Peripheral pulse harmonic analysis and its clinical application: A systematic review

Abstract

Introduction

Pulse harmonic analysis is a quantitative and objective methodology within traditional Chinese medicine (TCM) used to evaluate pulse characteristics. However, interpreting pulse wave data is challenging due to its inherent complexity. This study aims to provide a comprehensive review and comparison of existing human pulse wave harmonic analysis methods to elucidate their patterns and characteristics.

Methods

A systematic review of clinical research reports published from 1990 to 2021 was conducted, focusing on variations in harmonic characteristics across different medical conditions and physiological states. Keyword searches included terms related to analysis methods (e.g., "Pulse Spectrum," "harmonic analysis," "harmonic index") and measured indicators (e.g., "vascular response," "PPG," "Photoplethysmography," "aortic," "arterial," "blood pressure"). Supplementary research using PubMed's Mesh terms specifically targeted "Pulse wave analysis" within the methods and statistical analysis domain. Articles were filtered based on predefined criteria, including human participants and research related to pulse pressure or vascular volume changes. Conference papers, animal studies, and irrelevant research were excluded, with literature evaluation scales selected based on the retrieved research reports.

Results

Initially, 6487 research reports were identified, and after screening, 50 reports were included in the review. The analysis revealed that low-frequency harmonics increase following vigorous activity or sympathetic excitation but decrease during rest or parasympathetic excitation. Cardiovascular patients exhibited elevated first harmonics associated with the liver meridian, while diabetes patients displayed weakened third harmonics related to the spleen meridian. Liver dysfunction was linked to changes in the first harmonic, and cancer patients showed signs of liver and kidney yin deficiency in the first and second harmonics. These findings underscore the potential of harmonic analysis for TCM disease diagnosis and organ assessment. Moreover, individuals with conditions such as liver dysfunction, cancer, and gynecological disorders displayed distinct intensity patterns across harmonics one through ten compared to healthy controls, albeit with some variations. Heterogeneity in these studies mainly stemmed from differences in measurement methods and study populations. Additionally, research suggested that factors like blood circulation and cognitive activity influenced harmonic intensity.

Conclusions

In summary, this report consolidates prior research on pulse wave harmonics analysis, revealing unique patterns associated with various physiological conditions. Despite limitations, such as limited sample sizes in previous studies, the observed associations between physiological states and harmonics hold promise for potential clinical applications. This study lays a solid foundation for future applications of arterial wave harmonics analysis, promoting wider adoption of this analytical approach.

Graphical abstract

1. Introduction

Traditional Chinese medicine (TCM) is a widely practiced complementary and alternative medical system that has made significant contributions to modern medicine.¹ Within TCM, four diagnostic methods are employed to evaluate the condition of the human body: observation, listening and smelling, questioning, and pulse diagnosis. Pulse diagnosis, also referred to as pulse palpation or feeling, involves deducing the body's state by discerning the characteristics of the pulse waveform. For instance, a strong and gradually descending surging pulse may suggest an excess of internal heat, whereas a knotted pulse with irregular intervals could indicate stagnation of Qi (a vital energy concept in TCM) and blood.² Pulse diagnosis constitutes an essential facet of TCM, aiding practitioners in assessing an individual's overall health. This method entails the examination of pulse wave patterns, allowing for insights into the body's condition, and remains integral to the practice of TCM.

For thousands of years, TCM's pulse diagnosis has been documented in ancient texts such as the Huang Emperor's Canon of Eighty-One Difficult Issues (黃帝八十一難經 Huangdi Bashiyi Nanjing). According to this theory, signals within the pulse can offer valuable information about the state of internal organ systems. TCM practitioners leverage these pulse signals to discern fluctuations in the body's condition, establishing a vital foundation for disease diagnosis.

In recent decades, there has been a proliferation of pulse diagnostic instruments and pulse wave analysis systems designed to capture pulse waveform data.³ These devices employ diverse techniques, including laser-based sensors combined with fast Fourier transform (FFT) data analysis,⁴ fiber Bragg grating mechanisms with lever amplification,⁵ micro-electro-mechanical systems equipped with sensory arrays for recording pulse width information,⁶ as well as photoelectric and pressure sensors.^{7, 8, 9, 10} Additionally, Doppler ultrasonic devices have been employed to measure blood pressure waves and pulse signals at the wrist.^{11, 12, 13} These technological advancements have led to the creation of a variety of pulse diagnostic instruments that utilize different approaches for collecting pulse waveform data.

Despite the progress made in pulse diagnosis machines and analysis methods, there is presently no universally accepted standard for interpreting and gathering pulse data. As a result, we recognize the constraints within existing studies and have undertaken steps to compile and integrate prior research. In particular, we have presented a summary of pertinent studies on harmonics, which stem from pulse variations as detailed in Appendix I. This compilation can serve as a valuable reference for future researchers.

1.1. Pulse analysis based on TCM concepts

In the development of pulse diagnostic instruments and analysis techniques, principles from TCM have been incorporated. Noteworthy instances of such integration encompass the creation of a bi-sensing pulse diagnosis instrument, which integrates multiple detection positions,^{14, 15, 16} the design of a pulse measurement device equipped with piezoresistive sensors to gauge contact pressure and ascertain pulse depth based on the TCM concept of depth,¹⁷ the invention of a wearable device equipped with pressurizable airbags and adaptable pulse probes to align with the prescribed positions and depths according to the TCM concept,¹⁸ and the establishment of a pulse transducer and quantitative system rooted in Bayesian networks to establish a correlation between pulse waveforms and pulse types.¹⁹

The utilization of TCM-defined pulse detection positions and depths provides a contextual framework for interpreting pulse diagnosis and can enhance the overall efficacy of the diagnostic process. The following section introduces pulse analysis for disease detection, with a particular emphasis on the successful application and accumulation of knowledge in pulse spectrum analysis.

1.2. Pulse diagnosis instrument from China

In China, multiple research teams have successively published studies concerning pulse diagnosis devices. For instance, one group of researchers has introduced an approach that integrates pulse diagnosis devices with TCM diagnostic benchmarks. This approach focuses on analyzing the pulse patterns of individuals to evaluate the health status of vital organs like the heart, liver, spleen, lungs, and kidneys.²⁰ To enable real-time storage and analysis of pulse waveforms, the incorporation of sensors and an automated pressure mechanism for data acquisition and feature extraction from pulse waveforms can enhance the diagnostic capabilities of intelligent electronic pulse diagnosis devices.²¹

Another research team has developed a Chinese medicine pulse diagnostic device with a particular emphasis on pulse elements. This device incorporates sensors to collect comprehensive pulse pattern information aligned with TCM principles and precise identification of pulse points. The objective is to capture the essence of TCM's pulse diagnosis and promote its continuity and learning.²² Nonetheless, as pointed out by Chen in 2015, there are several existing challenges in the field of domestic Chinese pulse diagnosis research, including the absence of standardized quantitative criteria and obstacles to widespread clinical adoption.²³

1.3. Pulse analysis applied to detect disease

Pulse wave analysis has found applications in elucidating or forecasting the progression of various diseases, with diabetes being a particularly extensively researched subject.^{24, 25, 26, 27, 28, 29} As an illustration, a pulse acquisition system utilizing multiple independent pressure sensors demonstrated the ability to distinguish between patients with diabetes and healthy individuals with a notable classification accuracy of 90.2 %.³⁰

Pulse analysis has also been employed in the study of other diseases. For instance, Wei Jin developed a wrist pulse acquisition device known as Jin's pulse diagnosis (JPD) based on his over 40 years of clinical experience. JPD accurately identified cases of lung cancer in 78.13 % of instances by detecting the mechanical feedback of the radial pulse.³¹ Chronic conditions like diabetes, hypertension, nephropathy,^32,33 and cardiovascular disease³⁴ have also been predicted using pulse analysis. However, explaining the outcomes of these studies with a single theory is challenging due to variations in methodology.

1.4. The concept and application of the pulse spectrum analysis

Pulse spectrum analysis, pioneered by W. K. Wang, is a widely utilized technique for pulse diagnosis in clinical settings.^35,36 W. K. Wang and his research team uncovered associations between the vascular system of rats and harmonic components^37,38 and devised a model to expound upon these discoveries.³⁹ The model employs frequency domain analysis to extract harmonic attributes (n = 0∼10) from recorded pulse waveforms, encompassing parameters such as amplitude ratio (Cn), coefficient of variation of Cn (CVn), phase angle (Pn), and Standard Deviation (Pn_SD) (refer to Appendix I for definitions).^40,41 Each harmonic number corresponds to a specific viscera within the framework of TCM (refer to Table 1).^{41, 42, 43, 44}

Table 1.

