verify our findings.

Strengths and Limitations

In order to rule out a systematic bias, all patients received an intervention with both rest and sound, whereby the choice of which intervention to start with was randomized. Thus, pairwise comparisons could be performed to take into account intra-individual differences. The VascAssist is a validated method for determining established parameters such as vitals, PWV, Aix, or HRV. However, the VascAssist also computes other, less well validated parameters. Due to the scarce available data, an interpretation is only possible in the context of already established parameters. Certain drugs are vasoactive and can therefore influence the results of the cardiovascular parameters. Although concomitant medication was recorded, treatment with drugs such as cholinergic agonists/ antagonists or other autonomic modulators (eg, betablockers) was not an exclusion criterion for study participation. We used a single intervention in this proof-of concept study and did not collect follow-up data. Thus, we are not able to determine a potential long-term benefit. Further trials with repeated interventions and measurements as well as randomized trials using patient-reported and/or survival endpoints are warranted.

Conclusion

A single sound intervention in patients with cancer exerted beneficial effects on cardiovascular parameters, especially HRV and PWV. Both parameters indicate an impaired vascular function, due to an enhanced sympathetic tone, as in the context of chronic stress exposure. In comparison, these effects were not observed during a rest intervention, which suggests that sound interventions are capable of significantly reducing stress levels. Our data suggest, that sound intervention may have the potential to benefit cancer patients in terms of reducing stress levels and beneficial impact on the course of tumor diseases, and should therefore be studied further as a complement to conventional anti-cancer therapies.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Anna Hohneck

References

Chase

KM.

Multicultural music therapy: a review of literature. Music Ther Perspect. 2003;21:84-88.

Gutgsell

Schluchter

Margevicius

, et al. Music therapy reduces pain in palliative care patients: a randomized controlled trial. J Pain Symptom Manage. 2013;45:822-831.

Aalbers

Fusar-Poli

Freeman

, et al. Music therapy for depression. Cochrane Database Syst Rev. 2017;11:CD004517.

Guetin

Portet

Picot

, et al. Effect of music therapy on anxiety and depression in patients with Alzheimer’s type dementia: randomised, controlled study. Dement Geriatr Cogn Disord. 2009;28:36-46.

Zhang

Cai

, et al. Does music therapy enhance behavioral and cognitive function in elderly dementia patients? A systematic review and meta-analysis. Ageing Res Rev. 2017;35:1-11.

H-C

Wang

H-H

Chou

F-H

Chen

K-M.

The effect of music therapy on cognitive functioning among older adults: a systematic review and meta-analysis. J Am Medl Dir Assoc. 2015;16:71-77.

Schwantes

McKinney

Hannibal

Music therapy’s effects on levels of depression, anxiety, and social isolation in Mexican farmworkers living in the United States: a randomized controlled trial. Arts Psychother. 2014;41:120-126.

Mathew

Sundar

Subramaniam

Parmar

PN.

Music therapy as group singing improves Geriatric Depression Scale score and loneliness in institutionalized geriatric adults with mild depression: a randomized controlled study. Int J Educ Psychol Res. 2017;3:6.

Hilliard

RE.

Music therapy in hospice and palliative care: a review of the empirical data. Evid Based Complement Alternat Med. 2005;2:173-178.

10.

Stanczyk

MM.

Music therapy in supportive cancer care. Rep Pract Oncol Radiother. 2011;16:170-172.

11.

Stützlinger

Eisenmann

Laschkolnig

Mathis-Edenhofer

Pfabigan

RÄhrling

Krebs: Kann eine begleitende Musiktherapie zu besseren Behandlungsergebnissen beitragen. Themen-Check Medizin, Vorläufiger Basisbericht HT17. 2018;2:185.

12.

Carrieri

Peccatori

Boniolo

Supporting supportive care in cancer: the ethical importance of promoting a holistic conception of quality of life. Crit Rev Oncol Hematol. 2018;131:90-95.

13.

Reyes del Paso

Langewitz

Mulder

Van Roon

Duschek

The utility of low frequency heart rate variability as an index of sympathetic cardiac tone: a review with emphasis on a reanalysis of previous studies. Psychophysiology. 2013;50:477-487.

14.

Logan

Barksdale

Carlson

Rowsey

PJ.

Psychological stress and arterial stiffness in Korean Americans. J Psychosom Res. 2012;73:53-58.

15.

Chuang

C-Y

Han

W-R

P-C

Young

S-T.

Effects of music therapy on subjective sensations and heart rate variability in treated cancer survivors: a pilot study. Complement Ther Med. 2010;18:224-226.

16.

Zhou

Sui

Zhang

Wang

Music therapy on heart rate variability. Paper presented at: 2010 3rd International Conference on Biomedical Engineering and Informatics; Yantai, China; October 16-18, 2010.

17.

Sandler

Tamm

Fendel

Rose

Klapp

Bösel

Positive emotional experience: induced by vibroacoustic stimulation using a body monochord in patients with psychosomatic disorders: is associated with an increase in EEG-theta and a decrease in EEG-alpha power. Brain Topogr. 2016;29:524-538.

18.

Warth

Kessler

Koenig

Wormit

Hillecke

Bardenheuer

HJ.

