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Echocardiography is used to detect and monitor structural and functional cardiovascular diseases (CVD) by comparing quantitative measurements (such as heart wall thickness and chamber size) to population reference values.[[1]] Recently, the impact of ethnicity upon echo measurements has been raised. The Echocardiographic Normal Ranges Meta-Analysis of the Left heart (EchoNoRMAL),[[2]] an individual person meta-analysis with >20,000 participants, demonstrated important sex and ethnic differences in the normal echocardiographic reference ranges between NZ European, Asian and South Asian cohorts. Overall, the Asian cohorts had smaller hearts compared to the NZ European cohorts; and women had smaller hearts across all ethnic groups.[[2]]

Heart size is closely linked with body size, and guidelines recommend echocardiography measurements are indexed (divided by) by body surface area (BSA)[[1]] to allow comparison between individuals of differing sizes. But BSA is an imperfect indexation variable, and previous research suggests that body composition and fat free mass (FFM) is a better independent predictor of heart size than BSA.[[3,4]] Body composition is also linked to both sex and ethnicity: women have lower FFM than men for the same BMI; and Asian and Indian individuals have lower FFM than Caucasians of similar height and weight, who in turn have less FFM than African American individuals.[[5]] These differences may explain the sex and ethnic differences observed in heart size.

In New Zealand, CVD is a leading cause of mortality, and mortality rates are highest within the indigenous Māori[[6]] and Pacific populations.[[7]] Māori and Pacific individuals also have higher FFM compared with NZ Europeans;[[8]] therefore it is conceivable, indeed likely, that normal heart size is larger in Māori and NZ Pacific peoples. In the Hauora Manawa Heart Study,[[9]] echocardiography revealed that Māori had larger left ventricular (LV) and aortic dimensions, thicker LV walls and higher prevalence of LV hypertrophy (LVH) compared with non-Māori. Whilst this may reflect higher disease burden, it is probable that the true incidence of dilatation and LVH was overestimated by using the international reference values, as they were derived mostly from NZ European individuals.[[1]] At the time there were, and remain, no appropriate reference ranges for clinical application in Māori, nor indeed Pacific peoples.

Our objective was to establish normal reference ranges for echocardiography applicable to both New Zealand and Pacific Islands populations. Our hypothesis was that heart size would be larger in Māori and NZ Pacific peoples and that reference values that include indexation to BSA, which does not account for body composition, may be inappropriate in a cohort of mixed ethnicity. As a result, the echocardiography measurements may not be optimised in these groups, who are also at the higher risk of CVD.

Methods

Study population

This targeted cross-sectional study recruited three age-matched healthy cohorts: Māori, NZ Pacific, NZ European. Between July 2015 and September 2017, participants were recruited through convenience sampling (word of mouth, newspaper articles, primary care practices, workplaces, and recreational sporting groups). Consenting participants attended a single visit at our research facility Awhina Health Campus or at community clinics in various locations (including primary healthcare facilities and workplaces) where demographic data, and clinical and family history were collected, and clinical measurements were taken: height, weight, body composition (Tanita Body Composition Analyzer SC-330), automated blood pressure (BP), point of care total cholesterol and blood glucose (CardioChek PA); and where echocardiography was performed. Body mass index (BMI) was calculated (weight/height[[2]]) and BSA calculated by the DuBois formula.[[10]] Body composition was assessed using sex-specific non-athlete settings, and fat free mass (FFM) was calculated as total weight less fat mass, and included bone mass.

Participants were invited to begin their individual visit with the research team with a karakia, and also offered the remnant of their blood sample to take home. All remaining blood samples were collated in a single medical waste container (separate from general waste) for a cremation ceremony at the study completion. Participants were given a $20 fuel voucher as a koha, as well as pamphlets about reducing the risk of stroke, diabetes and heart disease. These were available in English, te reo Māori, Samoan and Tongan languages. All participants provided signed written consent. The study was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement[[11]] and was approved by the Southern Health and Disability Ethics Committee (approval number 15/STH/96).

Inclusion and exclusion criteria

Participants aged 18–50 years who self-identified as Māori, NZ European, or Pacific Island ethnicity, with good health, were invited. NZ Pacific peoples included participants who identified as either Cook Island Māori, Fijian, Niuean, Samoan, Tahitian or Tongan. Participants who identified as Fijian Indian Pacific were excluded. Other patient exclusion included: random (non-fasting) total cholesterol of >7·0mmol/L or glucose of >10mmol/L; BMI >40; currently or recently (<3 months) pregnant; hypertension (greater than 145/90 on two different automated BP measurements); history of CVD, diabetes, renal failure or other serious conditions (including lung disease or asthma on regular medication (N=2)); taking any cardiovascular medications (except statins); and significant incidental echo findings.

Ethnicity determination

Ethnicity was self-identified, and participants were able to select more than one group, in which case, group allocation was ascribed according to the prioritisation method in the New Zealand Ministry of Health’s ethnicity data protocol: 1) Māori, 2) Pacific, 3) Asian, 4) European.[[12]] This ensured that participants were only counted in one group. For example, if a participant reported both Māori and European ethnicity, they were allocated to the Māori group. If a participant selected Māori and Pacific, they were also allocated to the Māori group.