The corresponding viscera of TCM in pulse harmonic analysis.

No	viscera	Function of viscera	N	viscera	Function of viscera
0	Pericardium	The pericardiac pattern is when warm evils invade the heart's outer covering and cause symptoms like clouded spirit, delirious speech, and agitation. There are two forms: heat entering the pericardium and phlegm-damp pattern clouding the pericardium, both considered heart diseases.	6	Gallbladder	The gallbladder's main function is to secrete bile, which is formed from an excess of liver qi.
1	Liver	The liver stores the blood, governs free coursing, governs the sinews, governs the making of strategies. It opens at the eyes and its bloom is in the nails. It governs fright and is averse to wind.	7	Bladder	The bladder holds the office of river island (or regional rectifier), stores fluid, and by qi transformation lets it out.
2	Kidney	The kidney governs water, stores essence, governs reproduction, is the root of early heaven, governs the bone and engenders the marrow, has its blood in the hair of the head, opens at the ears and at the anus and genitals. A principal function of the kidney is to turn fluids into urine for discharge by the bladder.	8	Large intestine	The large intestine is said to govern transformation and conveyance of waste. Since it absorbs further fluid from the waste, it is also said to govern liquid.
3	Spleen	The spleen is ascribed the function of assimilating nutrients from food in the Stomach to make qi, blood, and fluids.	9	San jiao	The San Jiao Channel (also known as the Three Burners) traverses all three burners, establishing connections with numerous organs.
4	Lung	The lung governs qi, regulating the waterways, and the exterior of the entire body.	10	Small intestine	The small intestine holds the office of reception, i.e., it receives grain and water that has been decomposed in the stomach. It transforms this food further, extracting nutrients for the body. It governs the transformation of matter and the separation of the clear turbid.
5	Stomach	The stomach is the place where food first collects after it enters the body before it passes to the intestines, and where it is broken down to enable its "essence" (nutrients) to be absorbed into the body.	11	Heart	The heart governs the blood and vessels, stores the spirit, and opens at the tongue. Its associated channel connects with the small intestine, which is its corresponding exterior organ.

Pulse harmonic analysis represents a non-invasive diagnostic methodology that scrutinizes particular harmonic characteristics to establish connections between pulse waveform patterns and physical conditions, clinical interventions, or diseases. This approach has garnered popularity due to its capacity to offer valuable insights into various health parameters and holds the potential to contribute to the formulation of tailored treatment plans for patients.

Pulse harmonic analysis has been employed by both researchers and clinical practitioners of TCM to explore physiological phenomena and TCM's meridian theory.⁴⁵ However, a disparity exists between TCM's pulse diagnosis theory and the concept of pulse harmonic analysis. In TCM's pulse diagnosis theory, the measurement position of the pulse wave, rather than the harmonics derived from a single waveform, is associated with the functions of various organs. Conversely, the theory of pulse harmonic analysis places significant emphasis on the harmonics derived from a single waveform, even in cases where multiple positions are not measured.⁴² This discrepancy from TCM's organ-based pulse diagnosis concept raises questions about whether the concept of harmonics aligns with physiological states as understood in TCM.

While the concept of viscera in TCM pulse diagnosis may differ from that in pulse harmonic analysis, research on arterial pulse harmonic analysis has yielded evidence connecting it to TCM, including acupuncture^{46, 47, 48} and herbal studies.^49,50 For instance, the effects of acupuncture at Leg Three Li (足三里 zù sān lǐ, ST-36) and Sunken Valley (陷谷 xiàn gǔ, ST-43), two adjacent acupoints on the stomach meridian, are reflected in similar harmonic patterns characterized by a decreasing trend in P5, the phase angle of the fifth harmonic (one of the harmonic properties mentioned above).^46,47 The fifth harmonic is believed to correspond to the stomach meridian, aligning with observations in pulse harmonic analysis studies, as demonstrated in Table 1. Acupuncture at the Great Ravine (太溪 tài xī, KI-3), an acupoint on the kidney meridian, has been shown to decrease the phase angle in the second harmonic, corresponding to the kidney meridian, as indicated in Table 1⁴⁸.

Research on herbal medicine also lends support to the connection between pulse analysis and TCM theory. For instance, the herbal formula Six-Ingredient Rehmannia Decoction (六味地黃丸 liù wèi dì huáng tang) was found to significantly increase C2 and C3 (the harmonic properties of the second and third harmonics, corresponding to the kidney and spleen, respectively, as shown in Table 1; refer to Appendix I for definitions). This formula is believed to replenish the effects of the kidney and spleen according to TCM theory.⁴⁹ Another study demonstrated that eight herbs associated with the spleen meridian, including Semen Lablab (白扁豆 bái biǎn dòu), Fructus Amomi Globosi (砂仁 shā rén), Rhizoma Atractylodis Macrocephalae (白朮 bái zhú), Tuber Pinelliae (半夏 bàn xià), Radix Codonopsitis (黨參 dǎng sān), Citri Reticulatae Pericarpium (陳皮 chén pí), and Polygonati Rhizoma (黃精 huáng jīng), increase the intensity of the third harmonic (C3), corresponding to the spleen, as shown in Table 1⁵⁰. With the support provided by acupuncture and herbal research, pulse harmonic analysis may serve as a diagnostic aid or research tool for clinical TCM practitioners and researchers.

Pulse harmonic analysis plays a prominent role in clinical TCM practice, enjoying widespread usage. Nevertheless, a substantial challenge arises from the scarcity of literature that effectively integrates diverse harmonic characteristics, which poses a significant hurdle to accurately interpreting analysis outcomes. This limitation ultimately impedes the cultivation of a holistic comprehension of the intricate relationship between pulse wave characteristics and various health conditions. Although an article offers a broad overview of the theory and applications of pulse harmonic analysis,⁴² it does not undertake a comprehensive comparison of harmonic properties. Consequently, there arises a pressing necessity to critically examine the current knowledge base and evidence regarding the comparative analysis of harmonic properties across the accumulating studies in the field of pulse harmonic analysis.

1.5. The purpose of this study

The absence of a comprehensive understanding regarding the interplay between pulse wave harmonic properties and various physiological conditions underscores the imperative for a systematic review. This review serves as a pivotal means to consolidate and synthesize the extant knowledge and evidence pertaining to pulse wave harmonic properties. Its overarching aim is to establish standardized principles for health assessment and disease diagnosis through harmonic analysis. This objective arises from the prevailing disparities in methodology and the divergences between TCM pulse diagnosis theory and the concept of pulse harmonic analysis. To address these limitations and controversies, this systematic review endeavors to undertake a thorough evaluation of existing research. It seeks to furnish a comprehensive examination of pulse wave harmonic properties across diverse contexts.

2. Materials and methods

2.1. Databases employed for the search

We conducted a thorough search across online research literature databases for articles published in English or Chinese. These databases encompassed the Pubmed database and the EBSCOhost Research Databases. Access to the EBSCOhost Research Databases is granted through an annual subscription, which includes a total of 82 databases. This comprehensive collection comprises both subscribed and freely accessible databases. Noteworthy databases within this compilation encompass MEDLINE, CINAHL, APA PsycTests, AgeLine, and others as elaborated in Appendix II. The scope of this study encompasses all databases housed within the EBSCOhost Research Databases.

2.2. Keywords employed for the search

In this study, two categories of keywords were employed: those associated with analytical techniques and those linked to measured parameters. The analytical methods keywords consisted of "Pulse Spectrum," "harmonic analysis," and "harmonic index," while the keywords for measured indicators encompassed "vascular response," "PPG," "Photoplethysmography," "aortic," "arterial," and "blood pressure." The search results encompassed literature containing at least one keyword from the analytical methods group and one from the measured indicators group. No exclusion keywords were utilized in this search. The search strategy was structured as follows: ((Pulse Spectrum) OR (harmonic analysis) OR (harmonic index)) AND ((vascular response) OR (PPG) OR (Photoplethysmography) OR (aortic) OR (arterial) OR (blood pressure)).