Music therapy to promote psychological and physiological relaxation in palliative care patients: protocol of a randomized controlled trial. BMC Palliat Care. 2014;13:60.

19.

Gäbel

Garrido

Koenig

Hillecke

Warth

Effects of monochord music on heart rate variability and self-reports of relaxation in healthy adults. Complement Med Res. 2017;24:97-103.

20.

Baulmann

Weber

Mortensen

Messmethoden der arteriellen Gefäßsteifigkeit. Journal für Hypertonie-Austrian J Hypertens. 2010;14:18-24.

21.

Kraushaar

Dressel

Maßmann

Vascular robustness: the missing parameter in cardiovascular risk prediction. Prev Med Rep. 2018;9:107-113.

22.

Massmann

Stemler

Fries

Kubale

Kraushaar

Buecker

Automated oscillometric blood pressure and pulse-wave acquisition for evaluation of vascular stiffness in atherosclerosis. Clin Res Cardiol. 2017;106:514-524.

23.

Van Bortel

Laurent

Boutouyrie

, et al. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens. 2012;30:445-448.

24.

Williams

Mancia

Spiering

, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH). Eur Heart J. 2018;39:3021-3104.

25.

van den Berg

Rijnbeek

Niemeijer

, et al. Normal values of corrected heart-rate variability in 10-second electrocardiograms for all ages. Front Physiol. 2018;9:424.

26.

O’Neal

Chen

Nazarian

Soliman

EZ.

Reference ranges for short-term heart rate variability measures in individuals free of cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA). J Electrocardiol. 2016;49:686-690.

27.

Nunan

Sandercock

Brodie

DA.

A quantitative systematic review of normal values for short-term heart rate variability in healthy adults. Pacing Clin Electrophysiol. 2010;33:1407-1417.

28.

Walsh

Nelson

KA.

Autonomic nervous system dysfunction in advanced cancer. Support Care Cancer. 2002;10:523-528.

29.

Radin

Stone

Levine

, et al. Compassionate intention as a therapeutic intervention by partners of cancer patients: effects of distant intention on the patients’ autonomic nervous system. Explore. 2008;4:235-243.

30.

Electrophysiology TFotESoCtNASoP. Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation. 1996;93:1043-1065.

31.

DeGiorgio

Miller

Meymandi

, et al. RMSSD, a measure of vagus-mediated heart rate variability, is associated with risk factors for SUDEP: the SUDEP-7 Inventory. Epilepsy Behav. 2010;19:78-81.

32.

Pagani

Lombardi

Guzzetti

, et al. Power spectral density of heart rate variability as an index of sympatho-vagal interaction in normal and hypertensive subjects. J Hypertens. 1984;2:S383.

33.

Billman

GE.

The LF/HF ratio does not accurately measure cardiac sympatho-vagal balance. Front Physiol. 2013;4:26.

34.

Acharya

Joseph

Kannathal

Lim

Suri

JS.

Heart rate variability: a review. Med Biol Eng Comput. 2006;44:1031-1051.

35.

Guo

Koshy

Hui

, et al. Prognostic value of heart rate variability in patients with cancer. J Clin Neurophysiol. 2015;32:516-520.

36.

Zhou

Zhang

, et al. Heart rate variability in the prediction of survival in patients with cancer: a systematic review and meta-analysis. J Psychosom Res. 2016;89:20-25.

37.

Raglio

Oasi

Gianotti

, et al. Effects of music therapy on psychological symptoms and heart rate variability in patients with dementia. A pilot study. Curr Aging Sci. 2010;3:242-246.

38.

Faulkner

Jobling

March

Jiang

Hondermarck

. Tumor neurobiology and the war of nerves in cancer. Cancer Discov. 2019;9:702-710.

39.

Ekbom

Lundegårdh

McLaughlin

Nyrén

Relation of vagotomy to subsequent risk of lung cancer: population based cohort study. BMJ. 1998;316:518.

40.

Magnon

Hall

Lin

, et al. Autonomic nerve development contributes to prostate cancer progression. Science. 2013;341:1236361.

41.

Tibensky

Mravec

Role of the parasympathetic nervous system in cancer initiation and progression. Clin Transl Oncol. Published online August 8, 2020. doi:10.1007/s12094-020-02465-w

42.

Wilkinson

MacCallum

Flint

Cockcroft

Newby

Webb

DJ.

The influence of heart rate on augmentation index and central arterial pressure in humans. J Physiol. 2000;525(Pt 1):263.

43.

Ben-Shlomo

Spears

Boustred

, et al. Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects. J Am Coll Cardiol. 2014;63:636-646.

44.

Kong

Koh

Chang

, et al. Relationship between job stress and pulse wave velocity as a cardiovascular risk factor. Korean J Occup Environ Med. 2004;16:450-458.

45.

Vlachopoulos

Kosmopoulou

Alexopoulos

Ioakeimidis

Siasos

Stefanadis

Acute mental stress has a prolonged unfavorable effect on arterial stiffness and wave reflections. Psychosom Med. 2006;68:231-237.

46.

Vlachopoulos

Aggelakas

Ioakeimidis

, et al. Music decreases aortic stiffness and wave reflections. Atherosclerosis. 2015;240:184-189.