Echocardiography

Echocardiography was performed by experienced sonographers or cardiology fellows according to a standard research protocol adherent to the ASE Guidelines (Philips CX50 or Siemens SC2000prime). Full echo data are available, but this publication includes linear 2D measurements of the left heart: left ventricular internal end-diastolic dimension (LVIDd); left ventricular internal end-systolic dimension (LVIDs); left ventricular outflow tract (LVOT); and aortic root and proximal ascending aorta. These measurements were made (average of three beats) off-line (Philips Q Station), and by a single reader (GAW) at the conclusion of the study in random order blinded to ethnicity, sex or other clinical information. All measurements were obtained according to recommendations of the American Society of Echocardiography Chamber Quantification Guidelines.[[1]]

Statistical analysis

Exploratory data analysis revealed that all of the variables were normally distributed. Quantile regression was used to determine the 95th and 5th centiles to determine upper limits of normal (ULN) and lower limits of normal (LLN) for each echo measurement. ANOVA was used to determine difference between the three ethnic groups, sex and the interaction of sex and ethnicity. Post hoc analysis was performed using Tukey method.

Results

Study population

After initial screening, 372 participants attended the first visit and 109 were excluded, leaving a final cohort of 263: 71 Māori (43 female, 28 male); 53 NZ Pacific (26 female, 27 male); and 139 NZ European (74 female, 65 male) participants (Figure 1).

The groups were well-matched in terms of age, height, blood pressure and heart rate (Table 1). Significant differences were observed in weight and body composition, with Māori having higher weight, fat mass (FM), fat free mass (FFM) and bone mass than NZ Europeans in both males and females, and with Pacific peoples having the highest. The same pattern was observed in each sex and for calculated BMI and BSA: the NZ European cohort had the lowest, and Pacific the highest, with Māori in between. No significant differences were observed between self-reported physical activity status.

Linear measurements of the left ventricle

For linear LV measurements, the ULN and LLN were higher in men compared to women and varied significantly by ethnicity: the NZ European cohort had the smallest chambers compared to both the Pacific and Māori cohorts (Table 2). Indexation to BSA did not remove the sex differences but did change the order of the ethnic group differences, in such that now the NZ European group had the largest hearts. The only interaction between ethnicity and sex noted was for LVIDs and LVIDs/BSA, which are measures of both size and function.  

Post hoc analyses within these sex groups revealed trends towards the differences noted above, but the only significant difference in unindexed measurements was for LVIDs, where NZ Pacific men had larger LVIDs compared to both NZ European and Māori men (Figure 2). But, when indexed to BSA, these differences in men were eliminated; however, significant differences between ethnicities emerged in women. NZ Pacific women had smaller hearts compared to both the Māori and NZ European women (Figure 2).

Raw unindexed measures of the after larger and before LV. Men had larger LV outflow tract (LVOT), aortic root (AoR) and ascending aortic (AscAo) dimensions than women (Table 2), and significant differences were seen across ethnicities. The relationship was similar to that observed for LV measurements; the European cohort had the smallest compared to both the Pacific and Māori groups. Indexation removed the sex differences for both LVOT and AoR (Table 2) and introduced a significant interaction between ethnicity and sex for LVOT/BSA, and the relationship across the ethnic groups altered such that the European cohort no longer had the smallest measurements: NZ European women now had the largest LVOT/BSA measurements (Figure 3).

Comparison with other reference values

There was general agreement between the ULN seen in this NZ European cohort when compared to both ASE/EACVI and EchoNoRMAL indexed variables[[1,2]] for both men and women (Table 3) and where differences are seen, these are of marginal clinical relevance. However, comparing the distribution of the data for LVIDd with the ASE/EASCVI reference values, a substantial proportion (19% of European men, 26% of European women; 29% of Māori men, 42% of Māori women; and 15% of Pacific men, 27% of Pacific women) fell outside of the reference ranges for raw measurements of LVIDd (Figure 4). In both sexes, the data for Māori and Pacific peoples was shifted to the right for un-indexed LVIDd resulting in higher levels of “abnormal” measurements in Māori men (28.5%) and women (42.3%), but not Pacific participants. Indexation to BSA shifted the distributions to the left and eliminated all abnormal measurements in the Pacific group and a substantial proportion in the Māori groups. In the European group, indexation reduced this from 19–5% in men and 26–6% in women. In both the Māori and Pacific groups, the reduction was even greater: 29–7% in Māori men and 42–3% in Māori women; 15–0% in Pacific Island men and 27–0% in Pacific women.

View Supplementary Figures & Tables.

Discussion

This study has shown, important differences in echocardiographic reference ranges between New Zealanders of European, Māori and Pacific ethnic groups. The results are consistent with previous research showing that echocardiographic heart size, is dependent on sex and ethnicity,[[13,14]] and suggests that current international Caucasian reference values are not applicable in Aotearoa, and worse, will contribute to poorer health outcomes due to misdiagnosis when used in Māori and Pacific peoples. Specifically, we found that heart size is different among these ethnic groups, and that application of the current international guidelines, specifically indexation to BSA, is an imperfect adjustment that may mask the presence of pathological abnormalities.

Indexation to BSA is intended to allow fair comparison of heart size amongst people of different body habitus. But from this data, it is apparent that unintentional preference may be introduced in healthcare delivery, in a way that preferences NZ European ethnicity: for example, among Māori and NZ Pacific peoples using a reference range, derived from a Caucasian population, may result in misclassification of abnormal heart size (such as with cardiomyopathy) as normal with subsequent under-treatment. This is systemic racism and puts Māori and Pacific peoples at higher risk of worse CVD outcomes but could be overcome if ethnic-specific references ranges were adopted in Aotearoa.