In addition, further research was conducted using MeSH terms in the PubMed database, focusing specifically on the domain of methods and statistical analysis. The keyword set for this search was "Pulse wave analysis." The search strategy was formulated as follows: ("Pulse Wave Analysis/methods"[Mesh] OR "Pulse Wave Analysis/statistics and numerical data"[Mesh]).

2.3. Selection criteria

The articles retrieved from the search results underwent a manual filtering process based on their titles and abstracts. Articles failing to meet the following predefined criteria were excluded from further consideration.

• 1.Human Research Participants: Articles that did not involve human participants were excluded.
• 2.Assessment of Peripheral Pulse Pressure or Vascular Volume Change: Articles lacking an investigation into peripheral pulse pressure or vascular volume change were excluded.
• 3.Conducting Spectrum Analysis for Pulse Pressure Fluctuations: Articles that did not perform spectrum analysis on pulse pressure fluctuations were excluded.
• 4.Linking Harmonic Wave Indices with Daily Activities or Clinical Phenomena: Articles that did not attempt to establish a connection between harmonic wave indices and daily activities or clinical phenomena following pulse wave spectrum analysis were excluded.

After an initial screening conducted based on the title and abstract, we proceeded to a more in-depth analysis by assessing the full-text articles. The exclusion criteria applied throughout the full-text evaluation were as follows.

• 1.Relevance: Articles that did not align with the study's objectives were excluded.
• 2.Animal Studies: Studies conducted on animals were excluded from the analysis.
• 3.Accessibility: Articles without online electronic documentation were excluded.

Additionally, conference papers and posters were omitted from the search results. These materials were excluded because they often represent preliminary findings or are subsequently expanded upon in more comprehensive published papers.

2.4. Snowball searching

Following the procedures described above, citation references were gathered and arranged into a list after screening titles, abstracts, and full texts. Subsequently, researchers were tasked with a systematic evaluation of the titles, abstracts, and full texts of documents in this list, applying the previously established criteria. This process aimed to identify relevant research literature for the current study focused on pulse wave harmonic analysis.

2.5. Assessment of the quality of the included studies

All the studies included in our analysis adhere to the criteria set forth by the Joanna Briggs Institute (JBI) critical appraisal tools. These tools encompass assessments for various study types, including randomized controlled trials (RCTs),⁵¹ quasi-experimental studies, cross-sectional studies, and cohort studies,⁵² as detailed in Appendix III. The primary responsibility for conducting the critical appraisal was carried out by K. Y. Hsiao, with other co-authors responsible for the subsequent verification process.

2.6. Data extraction

We retrieved harmonic analysis results from the research reports, including numerical values like Cn, CVn, Pn, and Pn_SD. Each of these numerical values was annotated to provide context and highlight their importance within the respective study. Following this, we structured this data into datasets corresponding to each research report. The initial data extraction was carried out by K. Y. Hsiao, with oversight and validation provided by other co-authors.

3. Results

3.1. Study description

In this study, we initially identified 2938 records from the Pubmed database, 2605 records from the EBSCO database, and 944 records via Mesh term searching. After eliminating 2620 duplicate records and excluding 3867 records that did not align with our selection criteria based on titles and abstracts, we were left with 88 records for a comprehensive evaluation of their eligibility for full-text assessment. Among these, 4 articles were excluded due to a lack of electronic text availability, 29 were excluded for being unrelated to the study's topics, and 14 were excluded as they were animal studies. Ultimately, 41 studies met our inclusion criteria. Furthermore, we identified an additional 9 studies through citation tracking within these relevant documents. The screening process for research literature is visually represented in Fig. 1, and the key information from all the included literature is summarized in Appendix IV. A concise summary of the appraisal results can be found in Table 2.

Fig. 1.

Flowchart of the research literature screening process.

Table 2.

The result of critical appraisal.

Issue	The	Design	Score based on appropriate JBI appraisala													Overall appraisal
			1	2	3	4	5	6	7	8	9	10	11	12	13
Acupuncture	W. K. Wang et al., 1995	RCT	Y	Y	N	U	U	U	U	U	Y	U	Y	Y	U	Included
Acupuncture	W. K. Wang et al., 1996	Quasi-experimental	U	Y	Y	Y	Y	U	Y	U	U	NA	NA	NA	NA	Included
Acupuncture	W. K. Wang et al., 2000	Quasi-experimental	U	Y	Y	Y	Y	U	Y	U	Y	NA	NA	NA	NA	Included
Daily Activity, Diet, Acupuncture	T. L. Hsu et al., 2008	Quasi-experimental	U	Y	Y	Y	Y	U	Y	U	Y	NA	NA	NA	NA	Included
Acupuncture, CVD	H. Hsiu et al., 2013	Quasi-experimental	U	U	U	N	Y	U	Y	U	U	NA	NA	NA	NA	Included
ANA	C. W. Hsieh et al., 2003	Quasi-experimental	N	N	U	N	Y	U	Y	U	U	NA	NA	NA	NA	Included
ANA	C. W. Hsieh et al., 2003	Cross-sectional	Y	Y	Y	Y	N	U	Y	Y	NA	NA	NA	NA	NA	Included
Cancer	Y. C. Kuo et al., 2004	Cross-sectional	Y	Y	Y	Y	N	U	Y	U	NA	NA	NA	NA	NA	Included
Cancer, Gynecology	C. T. Chen et al., 2017	Cross-sectional	Y	Y	Y	Y	N	U	Y	Y	NA	NA	NA	NA	NA	Included
Cognitive	C. C. Chen et al., 2014	Quasi-experimental	U	Y	Y	N	Y	U	Y	Y	Y	NA	NA	NA	NA	Included
Cognitive	S. K. Lin et al., 2021	Cross-sectional	Y	Y	Y	Y	U	U	Y	Y	NA	NA	NA	NA	NA	Included
CV Risk in DM	C. W. Chang et al., 2018	Cross-sectional	Y	Y	Y	Y	Y	U	Y	Y	NA	NA	NA	NA	NA	Included
CV Risk in DM	C. W. Chang et al., 2018	Cohort	U	U	Y	U	U	U	Y	Y	U	U	Y	NA	NA	Included
CV Risk in DM	C. W. Chang et al., 2019	Cohort	N	N	Y	N	N	U	Y	Y	U	U	Y	NA	NA	Included
CV Risk in DM	C. W. Chang et al., 2019	Cohort	Y	N	Y	N	N	U	Y	Y	U	U	Y	NA	NA	Included
CV Risk in DM	K. M. Liao et al., 2019	Cohort	Y	N	Y	Y	N	U	Y	Y	U	U	Y	NA	NA	Included
CV Risk in DM	K. M. Liao et al., 2019	Cohort	Y	N	Y	U	U	U	Y	Y	U	U	Y	NA	NA	Included
CVD	C. Y. Chen et al., 1993	Cross-sectional	Y	Y	Y	Y	U	U	Y	Y	NA	NA	NA	NA	NA	Included
CVD	S. S. Chuang et al., 2006	Cross-sectional	Y	Y	Y	Y	U	U	Y	Y	NA	NA	NA	NA	NA	Included
CVD	W. A. Lu et al., 2006	Cross-sectional	Y	Y	Y	Y	U	U	Y	U	NA	NA	NA	NA	NA	Included
CVD	C. T. Chen et al., 2011	Cross-sectional	Y	Y	Y	Y	U	U	Y	Y	NA	NA	NA	NA	NA	Included
CVD	C. M. Huang et al., 2011	Cross-sectional	Y	Y	Y	Y	N	N	Y	Y	NA	NA	NA	NA	NA	Included
CVD	Y. C. Huang et al., 2019	Cross-sectional	Y	Y	Y	Y	N	N	Y	Y	NA	NA	NA	NA	NA	Included
CVD	H. Hsiu et al., 2022	Cross-sectional	Y	Y	Y	Y	N	N	Y	Y	NA	NA	NA	NA	NA	Included
Daily activity	M. Sherebrin et al., 1990	Cross-sectional	U	Y	Y	U	N	N	Y	U	NA	NA	NA	NA	NA	Included
Daily activity	W. K. Wang et al., 1996	Quasi-experimental	U	Y	Y	U	Y	N	Y	U	U	NA	NA	NA	NA	Included
Daily activity	Y. C. Su et al., 2000	Quasi-experimental	U	Y	Y	N	Y	N	Y	U	Y	NA	NA	NA	NA	Included
Daily activity	W. A. Lu et al., 2016	Cross-sectional	Y	Y	Y	Y	N	N	Y	Y	NA	NA	NA	NA	NA	Included
Daily activity	P. J. Chen et al., 2020	Cross-sectional	Y	Y	Y	Y	N	N	Y	Y	NA	NA	NA	NA	NA	Included
Diabetes, HTN	Y. W. Chang et al., 2016	Cross-sectional	Y	Y	Y	Y	N	N	Y	Y	NA	NA	NA	NA	NA	Included
Diabetes, HTN	G. D. Jindal et al., 2017	Cross-sectional	Y	Y	Y	Y	Y	U	Y	Y	NA	NA	NA	NA	NA	Included
Diabetes	C. K. Liao et al., 2020	Cross-sectional	Y	Y	Y	Y	Y	U	Y	Y	NA	NA	NA	NA	NA	Included
Diabetes	C. Y. Chen et al., 2021	Cross-sectional	Y	Y	Y	Y	Y	U	Y	Y	NA	NA	NA	NA	NA	Included
Diabetes	H. T. Wu et al., 2021	Cross-sectional	Y	Y	Y	Y	Y	U	Y	Y	NA	NA	NA	NA	NA	Included
Diet	W. K. Wang et al., 1994	Quasi-experimental	Y	Y	U	N	Y	N	Y	Y	U	NA	NA	NA	NA	Included
Diet	C. W. Chang et al., 2017	Quasi-experimental	Y	Y	Y	Y	Y	U	Y	Y	U	NA	NA	NA	NA	Included
Diet	C. W. Chang et al., 2019	Quasi-experimental	Y	Y	Y	Y	Y	U	Y	Y	U	NA	NA	NA	NA	Included
Gynecology	C. L. Hsu et al., 2014	Cross-sectional	Y	Y	Y	Y	N	N	Y	Y	NA	NA	NA	NA	NA	Included
Gynecology	C. Y. Chen et al., 2021	Cross-sectional	Y	Y	Y	Y	Y	U	Y	Y	NA	NA	NA	NA	NA	Included
HTN	J. C. Liu et al., 2021	Cross-sectional	Y	Y	Y	Y	N	U	Y	Y	NA	NA	NA	NA	NA	Included
Liver function	W. K. Wang et al., 1996	Cross-sectional	Y	Y	U	Y	N	N	Y	U	NA	NA	NA	NA	NA	Included
Liver function	W. A. Lu et al., 1996	Cross-sectional	Y	Y	Y	Y	N	N	Y	Y	NA	NA	NA	NA	NA	Included
Liver function	W. A. Lu et al., 1999	Cross-sectional	Y	Y	Y	Y	N	N	Y	Y	NA	NA	NA	NA	NA	Included
Liver function	J. H. Henriksen et al., 2012	Cross-sectional	Y	Y	Y	Y	N	N	Y	Y	NA	NA	NA	NA	NA	Included
Local	L. Bennett et al., 1990	Cross-sectional	Y	Y	Y	Y	N	N	Y	U	NA	NA	NA	NA	NA	Included
Local	H. Hsiu et al., 2012	Quasi-experimental	Y	Y	Y	N	Y	U	Y	Y	U	NA	NA	NA	NA	Included
Local	F. C. Lin et al., 2020	Cross-sectional	Y	Y	Y	Y	N	N	Y	Y	NA	NA	NA	NA	NA	Included
Others	J. M. Liou et al., 2011	Cross-sectional	Y	Y	Y	Y	N	N	Y	Y	NA	NA	NA	NA	NA	Included
Others	F. J. Chen et al., 2012	Cross-sectional	Y	Y	Y	Y	N	N	Y	Y	NA	NA	NA	NA	NA	Included
Others	Y. Lu et al., 2015	Cross-sectional	Y	Y	Y	Y	N	N	Y	Y	NA	NA	NA	NA	NA	Included

*Y = yes; N = no; U = unclear; NA = not applicable.

^aAppropriate appraisal for either RCT, cohort, cross-sectional, or quasi-experimental was used. RCT: 13 criteria, cohort: 11 criteria, cross-section: 8 criteria, quasi-experiment: 9 criteria; The detailed content of criteria appraisal for various types are elucidated in Appendix III.

3.2. Pulse wave acquirement

From the analysis of the 40 selected research reports, various methods have been devised for the measurement of pulse waves to facilitate harmonic analysis. Below, we list the equipment uncovered in our literature search.

• 1.Piezoelectric Devices: One widely adopted method for acquiring pulse waveforms for further investigation involves the use of piezoelectric devices, such as the PSL-200GL.⁵³ These devices have found utility across various research groups, including the team led by W. K. Wang.^{36,46, 47, 48,54, 55, 56, 57, 58}
• 2.Strain Gauge Disks: Another approach entails the application of strain gauge disks, exemplified by the KFG-2-120-D1-11. Dr. Hsiu's research team has employed these disks to develop a pulse diagnosis recording device.^{40,59, 60, 61, 62, 63, 64, 65, 66} Furthermore, a self-designed device equipped with a strain-gauge pressure sensor has been used to capture arterial pulse waves.⁶⁷
• 3.Photoplethysmography (PPG): PPG, a technique that gauges volume changes in peripheral blood vessels by detecting alterations in light absorption, has also been harnessed to measure pulse waves for harmonic analysis. Dr. Hsiu's team^40,60,64,68 and other research groups^{69, 70, 71, 72, 73, 74} have employed this method.
• 4.
  Commercial Devices: Multiple research teams have employed commercial devices for pulse wave detection. Below is a comprehensive list of these commercial devices:

  • (1).
    TD01C Pulse Wave Analyzer: This device records radial artery pulse pressure waveforms by positioning a pressure transducer. It operates by periodically injecting water into a latex tube at a fixed frequency for data collection. Subsequently, the collected data is processed and analyzed for evaluation.⁷⁵
  • (2).
    PDS-2010 Skylark Pulse Analysis System: This system measures pulse waves by assessing horizontal and vertical changes on the X, Y, and Z-axes of the measurement unit. It converts analogous electrical signals from wrist artery waves into digital data, which is then stored on a computer for further analysis.⁷⁶
  • (3).
    Freescan: Developed by Maisense Inc., this instrument concurrently measures pressure waves in the left radial artery and functions as an ECG-I lead. It records pressure fluctuations in the artery through the use of piezoelectric material, reflecting pulse wave changes based on arterial blood flow speed. Additionally, it collects ECG-I data through hand electrodes.⁷⁷
  • (4).
    ANSWatch®: This device employs an oscillatory method, involving the inflation of an airbag to high pressure, gradual deflation, and the analysis of the blood pressure wave transmitted from the radial artery. This method provides measurements such as mean blood pressure, systolic pressure, and diastolic pressure.⁷⁸
  • (5).
    Peripheral Pulse Analyzer: Developed by the Electronic Division of Bhabha Atomic Research Centre in Mumbai, this device measures the rate of change of electrical impedance (dZ/dt) at the wrist while the subject is in a supine position, primarily for variability analysis.⁷⁹
  • (6).
    Hospital Vital Sign Monitoring Equipment: Originally designed for monitoring patients' vital signs in healthcare settings, equipment such as COLIN BP-508 ^80,81 and TM-2420 ⁸² has also been utilized as a data source for pulse analysis.

Numerous techniques and devices have been employed to measure pulse waves for harmonic analysis, encompassing photoplethysmography, commercially available devices, and custom-designed equipment. These devices have yielded valuable insights in the realm of pulse diagnosis and have been pivotal for subsequent analysis and practical applications.

The aforementioned devices possess the capability to capture an individual's pulse wave signal and subsequently deconstruct it into multiple harmonics using FFT. In the following section, our focus will center on Cn, which represents the amplitude of the nth harmonic component. This value is derived by dividing the amplitude of the nth harmonic component by the amplitude of the zeroth harmonic, with 'n' denoting the harmonic wave's order. Furthermore, we will delve into the examination of phase angle values associated with each harmonic wave, referred to as Pn. Detailed definitions of Cn and Pn can be found in Appendix I.

3.3. Variations in pulse harmonics across different physiological states

After reviewing research reports, we have identified several themes for exploring variations in pulse harmonics across diverse physiological conditions. These themes encompass daily activities, acupuncture interventions, herbal diets, diseases, local blood circulation status, mental states, aging, and cognitive activities. Fig. 2 visually represents the research counts associated with each of these themes, which we will discuss in detail in the subsequent sections.