Globally, echocardiography is the main tool used to diagnose and monitor pathological cardiac changes, and its use will grow as the size and cost of equipment declines rapidly. However, normal echo reference ranges are yet to be determined for many ethnic groups. Given the dependence upon echocardiography, and in particular LV linear dimensions, to diagnose CVD, and guide interventions, timely and appropriate detection of abnormal heart size is paramount. Similar to other Indigenous populations, Māori and NZ Pacific peoples have the worst cardiovascular outcomes of all New Zealanders,[[6,7]] and are over-represented in almost every type of CVD. Further, CVD risk factors such as diabetes, hypertension and dyslipidaemia, are also more prevalent in Māori and NZ Pacific populations[[7,15]] as is rheumatic heart disease.[[16]] The results of this study indicate that the application of current normal reference indexed values, derived from mostly European individuals, is inappropriate and may lead to delayed diagnosis, especially if indexation to BSA is used.

Optimal identification of disease and provision of appropriate care requires appropriate reference ranges for each ethnic group and for both sexes. This is especially true given that many guidelines for evidence-based interventions incorporate thresholds based on echocardiographic measurements, such as those for valve replacement.[[17]] The impetus for the current study, was the lack of reference echocardiographic data on healthy Māori and Pacific populations. Differences in reference ranges have previously been demonstrated in other ethnicities and confirmed in the EchoNoRMAL study.[[2]] However, being an individual participant meta-analysis, it was limited by potentially different echo methods and analysis across the different countries. The World Alliance of Societies of Echocardiography Normal Values Study (WASE)[[18]] has recently reported a large international dataset (analysed centrally) to answer this question and provided more evidence that echo measurements are different between people of European ethnicity and others, especially Asian people who have smaller hearts. Unfortunately, the WASE study does not include Indigenous populations, nor any Pacific Island populations, nor indeed many populations anticipated to have different body composition than NZ Europeans.

It is likely that body composition is a key contributor to the ethnic differences in echocardiographic measurements observed in the current study and others since FFM has previously been linked to heart size.[[3,4]] Several studies have shown that for the same body mass index (BMI), Māori and Pacific people have a higher proportion of FFM for a given BMI than NZ Europeans of similar size.[[8,19,20]] Therefore, Māori and Pacific individuals could be expected to have larger hearts. However, if this is so, it is because of increased FFM, not increased BSA. Because BSA is a crude measure of body size, it is impossible to differentiate whether two people of similar BSA have the same body composition and using it as an indexing variable to minimise differences between individuals is flawed. Furthermore, a measurement that is essentially a surrogate for the surface, are of the skin that was derived initially from nine individuals over 100 years ago, and may have little relevance to modern humans. Verbraecken et al[[21]] have recently shown that the DuBois & DuBois BSA calculator underestimates BSA in traditionally-defined obese individuals by up to 5%, and they point out that differences in nutrition and exercise may have led to changes in body composition. However, this problem may not be limited to the DuBois & DuBois calculation. In a comparison of 25 BSA formulae an alarming discrepancy was noted such that the authors noted: “Differences among calculations made by the formulae are so great that, in certain cases, they may considerably affect patients’ mortality, especially for people with an abnormal physique or for children.”[[22]] To our knowledge, there have been no BSA derivation cohorts based in Aotearoa, nor indeed, any that included Māori and Pacific people who have different body composition. It is what the skin is covering that matters, and specifically how much fat free mass.

Historically, indexation to BSA was believed to remove the differences in heart size between men and women, but we now understand this not to be the case and the current guidelines provide different indexed values for men and women.[[1]] These differences in men and women can be explained by differences in body composition also. We believe that the difference between ethnicities can also be explained by differences in body composition. And by indexing echo measurements to BSA, the ability to detect structural abnormalities is reduced in Māori and Pacific peoples. The differences seen in this study could also be explained by small differences in blood pressure observed between the ethnic groups in women (both systolic and diastolic) and men (diastolic only). But if the differences are linked to higher blood pressure in Māori and Pacific peoples, this provides even more compelling reason to not minimise the structural changes by dividing by BSA. It is unacceptable to apply reference ranges derived from one population to all other populations. Without appropriate reference ranges, timely and appropriate diagnosis and management is potentially compromised. In children, a different approach is used that measures the deviation from the mean (using standard deviations), and although FFM has also been shown to be the best predictor of heart size in children,[[3]] there is a paucity of data with regard to ethnicity and normal heart size in children and certainly none in Aotearoa.

Limitations

This study restricted the entry to adults 18–50 years because the risk of silent CVD increases with age, and careful (and potentially invasive) steps would have been needed to rule out CVD in older participants. This is an area for future research.

The results may have been influenced by the inclusion of overweight individuals. Initially we planned to exclude participants with BMI >35, but this would have excluded the majority of Pacific and some Māori participants. Therefore, a pragmatic decision was made to exclude participants with BMI >40. This also reflects the uncertainty of the use of BMI cutoffs in people of different ethnicity and different body composition, such as both the Māori and Pacific cohorts in the study, making the definition of obesity challenging. Furthermore, this population reflects a real-world cohort of healthy, younger individuals. Similarly, the results may have been influenced by physical activity, but self-reported activity was not different. Nevertheless, it would be useful to incorporate an objective measurement of physical fitness in future research to determine whether the increase in heart size seen in this cohort is linked to increased physical activity, as it has been in athletes in the past.