Fig. 2.

The counts of research in each issue.

3.3.1. Daily activities

The state of the autonomic nervous system can have a notable impact on the fluctuations in the harmonic characteristics of pulse waves observed during daily activities. The autonomic nervous system encompasses both the sympathetic nervous system, responsible for the "fight or flight" response, and the parasympathetic nervous system, responsible for the "rest and digest" response, which are linked to distinct physiological responses.⁸³ Several studies have established a clear connection between the autonomic nervous system and pulse wave spectra. For instance, the administration of atropine, which inhibits the parasympathetic system, results in a significant increase in C2 and a decrease in C5, C6, C7, C8, and C9 ⁸⁰. Likewise, elevated respiratory rates, indicative of sympathetic activation, have been correlated with noteworthy increases in C2 and reductions in other high-frequency harmonics.⁸¹ These findings underscore how shifts in the state of the autonomic nervous system can instigate variations in pulse wave spectra during daily activities. Furthermore, the distinctions in pulse harmonic analysis between activities dominated by the sympathetic nervous system (e.g., exercise or ingestion) and those dominated by the parasympathetic nervous system (e.g., sleep or bathing) highlight the presence of distinct pulse harmonic patterns in response to these different physiological states.

The act of consuming food and beverages, known as ingestion, has garnered significant research attention, primarily due to its influence on sympathetic activity.⁸⁴ Previous investigations have revealed that ingestion can bring about alterations in the low-frequency harmonic components of pulse waves, particularly in terms of C1, C2, and C3. Furthermore, it has been established that the specific type of food or beverage ingested can further influence these modifications.^36,54,85,86 Pulse wave spectrum analysis has shown that prandial (related to eating a meal) activities can lead to an increase in C2 and C4, coupled with a decrease in C5 to C9.⁵⁷ In a separate study, ingestion was associated with an increase in C1 and C2, along with a decrease in C3, C5 to C10, while defecation (the elimination of waste from the body) was linked to an increase in C4 to C8 and a decrease in C2.⁸⁷ Additionally, a 24-h fasting period resulted in a significant increase in C2 for the radial pulse, accompanied by a notable decrease in C6.⁸⁸ The collective body of prior research underscores how ingestion can impact the characteristics of low-frequency harmonics, with a particular focus on its effects on sympathetic activity. The results of pulse wave spectrum analysis indicate that ingestion, including considerations such as the type of food or drink consumed and fasting periods, can have distinct effects on these harmonics.

Extensive research has been dedicated to the study of exercise, a factor known to potentially stimulate sympathetic activities.⁸⁹ Numerous investigations have delved into the variations in harmonics that transpire during physical activity. For instance, one study noted that climbing up and down four floors resulted in heightened amplitudes for C2 through C6.⁷⁰ In another study, jogging on a treadmill was associated with increased intensity in C1 and C2, accompanied by decreased intensity in C3 to C9.⁸⁷ Furthermore, Taichi practice has been observed to elevate the intensity of C1 and C2 while reducing the intensity of C4 ⁷³. These findings collectively point to the fact that low-frequency harmonics, such as C1 and C2, exhibit heightened intensities during sympathetic responses, underscoring the interconnectedness between the autonomic nervous system and pulse wave harmonics in reaction to physical exertion. Consequently, it can be inferred that the harmonics of pulse waves are influenced by the sympathetic responses incited during exercise.

Activities characterized by parasympathetic dominance, such as sleep⁹⁰ and bathing,⁹¹ typically lead to an augmentation in the intensities of C4 through C10, accompanied by a reduction in C1 and C2.⁸⁷ Notably, a study involving four individual cases revealed that sleep induced a significant increase in the intensities of C6 and C9.⁹² These findings provide further evidence supporting the association between parasympathetic nervous activity and high-frequency harmonics during the parasympathetic 'rest and digest' response.

Contrary to what might be anticipated, cold stimulation has been identified as a stimulus that activates sympathetic nerves.⁹³ Nevertheless, it has been observed that cold stimulation elicits an increase in the intensity of higher-frequency harmonics, specifically C5 to C10, but not C2.⁶⁰ This observed phenomenon is likely attributable to vasoconstriction, a physiological response wherein blood vessels constrict in reaction to cold stimuli.⁹⁴ This biological response can result in reduced blood flow to the exposed area subjected to the cold stimulus, potentially leading to decreased intensities in the low-frequency harmonics.⁶⁹

3.3.2. Acupuncture

Several studies have provided evidence that acupuncture treatments can induce alterations in the harmonic characteristics of pulse waves. For example, research has shown that specific acupuncture points, such as Leg Three Li (足三里 zù sān lǐ, ST-36) and Sunken Valley (陷谷xiàn gǔ, ST-43), which lie along the stomach meridian (胃經wèi jīng), are associated with the fifth harmonic corresponding to the stomach meridian.^46,47,54 Furthermore, the acupuncture point the Great Ravine (太溪tài xī, KI-3), situated on the kidney meridian (腎經shèn jīng), has been linked to the second harmonic pertaining to the kidney meridian.⁴⁸ When acupuncture points on the same meridian are stimulated, pulse wave harmonic measurements exhibit responses specific to particular harmonics, which are in turn associated with the viscera (臟腑zàng fǔ) linked to that meridian. These findings suggest a connection between pulse harmonic analysis and the TCM concept of viscera (臟腑zàng fǔ).

3.3.3. Herbal diet

In TCM, it is believed that specific plants have the potential to influence the condition of the viscera (臟腑zàng fǔ). According to the pulse harmonic theory, changes in the harmonic characteristics of the pulse wave may occur in response to variations in the state of the viscera.⁴² There is evidence suggesting that the harmonic characteristics of individuals taking different TCM herbal medicines may be impacted.

The effects of TCM herbal medicines on pulse harmonics often manifest as intricate changes involving multiple harmonics, which can pose challenges in interpretation. For instance, the consumption of Ganoderma lucidum (靈芝líng zhī) was found to increase the intensities of C3, C6, and C9, while decreasing the intensity of C2. Both Panax ginseng (人參rén shēn) and American ginseng (花旗參huā qíshēn) were observed to enhance the intensities of C6, C7, and C8, while diminishing the intensity of C2 and C9. Additionally, both groups exhibited increased intensities in C4 and C5, whereas only the American ginseng (花旗參huā qíshēn) group demonstrated a significant increase in C3 intensity.³⁶ Ingesting coffee has been shown to increase the intensities of C3, C6, and C9, while the consumption of tea can also influence the intensities of various harmonics.^85,86 Overall, the effects of different substances and practices on pulse harmonics can be intricate and multifaceted.

According to TCM theory, Chinese herbal medicine is believed to have the potential to influence multiple viscera. For instance, Panax ginseng (人參rén shēn) is thought to impact the heart, spleen, and lung meridians, with the spleen meridian indirectly affecting the stomach, as per classical TCM theory. In alignment with harmonic theory, this corresponds to the third (spleen), fourth (lung), and fifth (stomach) harmonics being influenced. However, empirical research indicates a more intricate interplay of affected harmonics, introducing complexity to the observed outcomes. The changes in harmonics induced by herbal medicine are often multifaceted and involve alterations in multiple harmonics. It remains unclear whether these resultant harmonic variations can be accurately attributed to the TCM concept. Further discussion is warranted to comprehensively explore this relationship.

3.3.4. Relationship with diseases

The results of pulse analysis for disease are divided into several thematic categories. These themes include cardiovascular disease, metabolic symptoms, liver dysfunction, gynecological diseases, cancer, and other diseases.

3.3.4.1. Cardiovascular disease

Pulse wave harmonic analysis has been employed for predicting the risk of cardiovascular disease, with particular attention given to the harmonic features C1, C4, and C5, which have shown significant indications. Researchers have observed that individuals with cardiovascular diseases, including those in the postoperative phase after coronary artery bypass graft (CABG) surgery,⁷¹ cardiac artery disease,⁹⁵ and vascular sclerosis,⁶⁶ often exhibit a higher intensity of C1 compared to healthy controls. Conversely, the intensity of C4 in patients with specific cardiovascular conditions tends to be lower than that in healthy individuals. This trend has been noted in cases involving coronary artery bypass graft (CABG) surgery,⁷¹ palpitations,⁶⁷ and cardiac artery disease.⁹⁵ Additionally, in some instances, C5 in patients with cardiovascular diseases has been found to be higher in intensity than in their healthy counterparts. Such findings have been documented in cases of palpitations⁶⁷ and cardiac artery disease.⁹⁵ It is noteworthy that acupuncture has been shown to bring about alterations in pulse harmonics, particularly on the side affected by a stroke, resulting in an increased intensity of C5.⁶¹ In summary, the existing evidence suggests that individuals with cardiovascular diseases often exhibit higher intensities of C1 and lower intensities of higher-frequency harmonics like C4 and C5 when compared to control groups.

While the evidence presented in the previous section highlights the importance of C1, C4, and C5 as indicators of cardiovascular disease in pulse harmonic analysis, there are exceptions to this pattern. For example, in patients with uncomplicated myocardial infarction, it was observed that C2 and C3 decreased, while C0 gradually increased upon their arrival at the emergency room. However, no significant changes were noted in C1, C4, and C5.⁹⁶ In addition to the intensity of harmonics, variations in harmonic intensity can also be employed to detect the occurrence of stroke. In a study, the coefficients of variation (CV1 to 7) on the stroke-affected side were found to be higher than those on the healthy side, and the CV1, CV3 to 5, and CV7 on the affected side were also higher than those on both sides of the control group (CVn refers to the coefficient of variation of the nth harmonic intensity, as detailed in Appendix I).⁵⁹ This article suggests that although C1, C4, and C5 have traditionally been considered crucial markers for identifying cardiovascular disease through pulse harmonic analysis, anomalies and deviations in harmonic intensity could potentially serve as indications of stroke.

To summarize, the collective findings from various studies indicate that in pulse harmonic analysis, the intensity of C1, C4, and C5 can serve as valuable indicators for predicting cardiovascular disease. In most cases of cardiovascular diseases, there is a pattern of higher C1 intensity and lower C4 and C5 intensity compared to healthy controls. Additionally, deviations in harmonic intensity can potentially signal the occurrence of a stroke.

3.3.4.2. Metabolic syndromes

Pulse wave analysis of metabolic syndrome, without further subdivision, revealed that patients exhibited lower C1 and C2 values and higher C4 to C9 values compared to healthy individuals.⁶⁸ The subsequent sections will delve into two frequently encountered metabolic syndromes: hypertension and diabetes, respectively.

3.3.4.3. Hypertension

Hypertension has been linked to specific characteristics in pulse wave analysis, including elevated values of C1 and reduced values of C3 and C4.⁹⁷ Other studies have indicated that hypertensive patients exhibit higher values of C1 to C5 and lower values of P2 to P8 compared to healthy controls.⁶⁵ Additionally, mild hypertension has been associated with increased C1 and C2 values.⁷⁹ In summary, a heightened C1 level is recognized as a significant indicator of pulse wave characteristics in hypertension.

3.3.5. Diabetes

There is conflicting evidence concerning pulse wave analysis in diabetic patients. Some studies have revealed that diabetic individuals exhibit lower C1 and C5 values in comparison to healthy controls,²⁸ while others have found higher C1 values in diabetic patients than in controls.²⁹ Additionally, C0 has been reported to be weaker in diabetic patients than in healthy controls.⁷⁴ Furthermore, pulse wave analysis has been employed to predict diabetes risk in women, with the diabetes group demonstrating higher C1 and C2 values and lower C3 values compared to the control group.²⁹ However, these findings are not consistently uniform, with C1 reported as both higher²⁹ and lower^28,79 in diabetic patients relative to healthy controls. Further research is warranted to determine the most reliable indicators for predicting diabetes using pulse wave analysis.

The variability in findings across different studies regarding pulse wave analysis in diabetic patients may arise from the fact that diabetic patients often have a heightened risk of cardiovascular disease, resulting in conflicting outcomes in the literature. Nevertheless, when examining studies with larger sample sizes,²⁹ it becomes apparent that diabetes impacts C0 to C5, and consistently low C3 values align with the TCM concept of spleen deficiency. Despite these disparities, it is evident that diabetes does indeed influence pulse wave analysis.

3.3.6. Summary of metabolic syndromes

Pulse wave analysis is extensively employed as a diagnostic tool for various metabolic diseases, such as hypertension and diabetes. In hypertension, a heightened C1 level is recognized as a significant indicator of pulse wave characteristics. However, the evidence regarding pulse wave analysis in patients with diabetes is inconsistent, likely due to the frequent coexistence of cardiovascular disease risk factors in diabetic patients. Nevertheless, despite these inconsistencies, pulse wave analysis holds promise in furnishing diagnostic insights into various metabolic diseases.

3.3.6.1. Cardiovascular risk in diabetic patients

Several studies have identified the first, fourth, and fifth harmonics as potential valuable indicators for predicting cardiovascular disease in individuals with Type 2 diabetes mellitus (T2DM). For instance, lower P5 levels have been observed in T2DM patients with severe silent myocardial ischemia compared to control groups.⁹⁸ Furthermore, there is evidence supporting the potential of C1 and C4 as predictors of cardiovascular risk in T2DM individuals. Specifically, elevated C1 levels have been associated with an increased risk of nonfatal myocardial infarction,²⁴ cardiovascular mortality, major adverse cardiovascular events, and adverse microvascular outcomes.^26,99 Conversely, a lower C4 compared to the average has been linked to an increased risk of adverse cardiac events in asymptomatic T2DM patients.²⁵ Additionally, the coefficient of variation of C4 (CV4) has shown promise as a predictor of cardiovascular mortality, macrovascular events, and microvascular events.²⁷ In summary, research suggests that features within C1 and C4 have the potential to serve as valuable indicators for predicting cardiovascular risk in individuals with T2DM.

3.3.6.2. Liver dysfunction

Researchers have devised methods to identify abnormal liver function using pulse harmonic analysis. Through the examination of harmonic characteristics, including C1, C3, C4, and C6, which can exhibit either elevation or reduction depending on the type of abnormal liver function, criteria for detecting abnormal liver function have been established in patients with varying degrees of abnormal blood values and liver function. This encompasses individuals with suspected abnormal liver function as well as those with severe abnormal liver function.^56,58,100 Additionally, a separate study focused on more severe liver conditions, such as cirrhosis, and discovered distinctive pulse harmonic patterns in patients with cirrhosis when compared to a control group. These patterns included higher C4 values, lower values for C1 to C3, and reduced values for C5 to C12.⁸² These findings imply that the harmonic profiles associated with abnormal liver function can differ based on the severity of the liver issue, potentially indicating a progression from milder to more severe health conditions.

3.3.6.3. Gynecological disease or pregnancy

Harmonic analysis has also been applied to investigate female physiology, particularly in various clinical contexts. For instance, in patients diagnosed with polycystic ovary syndrome, there are elevated C1 values and decreased values for C4, CV2, and CV6 compared to healthy controls.⁶² Among breast cancer patients, we observe reduced values for C1, C2, and P1, along with heightened values for P7, P9, CV2, and CV3 when compared to the control group.⁶³ Pregnant women exhibit weaker values for C3 and C5 and stronger values for C2 and C4 in contrast to non-pregnant women. Conversely, postmenopausal women display stronger C1 values and weaker C4 values compared to their non-pregnant counterparts.¹⁰¹ These findings indicate that distinct pulse wave patterns can be identified in women, depending on the specific physiological or pathological condition under investigation, even if these conditions are associated with female reproductive or endocrine functions.

3.3.6.4. Cancer

Harmonic pulse analysis has found application in assessing cancer patients. Studies have revealed that cancer patients exhibit higher values for CV1 to 6 when compared to healthy controls.⁵⁵ Moreover, on the day of their demise, values for CV1 to 4 experience further elevation in comparison to their preceding state. These findings suggest that the increased values of CVn in cancer patients, relative to healthy controls, may signify an irregular and unstable pattern in the intensities of most harmonic waves, indicative of a disturbance in physiological regulation.

Furthermore, in addition to CVn, variations in the values of Cn have been observed in cancer patients. Specifically, in the pulse wave harmonic analysis conducted on breast cancer patients, it was found that values of C1, C2, and P1 were lower, while values of P7, P9, CV2, and CV3 were higher when compared to the control group.⁶³ The values of C1 and C2 are associated with the liver viscera and kidney viscera and meridians, as detailed in Table 1. It is noteworthy that clinical observations have indicated that cancer patients frequently exhibit signs of kidney and liver deficiency, which may be reflected in the lower values of C1 and C2 observed in comparison to healthy controls.