The study may be underpowered for some measurements and the smaller Māori and Pacific cohorts might have resulted in a failure to detect small, but clinically meaningful, differences for some variables. Nevertheless, the testing of our primary hypothesis remains robust. Furthermore, the number of observations over the age range presented is at least the same, if not greater than, reported in the WASE study.[[18]]

Another potential limitation is that measurements were made by one investigator (GAW), but this investigator is highly experienced and has led CORE lab analysis in several large trials. Measurements were made in random order, blinded to the participants’ age, sex and ethnicity. Any measurement bias that remains applies to all three groups. We are also reassured by the similarity between our NZ European cohort reference limits and those published in the ASE/EACVI guidelines,[[1]] and the EchoNoRMAL Collaboration.[[2]]

Lastly, it is unclear what the impact of using these new ranges will impact on clinical management and outcomes: longitudinal data are needed. However, it is likely that under-recognition of pathology (by “indexing out” abnormalities using BSA) has occurred and to avoid this, indexed measurements should be used cautiously until we have longitudinal data.

Conclusion

Applying the current international echocardiography reference ranges indexed to BSA in Aotearoa will under-diagnose cardiac enlargement in some Māori and Pacific Island patients, and introduce unintentional bias that preferences the detection of pathology in NZ Europeans. In other words, the application of reference ranges developed in Caucasian to Māori and Pacific patients is an example of systemic racism. This study highlights the need for ethnic-specific normal ranges and highlights the unintended consequences that arise from using a one-size approach derived from European cohorts in different ethnic groups. Whilst it may seem ideal to index measurements to a measure of body size to enable comparison across people of different sizes, this study clearly shows there is potential for delayed diagnosis if ethnic-specific reference ranges are not used and applied. Ultimately, these new reference ranges need to be prospectively linked to clinical outcomes, but it’s intuitive that if clinicians are following clinical guidelines that include linear echo measurements, and are making judgements about pathology based on international reference ranges derived from Europeans, misclassification is likely in Māori and Pacific peoples.

Summary

Abstract

Aim

To develop ethnic-specific echocardiography reference ranges for Aotearoa, and to investigate the impact of indexation to body surface area (BSA). Current reference international ranges are derived from people of mostly NZ European ethnicity and may not be appropriate for Māori and New Zealanders of Pacific ethnicity, who both experience high rates of cardiovascular disease.

Method

Echocardiography was performed in a cross-sectional study of 263 healthy adults (18–50 years): Māori (N=71, 43 female), Pacific (N=53, 28 female), European (N=139, 74 female). Linear measurements of the left heart are reported and indexed to BSA. The upper/lower limit of normal (ULN/LLN) by ethnicity and sex were derived (quantile regression). Ethnic- and sex-specific differences were examined using ANOVA.

Results

The ULN was higher for all un-indexed dimensions in men compared to women, and for most indices the ULN was smallest in NZ Europeans and largest in Māori and Pacific peoples. Indexation reversed these relationships: NZ Europeans had higher ULN for many measurements.

Conclusion

Indexing to BSA introduced bias that preferences the NZ European ethnicity by creating an upper limit reference threshold that far exceeds this sample’s upper range. As a result, this may lead to under-recognition of cardiac enlargement in Māori and Pacific patients, and in particular for women. Unique reference ranges for all ethnic groups and sexes are required to optimally detect and manage cardiovascular diseases (CVD) in Aotearoa.

Author Information

Gillian A Whalley: Department of Medicine and HeartOtago, Otago School of Medicine, The University of Otago, Dunedin, New Zealand; Unitec Institute of Technology, Auckland, New Zealand. Allanah Harrington: Unitec Institute of Technology, Auckland, New Zealand; Dunedin Hospital, Southern District Health Board, Dunedin, New Zealand. Jonathan Christiansen: Waitematā District Health Board, Auckland, New Zealand. Bettina Ikenasio: Unitec Institute of Technology, Auckland, New Zealand Arun Deo: Unitec Institute of Technology, Auckland, New Zealand Greg D Gamble: Department of Medicine, The University of Auckland, Auckland, New Zealand Sue Crengle: Department of Preventive and Social Medicine, Otago School of Medicine, The University of Otago, Dunedin, New Zealand.

Acknowledgements

This study was funded by a Health Research Council of New Zealand Research Partnerships for New Zealand Health Delivery grant (grant number 14/718).

Correspondence

Professor Gillian Whalley: Department of Medicine, Otago Medical School, University of Otago, PO Box 56 Dunedin 9054. P: 021306059.

Correspondence Email

gillian.whalley@otago.ac.nz

Competing Interests

Nil.

1) Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American society of echocardiography and the European association of cardiovascular imaging. Eur Heart J Cardiovasc Imaging. 2015;16(3):233-71.

2) The EchoNoRMAL Collaboration. Ethnic-specific normative reference values for echocardiographic LA and LV Size, LV Mass, and systolic function: The EchoNoRMAL study. JACC Cardiovasc Imaging. 2015;8(6):656-65.

3) Daniels SR, Kimball TR, Morrison JA, et al. Effect of lean body mass, fat mass, blood pressure, and sexual maturation on left ventricular mass in children and adolescents: Statistical, biological, and clinical significance. Circulation. 1995;92(11):3249-54.

4) Whalley GA, Gamble GD, Doughty RN, et al. Left ventricular mass correlates with fat-free mass but not fat mass in adults. J Hypertens. 1999;17(4):569-74.

5) Hull HR, Thornton J, Wang J, et al. Fat-free mass index: Changes and race/ethnic differences in adulthood. Int J Obes. 2011;35(1):121-7.

6) Chan WC, Wright C, Riddell T, et al. Ethnic and socioeconomic disparities in the prevalence of cardiovascular disease in New Zealand. N Z Med J. 2008;121(1285):11-20.

7) Sundborn G, Metcalf PA, Gentles D, et al. Ethnic differences in cardiovascular disease risk factors and diabetes status for Pacific ethnic groups and Europeans in the Diabetes Heart and Health Survey (DHAH) 2002-2003, Auckland New Zealand. N Z Med J. 2008;121(1281):28-39.

8) Rush EC, Freitas I, Plank LD. Body size, body composition and fat distribution: comparative analysis of European, Maori, Pacific Island and Asian Indian adults. Br J Nutr. 2009;102(04):632-41.

9) Whalley GA, Pitama S, Troughton RW, et al. Higher prevalence of left ventricular hypertrophy in two Māori cohorts: Findings from the Hauora Manawa/Community Heart Study. Aust N Z J Public Health. 2015;39(1):26-31.

10) Du Bois, D. and Du Bois EF. A Formula to Estimate the Approximate Surface Area if Height and Weight Be Known. Arch Intern Med. 1916;17(6):863-71.

11) von Elm E, Altman DG, Egger M, et al. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: Guidelines for reporting observational studies. Int J Surg. 2014;12(12):1495-9.

12) Ministry of Health, Health Information Standards Organisation. HISO 10001:2017 Ethnicity Data Protocols. Wellington; 2017.

13) Choi JO, Shin MS, Kim MJ, et al. Normal echocardiographic measurements in a Korean population study: Part I. cardiac chamber and great artery evaluation. J Cardiovasc Ultrasound. 2015;23(3):158-72.

14) Qureshi WT, Leigh JA, Swett K, et al. Comparison of echocardiographic measures in a hispanic/latino population with the 2005 and 2015 American society of echocardiography reference limits (The Echocardiographic Study of Latinos). Circ Cardiovasc Imaging. 2016;9(1):1-8.

15) McDonald-Sundborn G, Metcalf P, Scragg R, et al. Ethnic differences in the prevalence of new and known diabetes mellitus, impaired glucose tolerance, and impaired fasting glucose. Diabetes Heart and Health Survey (DHAH) 2002-2003, Auckland New Zealand. N Z Med J. 2007;120(1257):1-12.

16) Wilson N. Rheumatic Heart Disease in Indigenous Populations—New Zealand Experience. Hear Lung Circ. 2010;19(5–6):282-8.

17) Falk V, Baumgartner H, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur J Cardio-Thoracic Surg. 2017;52(4):616-64.

18) Asch FM, Miyoshi T, Addetia K, et al. Similarities and Differences in Left Ventricular Size and Function among Races and Nationalities: Results of the World Alliance Societies of Echocardiography Normal Values Study. J Am Soc Echocardiogr. 2019 Nov 1;32(11):1396-1406.e2.

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20) Rush E, Plank L, Chandu V, et al. Body size, body composition, and fat distribution: A comparison of young New Zealand men of European, Pacific Island, and Asian Indian ethnicities. N Z Med J. 2004;117(1207):1-8.

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22) Redlarski G, Palkowski A, Krawczuk M. Body surface area formulae: An alarming ambiguity. Sci Rep. 2016;6.

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Echocardiography is used to detect and monitor structural and functional cardiovascular diseases (CVD) by comparing quantitative measurements (such as heart wall thickness and chamber size) to population reference values.[[1]] Recently, the impact of ethnicity upon echo measurements has been raised. The Echocardiographic Normal Ranges Meta-Analysis of the Left heart (EchoNoRMAL),[[2]] an individual person meta-analysis with >20,000 participants, demonstrated important sex and ethnic differences in the normal echocardiographic reference ranges between NZ European, Asian and South Asian cohorts. Overall, the Asian cohorts had smaller hearts compared to the NZ European cohorts; and women had smaller hearts across all ethnic groups.[[2]]

Heart size is closely linked with body size, and guidelines recommend echocardiography measurements are indexed (divided by) by body surface area (BSA)[[1]] to allow comparison between individuals of differing sizes. But BSA is an imperfect indexation variable, and previous research suggests that body composition and fat free mass (FFM) is a better independent predictor of heart size than BSA.[[3,4]] Body composition is also linked to both sex and ethnicity: women have lower FFM than men for the same BMI; and Asian and Indian individuals have lower FFM than Caucasians of similar height and weight, who in turn have less FFM than African American individuals.[[5]] These differences may explain the sex and ethnic differences observed in heart size.

In New Zealand, CVD is a leading cause of mortality, and mortality rates are highest within the indigenous Māori[[6]] and Pacific populations.[[7]] Māori and Pacific individuals also have higher FFM compared with NZ Europeans;[[8]] therefore it is conceivable, indeed likely, that normal heart size is larger in Māori and NZ Pacific peoples. In the Hauora Manawa Heart Study,[[9]] echocardiography revealed that Māori had larger left ventricular (LV) and aortic dimensions, thicker LV walls and higher prevalence of LV hypertrophy (LVH) compared with non-Māori. Whilst this may reflect higher disease burden, it is probable that the true incidence of dilatation and LVH was overestimated by using the international reference values, as they were derived mostly from NZ European individuals.[[1]] At the time there were, and remain, no appropriate reference ranges for clinical application in Māori, nor indeed Pacific peoples.