The findings of this research suggest a potential correlation between harmonic information in cancer patients and their physiological condition. Notably, the elevated values of CVn in cancer patients compared to healthy controls may indicate an instability and irregularity in the intensities of most harmonic waves, possibly signaling a disruption in physiological regulation. Conversely, the lower values of C1 and C2 observed in cancer patients in comparison to healthy controls can be indicative of kidney and liver deficiencies, conditions commonly observed in cancer patients based on clinical experience. Collectively, these findings offer valuable insights into potential physiological variations occurring in cancer patients.

3.3.6.5. Other diseases

Pulse harmonic analysis has also been applied to investigate atopic dermatitis and another unmentioned disease category. Specifically, in atopic dermatitis patients, lower C3 values have been observed in comparison to healthy controls.¹⁰² Notably, the third harmonic is associated with the spleen viscera and meridian, and clinical observations suggest that atopic dermatitis patients frequently display signs of spleen deficiency.

Another condition investigated through pulse harmonic analysis is adhesive capsulitis, commonly known as frozen shoulder.⁴⁰ In this study, pulse recordings from individuals with frozen shoulder were assessed using two distinct methods. Results obtained at the wrist using a strain gauge indicated elevated values for C1 to 4, lower values for P2 to 8, higher CV1, and increased P1_SD to P10_SD values compared to healthy individuals. Similarly, results obtained using a photoplethysmography (PPG) device on the fingers displayed analogous findings, with increased values for C1 to 4, decreased values for P1 to 4, elevated CV1 to 10, and higher P3SD to P10SD values in comparison to the control group. These outcomes suggest that the harmonic characteristics observed in individuals with frozen shoulder remain consistent, albeit minor variations may arise due to differences in measurement devices.

3.3.7. Influence on local blood circulation

Pulse wave harmonic analysis serves as a valuable method for assessing local blood circulation. To illustrate, paraplegic individuals exhibiting reduced intensities in C1, C2, and C3 harmonics, as assessed through measurements at the buttocks, are at an elevated risk of developing pressure ulcers.⁶⁹ Harmonics can provide insights into the quality of local blood circulation, and, conversely, the quality of local blood circulation can influence the outcomes of pulse wave harmonic analysis. In cases of frozen shoulders, pulse wave measurements obtained via a strain gauge at the wrist may vary from those obtained using a PPG device at the finger, potentially due to differences in local circulation at the measurement site.⁴⁰ In summary, pulse wave harmonic analysis serves as a valuable tool for assessing local blood circulation and identifying potential risks associated with conditions such as pressure ulcers. Furthermore, it's worth noting that temperature can also induce changes in local circulation, a topic we will explore in the following section.

Temperature variations can exert an influence on blood circulation, which, in turn, can have repercussions on pulse wave attributes. Generally, it is understood that heat stimuli prompt vasodilation, leading to heightened blood flow,¹⁰³ whereas cold stimuli induce vasoconstriction, resulting in reduced blood flow.^93,94 Notably, pulse wave harmonic analysis following exposure to cold stimuli has demonstrated an elevation in the intensity of high-frequency harmonics, particularly within the C4 to C10 range.⁶⁰ Conversely, localized heating has been observed to augment the intensity of C1 to C3 harmonics.¹⁰⁴ These observations underscore the notion that temperature-induced alterations in local blood flow can bring about changes in pulse wave characteristics. Although pulse diagnosis theoretically has the potential to assess systemic symptoms, it may also be subject to influence by the local vascular condition.

3.3.8. Response to mental state

Emotional states have also been investigated through pulse wave analysis. Among patients with bipolar disorder, it was observed that C4 values, indicative of the amplitude of the fourth harmonic component, were lower on the right side in comparison to the control group.¹⁰⁵ Notably, the fourth harmonic corresponds to the lung meridian, as delineated in Table 1. In accordance with TCM theory, emotional issues are often associated with Qi stagnation (氣滯 qì zhì, signifying the blockage of bodily energy flow), and the lung is believed to play a pivotal role in the regulation of Qi (氣 qì, representing bodily energy).

3.3.9. Response to aging and mental activity

Earlier studies have indicated that the values of C2 and C6, reflecting the amplitudes of the second and sixth harmonics, decrease as individuals age.⁷⁰ The notable decline in C2 holds particular significance and can be construed as an indicator of kidney deficiency. In accordance with TCM principles, the aging process is linked to kidney deficiency, and the kidney is associated with the second harmonic, as detailed in Table 1. Consequently, the decrease in C2 values with advancing age underscores the importance of accounting for age as a factor when interpreting results derived from pulse wave harmonic analysis.

Dementia, a common age-related symptom, has been the subject of research employing pulse wave harmonic analysis. In Alzheimer's disease, the most prevalent form of dementia, it was observed that intensities of C3 to C10 harmonics were higher in patients compared to healthy elderly individuals.⁶⁴ These findings suggest that differences in the intensity of high-frequency harmonics (C3 to 10) may possess the potential to distinguish cases of dementia. However, it's worth noting that dysfunction of the sympathetic nervous system can also elevate the intensity of high-frequency harmonics, including those within the C3 to C10.⁸⁰ Importantly, Alzheimer's disease patients frequently exhibit sympathetic nervous system dysfunction.¹⁰⁶ As a result, it remains uncertain whether the heightened high-frequency harmonics intensity observed in dementia patients, in contrast to healthy subjects, is primarily attributable to dementia or sympathetic nervous dysfunction.

In contrast to Alzheimer's disease, cognitive tasks elicit distinct harmonic patterns. For instance, a study revealed that extended engagement in cognitive tasks resulted in notable elevations in C2 and C5 values during the initial days, followed by a sudden surge in C1 values between days 3 and 8.⁷² These patterns, evident in pulse wave analysis outcomes, signify a shift in an individual's response to cognitive stress or cognitive strategies as they continue to engage in cognitive tasks. However, it's important to note that the low-frequency harmonics generated by cognitive tasks appear to present a contrasting result when compared to the high-frequency harmonics observed in Alzheimer's disease.

Prolonged cognitive tasks can result in alterations in high-frequency harmonics. For instance, in healthy young individuals, engaging in 4 h of computer gaming leads to an increase in the amplitude intensity of the third, fourth, fifth, and sixth harmonics.¹⁰⁷ In this particular case, attributing the changes in harmonic characteristics exclusively to either fatigue or cognitive stimulation presents a considerable challenge.

4. Discussion

In TCM, harmonic analysis of pulse waves assesses visceral health.^42,43 However, the lack of a standardized scale hampers clinical validation. This study aims to establish harmonic analysis for disease diagnosis and organ assessment. Our findings correlate harmonics with diseases in TCM. For example, cardiovascular patients show elevated first harmonics linked to the liver meridian. Diabetes patients exhibit weakened third harmonics associated with the spleen meridian. Liver dysfunction relates to changes in the first harmonic, while cancer patients display signs of liver and kidney yin deficiency in the first and second harmonics. This underscores harmonic analysis as a promising tool for TCM disease diagnosis and visceral assessment.

Harmonic patterns, which demonstrate correlations with TCM viscera and adhere to classical TCM principles, have been identified in various medical conditions. For instance, significant variations in low-frequency harmonic intensity have consistently emerged in the context of cardiovascular disease. In this scenario, patients frequently exhibit either elevated or reduced C1 values, attributed to the liver meridian.^{24,26,65,66,68,79,95,97} Similarly, in line with TCM theory linking diabetes to the spleen meridian, empirical findings from pulse wave harmonic analysis demonstrate a notable increase in C3 values among individuals affected by diabetes, corresponding to the spleen meridian.^{66,96, 97, 98} However, existing research predominantly focuses on specific diseases, such as cardiovascular disease and diabetes, thereby lacking a comprehensive perspective. Despite these insights, the precise harmonic values relevant to cardiac assessment remain elusive. Consequently, a more comprehensive discussion is essential to elucidate the heart's role within the context of TCM pulse diagnosis for cardiovascular diseases.