Our objective was to establish normal reference ranges for echocardiography applicable to both New Zealand and Pacific Islands populations. Our hypothesis was that heart size would be larger in Māori and NZ Pacific peoples and that reference values that include indexation to BSA, which does not account for body composition, may be inappropriate in a cohort of mixed ethnicity. As a result, the echocardiography measurements may not be optimised in these groups, who are also at the higher risk of CVD.

Methods

Study population

This targeted cross-sectional study recruited three age-matched healthy cohorts: Māori, NZ Pacific, NZ European. Between July 2015 and September 2017, participants were recruited through convenience sampling (word of mouth, newspaper articles, primary care practices, workplaces, and recreational sporting groups). Consenting participants attended a single visit at our research facility Awhina Health Campus or at community clinics in various locations (including primary healthcare facilities and workplaces) where demographic data, and clinical and family history were collected, and clinical measurements were taken: height, weight, body composition (Tanita Body Composition Analyzer SC-330), automated blood pressure (BP), point of care total cholesterol and blood glucose (CardioChek PA); and where echocardiography was performed. Body mass index (BMI) was calculated (weight/height[[2]]) and BSA calculated by the DuBois formula.[[10]] Body composition was assessed using sex-specific non-athlete settings, and fat free mass (FFM) was calculated as total weight less fat mass, and included bone mass.

Participants were invited to begin their individual visit with the research team with a karakia, and also offered the remnant of their blood sample to take home. All remaining blood samples were collated in a single medical waste container (separate from general waste) for a cremation ceremony at the study completion. Participants were given a $20 fuel voucher as a koha, as well as pamphlets about reducing the risk of stroke, diabetes and heart disease. These were available in English, te reo Māori, Samoan and Tongan languages. All participants provided signed written consent. The study was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement[[11]] and was approved by the Southern Health and Disability Ethics Committee (approval number 15/STH/96).

Inclusion and exclusion criteria

Participants aged 18–50 years who self-identified as Māori, NZ European, or Pacific Island ethnicity, with good health, were invited. NZ Pacific peoples included participants who identified as either Cook Island Māori, Fijian, Niuean, Samoan, Tahitian or Tongan. Participants who identified as Fijian Indian Pacific were excluded. Other patient exclusion included: random (non-fasting) total cholesterol of >7·0mmol/L or glucose of >10mmol/L; BMI >40; currently or recently (<3 months) pregnant; hypertension (greater than 145/90 on two different automated BP measurements); history of CVD, diabetes, renal failure or other serious conditions (including lung disease or asthma on regular medication (N=2)); taking any cardiovascular medications (except statins); and significant incidental echo findings.

Ethnicity determination

Ethnicity was self-identified, and participants were able to select more than one group, in which case, group allocation was ascribed according to the prioritisation method in the New Zealand Ministry of Health’s ethnicity data protocol: 1) Māori, 2) Pacific, 3) Asian, 4) European.[[12]] This ensured that participants were only counted in one group. For example, if a participant reported both Māori and European ethnicity, they were allocated to the Māori group. If a participant selected Māori and Pacific, they were also allocated to the Māori group.

Echocardiography

Echocardiography was performed by experienced sonographers or cardiology fellows according to a standard research protocol adherent to the ASE Guidelines (Philips CX50 or Siemens SC2000prime). Full echo data are available, but this publication includes linear 2D measurements of the left heart: left ventricular internal end-diastolic dimension (LVIDd); left ventricular internal end-systolic dimension (LVIDs); left ventricular outflow tract (LVOT); and aortic root and proximal ascending aorta. These measurements were made (average of three beats) off-line (Philips Q Station), and by a single reader (GAW) at the conclusion of the study in random order blinded to ethnicity, sex or other clinical information. All measurements were obtained according to recommendations of the American Society of Echocardiography Chamber Quantification Guidelines.[[1]]

Statistical analysis

Exploratory data analysis revealed that all of the variables were normally distributed. Quantile regression was used to determine the 95th and 5th centiles to determine upper limits of normal (ULN) and lower limits of normal (LLN) for each echo measurement. ANOVA was used to determine difference between the three ethnic groups, sex and the interaction of sex and ethnicity. Post hoc analysis was performed using Tukey method.

Results

Study population

After initial screening, 372 participants attended the first visit and 109 were excluded, leaving a final cohort of 263: 71 Māori (43 female, 28 male); 53 NZ Pacific (26 female, 27 male); and 139 NZ European (74 female, 65 male) participants (Figure 1).

The groups were well-matched in terms of age, height, blood pressure and heart rate (Table 1). Significant differences were observed in weight and body composition, with Māori having higher weight, fat mass (FM), fat free mass (FFM) and bone mass than NZ Europeans in both males and females, and with Pacific peoples having the highest. The same pattern was observed in each sex and for calculated BMI and BSA: the NZ European cohort had the lowest, and Pacific the highest, with Māori in between. No significant differences were observed between self-reported physical activity status.