In the synthesized literature reviewed in this study, it is noted that there is an association between the first harmonic of pulse waves and cardiovascular diseases, and cardiovascular diseases are linked to the liver in TCM. According to TCM theory, the liver's role in blood storage is crucial for regulating venous return and safeguarding cardiopulmonary function. Consequently, the concept of the liver storing blood encompasses its relationship with total blood flow volume and coagulation as well.¹⁰⁸ Therefore, this also underscores the correlation between liver function and cardiovascular function, and the measurement and recording of pulse wave harmonics are pertinent to the assessment of the first harmonic.

In our ongoing exploration of factors relevant to cardiovascular health, we conducted a deeper investigation into the significance of C4 and C5. Specifically, the 4th harmonic is associated with the lung meridian and plays a significant role in the flow of Qi. Within the TCM paradigm, there exists a fundamental concept: the close interplay between Qi and blood, which suggests that cardiovascular conditions might be reflected in C4. On the contrary, the 5th harmonic is primarily linked to the stomach meridian, focusing on digestive functions rather than cardiovascular functions. Elucidating the potential connection between C5 and cardiovascular diseases demands further substantiating evidence and thorough discussion.

Diabetes is another aspect explored in our research utilizing pulse harmonic analysis. Within the framework of TCM, diabetes is often referred to as "wasting-thirst," a terminology deeply rooted in the extensive clinical expertise of TCM practitioners. Among the diverse manifestations of diabetes, spleen qi deficiency stands out as a common pattern. When the spleen and stomach are afflicted by pathogenic heat, it can result in damage to spleen yin, which elucidates the prevalent symptoms of thirst and increased appetite frequently observed in diabetic individuals. A spleen weakened by qi deficiency struggles to effectively convert food and water into the essential substances necessary for maintaining regular bodily functions. Consequently, after digestion, food and water are diverted into the urine, resulting in sweet urine. Moreover, the insufficient nourishment supplied by food essence gradually leads to muscle deterioration, a notable consequence of diabetes.¹⁰⁹ Our research findings, as consolidated in this study, also shed light on the connection between diabetes-induced spleen weakness and the spleen meridian, as demonstrated by a reduction in the harmonic strength of the third spleen meridian.

Drawing from the evidence discussed above, it is postulated that each harmonic wave mirrors the state of a particular internal organ.^{41, 42, 43} Nonetheless, research has revealed that the alterations in harmonics following illness, herbal remedies, or daily activities may extend beyond fluctuations in a single harmonic wave. In fact, multiple harmonic signals have been employed as predictive indicators in studies related to liver function.^56,100 As a result, it is advisable to take into account multiple harmonics when employing harmonic analysis for the development of predictive models in future studies.

Daily activities that evoke high-frequency or low-frequency harmonic responses are closely linked to autonomic nervous system responses. High-intensity high-frequency harmonics are likely to be generated during periods of rest, such as during sleep,^87,92 or when the parasympathetic nervous system is stimulated.⁸⁰ Conversely, high-intensity low-frequency harmonics are more likely to emerge during active phases, like exercise⁸⁷ and Tai Chi.⁷³ These findings align with prior research.¹¹⁰ However, within the realm of daily activities, harmonic variations often encompass multiple frequencies, thereby introducing complexity into the interpretation of these changes concerning TCM viscera.

According to classical TCM theory, the heart not only plays a role in cardiovascular function but also in mental activities. Prior research has indicated that dementia patients exhibit an overall reduction in harmonic intensity, with high-frequency harmonics dominating, but they do not display the same elevated C1 intensity observed in cardiovascular disease.⁶⁴ This finding may appear contradictory. In healthy individuals, cardiac output increases along with increased oxygen demand to the brain following cognitive tasks.¹¹¹ Conversely, individuals with mild cognitive impairment demonstrate insufficient cardiac output and reduced cerebral perfusion in response to mental stress.¹¹² Consequently, we posit that the measurements taken in previous studies on dementia patients reflect a resting state and may not accurately represent cognitive function. Further research is warranted to investigate whether low-frequency harmonic variations similar to those observed in cardiovascular diseases can be detected following cognitive tasks.

Our study builds upon Wang's 1991 research on pulse wave harmonic analysis, which revealed resonance-like interactions between the aorta and adjacent organs, particularly after branch ligation.⁴¹ A subsequent literature review also gathered relevant research on pressure pulse waves in blood distribution and health monitoring.⁴² However, this review lacks a comprehensive overview, combines results from both animal and human experiments, and has limited connections to TCM concepts. In contrast, our systematic review incorporates recent human studies from the past decade, enhancing our understanding of pulse wave harmonic analysis and providing contemporary findings that further validate the field's theoretical foundation.

Despite the valuable insights provided by the existing literature on pulse wave harmonics analysis, certain limitations remain to be addressed. Firstly, a larger sample size is necessary to provide a more comprehensive elucidation of this field, ensuring the reliability and generalizability of the findings. Secondly, current research predominantly relies on cross-sectional studies, lacking longitudinal, long-term tracking, which hinders our ability to capture the trends in pulse wave harmonics analysis. Lastly, the present studies have not synchronously incorporated assessments of organ conditions from a TCM perspective, making it challenging to directly explore the relationship between pulse wave harmonics analysis and TCM concepts.

To overcome the mentioned limitations, future research can take several directions. Firstly, research designs should embrace larger sample sizes to enhance statistical power. Secondly, longitudinal investigations can be conducted to trace the long-term variations in pulse wave harmonics analysis, facilitating a deeper understanding of its dynamics. Additionally, the inclusion of clinical assessments by expert TCM practitioners or organ-related functional scales can provide a more comprehensive exploration of the theoretical foundation linking pulse wave harmonics analysis with TCM concepts, thereby solidifying the theoretical underpinnings of this research area. These improvements will contribute to a deeper comprehension of the applications and potential value of pulse wave harmonics analysis, while also stimulating further advancements in this field in future research endeavors.

5. Conclusion

In summary, it is evident that the intensity of low-frequency harmonics in pulse waves is influenced by physiological arousal and activity levels. Extensive research in the literature has focused on investigating the connection between these harmonics and cardiovascular disease as well as metabolic conditions. Past studies have revealed that individuals with cardiovascular disease typically exhibit heightened intensities in the first harmonics compared to their healthy counterparts, while diabetic patients often present with reduced intensities in the third harmonics in comparison to healthy individuals. Conversely, individuals with various medical conditions, such as metabolic disorders, liver dysfunction, cancer, and gynecological diseases, have displayed distinctive intensities across multiple harmonics ranging from the first to the tenth when compared to healthy controls, despite some inconsistencies in research findings. Summary of the conclusion is shown in Table 3.

Table 3.

Summary of the conclusion.

Main Findings	Description
1. Influence of Physiological Factors	The intensity of low-frequency harmonics in pulse waves is notably affected by physiological arousal and activity levels.
2. Connection to Cardiovascular Disease	Prior research has highlighted a strong association between low-frequency harmonics, particularly the first harmonics, and cardiovascular disease. Patients with cardiovascular disease tend to exhibit higher intensities in the first harmonics when compared to healthy individuals.
3. Association with Metabolic Conditions	Diabetic patients, on the other hand, often show reduced intensities in the third harmonics, providing insights into the potential use of harmonics as indicators of metabolic conditions.
4. Variability in Medical Conditions	Individuals with a range of medical conditions, including metabolic disorders, liver dysfunction, cancer, and gynecological diseases, display unique intensity patterns across multiple harmonics (from the first to the tenth) compared to healthy controls. However, there are some inconsistencies in research findings.

However, the limited sample sizes in current studies on these topics underscore the need for further research into other pathological states or treatment effects. Consequently, it is imperative to continue exploring the potential clinical utility of pulse wave analysis and low-frequency harmonics as biomarkers for assessing cardiovascular and metabolic health.

Funding source

This work was supported by the National Science and Technology Council (Ministry of Science and Technology (MOST 111-2320-B-039-057). The Chinese Medicine Research Center, China Medical University via the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project of the Ministry of Education (Taiwan).

Declaration of competing interest

None.

List of abbreviations

Traditional Chinese medicine

(TCM)

Fast Fourier Transform

(FFT)

Jin's pulse diagnosis

(JPD)

Amplitude Ratio of nth harmonic

(Cn)

Coefficient of Variation of Cn

(CVn)

Phase Angle of nth harmonic

(Pn)

Standard Deviation of Pn

(Pn_SD)

Coronary Artery Bypass Graft

(CABG)

Type 2 Diabetes Mellitus

(T2DM)

Photoplethysmography

(PPG)

Appendix A. Supplementary data

The following is the Supplementary data to this article.