Linear measurements of the left ventricle

For linear LV measurements, the ULN and LLN were higher in men compared to women and varied significantly by ethnicity: the NZ European cohort had the smallest chambers compared to both the Pacific and Māori cohorts (Table 2). Indexation to BSA did not remove the sex differences but did change the order of the ethnic group differences, in such that now the NZ European group had the largest hearts. The only interaction between ethnicity and sex noted was for LVIDs and LVIDs/BSA, which are measures of both size and function.  

Post hoc analyses within these sex groups revealed trends towards the differences noted above, but the only significant difference in unindexed measurements was for LVIDs, where NZ Pacific men had larger LVIDs compared to both NZ European and Māori men (Figure 2). But, when indexed to BSA, these differences in men were eliminated; however, significant differences between ethnicities emerged in women. NZ Pacific women had smaller hearts compared to both the Māori and NZ European women (Figure 2).

Raw unindexed measures of the after larger and before LV. Men had larger LV outflow tract (LVOT), aortic root (AoR) and ascending aortic (AscAo) dimensions than women (Table 2), and significant differences were seen across ethnicities. The relationship was similar to that observed for LV measurements; the European cohort had the smallest compared to both the Pacific and Māori groups. Indexation removed the sex differences for both LVOT and AoR (Table 2) and introduced a significant interaction between ethnicity and sex for LVOT/BSA, and the relationship across the ethnic groups altered such that the European cohort no longer had the smallest measurements: NZ European women now had the largest LVOT/BSA measurements (Figure 3).

Comparison with other reference values

There was general agreement between the ULN seen in this NZ European cohort when compared to both ASE/EACVI and EchoNoRMAL indexed variables[[1,2]] for both men and women (Table 3) and where differences are seen, these are of marginal clinical relevance. However, comparing the distribution of the data for LVIDd with the ASE/EASCVI reference values, a substantial proportion (19% of European men, 26% of European women; 29% of Māori men, 42% of Māori women; and 15% of Pacific men, 27% of Pacific women) fell outside of the reference ranges for raw measurements of LVIDd (Figure 4). In both sexes, the data for Māori and Pacific peoples was shifted to the right for un-indexed LVIDd resulting in higher levels of “abnormal” measurements in Māori men (28.5%) and women (42.3%), but not Pacific participants. Indexation to BSA shifted the distributions to the left and eliminated all abnormal measurements in the Pacific group and a substantial proportion in the Māori groups. In the European group, indexation reduced this from 19–5% in men and 26–6% in women. In both the Māori and Pacific groups, the reduction was even greater: 29–7% in Māori men and 42–3% in Māori women; 15–0% in Pacific Island men and 27–0% in Pacific women.

View Supplementary Figures & Tables.

Discussion

This study has shown, important differences in echocardiographic reference ranges between New Zealanders of European, Māori and Pacific ethnic groups. The results are consistent with previous research showing that echocardiographic heart size, is dependent on sex and ethnicity,[[13,14]] and suggests that current international Caucasian reference values are not applicable in Aotearoa, and worse, will contribute to poorer health outcomes due to misdiagnosis when used in Māori and Pacific peoples. Specifically, we found that heart size is different among these ethnic groups, and that application of the current international guidelines, specifically indexation to BSA, is an imperfect adjustment that may mask the presence of pathological abnormalities.

Indexation to BSA is intended to allow fair comparison of heart size amongst people of different body habitus. But from this data, it is apparent that unintentional preference may be introduced in healthcare delivery, in a way that preferences NZ European ethnicity: for example, among Māori and NZ Pacific peoples using a reference range, derived from a Caucasian population, may result in misclassification of abnormal heart size (such as with cardiomyopathy) as normal with subsequent under-treatment. This is systemic racism and puts Māori and Pacific peoples at higher risk of worse CVD outcomes but could be overcome if ethnic-specific references ranges were adopted in Aotearoa.

Globally, echocardiography is the main tool used to diagnose and monitor pathological cardiac changes, and its use will grow as the size and cost of equipment declines rapidly. However, normal echo reference ranges are yet to be determined for many ethnic groups. Given the dependence upon echocardiography, and in particular LV linear dimensions, to diagnose CVD, and guide interventions, timely and appropriate detection of abnormal heart size is paramount. Similar to other Indigenous populations, Māori and NZ Pacific peoples have the worst cardiovascular outcomes of all New Zealanders,[[6,7]] and are over-represented in almost every type of CVD. Further, CVD risk factors such as diabetes, hypertension and dyslipidaemia, are also more prevalent in Māori and NZ Pacific populations[[7,15]] as is rheumatic heart disease.[[16]] The results of this study indicate that the application of current normal reference indexed values, derived from mostly European individuals, is inappropriate and may lead to delayed diagnosis, especially if indexation to BSA is used.

Optimal identification of disease and provision of appropriate care requires appropriate reference ranges for each ethnic group and for both sexes. This is especially true given that many guidelines for evidence-based interventions incorporate thresholds based on echocardiographic measurements, such as those for valve replacement.[[17]] The impetus for the current study, was the lack of reference echocardiographic data on healthy Māori and Pacific populations. Differences in reference ranges have previously been demonstrated in other ethnicities and confirmed in the EchoNoRMAL study.[[2]] However, being an individual participant meta-analysis, it was limited by potentially different echo methods and analysis across the different countries. The World Alliance of Societies of Echocardiography Normal Values Study (WASE)[[18]] has recently reported a large international dataset (analysed centrally) to answer this question and provided more evidence that echo measurements are different between people of European ethnicity and others, especially Asian people who have smaller hearts. Unfortunately, the WASE study does not include Indigenous populations, nor any Pacific Island populations, nor indeed many populations anticipated to have different body composition than NZ Europeans.

It is likely that body composition is a key contributor to the ethnic differences in echocardiographic measurements observed in the current study and others since FFM has previously been linked to heart size.[[3,4]] Several studies have shown that for the same body mass index (BMI), Māori and Pacific people have a higher proportion of FFM for a given BMI than NZ Europeans of similar size.[[8,19,20]] Therefore, Māori and Pacific individuals could be expected to have larger hearts. However, if this is so, it is because of increased FFM, not increased BSA. Because BSA is a crude measure of body size, it is impossible to differentiate whether two people of similar BSA have the same body composition and using it as an indexing variable to minimise differences between individuals is flawed. Furthermore, a measurement that is essentially a surrogate for the surface, are of the skin that was derived initially from nine individuals over 100 years ago, and may have little relevance to modern humans. Verbraecken et al[[21]] have recently shown that the DuBois & DuBois BSA calculator underestimates BSA in traditionally-defined obese individuals by up to 5%, and they point out that differences in nutrition and exercise may have led to changes in body composition. However, this problem may not be limited to the DuBois & DuBois calculation. In a comparison of 25 BSA formulae an alarming discrepancy was noted such that the authors noted: “Differences among calculations made by the formulae are so great that, in certain cases, they may considerably affect patients’ mortality, especially for people with an abnormal physique or for children.”[[22]] To our knowledge, there have been no BSA derivation cohorts based in Aotearoa, nor indeed, any that included Māori and Pacific people who have different body composition. It is what the skin is covering that matters, and specifically how much fat free mass.

Historically, indexation to BSA was believed to remove the differences in heart size between men and women, but we now understand this not to be the case and the current guidelines provide different indexed values for men and women.[[1]] These differences in men and women can be explained by differences in body composition also. We believe that the difference between ethnicities can also be explained by differences in body composition. And by indexing echo measurements to BSA, the ability to detect structural abnormalities is reduced in Māori and Pacific peoples. The differences seen in this study could also be explained by small differences in blood pressure observed between the ethnic groups in women (both systolic and diastolic) and men (diastolic only). But if the differences are linked to higher blood pressure in Māori and Pacific peoples, this provides even more compelling reason to not minimise the structural changes by dividing by BSA. It is unacceptable to apply reference ranges derived from one population to all other populations. Without appropriate reference ranges, timely and appropriate diagnosis and management is potentially compromised. In children, a different approach is used that measures the deviation from the mean (using standard deviations), and although FFM has also been shown to be the best predictor of heart size in children,[[3]] there is a paucity of data with regard to ethnicity and normal heart size in children and certainly none in Aotearoa.

Limitations

This study restricted the entry to adults 18–50 years because the risk of silent CVD increases with age, and careful (and potentially invasive) steps would have been needed to rule out CVD in older participants. This is an area for future research.

The results may have been influenced by the inclusion of overweight individuals. Initially we planned to exclude participants with BMI >35, but this would have excluded the majority of Pacific and some Māori participants. Therefore, a pragmatic decision was made to exclude participants with BMI >40. This also reflects the uncertainty of the use of BMI cutoffs in people of different ethnicity and different body composition, such as both the Māori and Pacific cohorts in the study, making the definition of obesity challenging. Furthermore, this population reflects a real-world cohort of healthy, younger individuals. Similarly, the results may have been influenced by physical activity, but self-reported activity was not different. Nevertheless, it would be useful to incorporate an objective measurement of physical fitness in future research to determine whether the increase in heart size seen in this cohort is linked to increased physical activity, as it has been in athletes in the past.

The study may be underpowered for some measurements and the smaller Māori and Pacific cohorts might have resulted in a failure to detect small, but clinically meaningful, differences for some variables. Nevertheless, the testing of our primary hypothesis remains robust. Furthermore, the number of observations over the age range presented is at least the same, if not greater than, reported in the WASE study.[[18]]

Another potential limitation is that measurements were made by one investigator (GAW), but this investigator is highly experienced and has led CORE lab analysis in several large trials. Measurements were made in random order, blinded to the participants’ age, sex and ethnicity. Any measurement bias that remains applies to all three groups. We are also reassured by the similarity between our NZ European cohort reference limits and those published in the ASE/EACVI guidelines,[[1]] and the EchoNoRMAL Collaboration.[[2]]

Lastly, it is unclear what the impact of using these new ranges will impact on clinical management and outcomes: longitudinal data are needed. However, it is likely that under-recognition of pathology (by “indexing out” abnormalities using BSA) has occurred and to avoid this, indexed measurements should be used cautiously until we have longitudinal data.

Conclusion

Applying the current international echocardiography reference ranges indexed to BSA in Aotearoa will under-diagnose cardiac enlargement in some Māori and Pacific Island patients, and introduce unintentional bias that preferences the detection of pathology in NZ Europeans. In other words, the application of reference ranges developed in Caucasian to Māori and Pacific patients is an example of systemic racism. This study highlights the need for ethnic-specific normal ranges and highlights the unintended consequences that arise from using a one-size approach derived from European cohorts in different ethnic groups. Whilst it may seem ideal to index measurements to a measure of body size to enable comparison across people of different sizes, this study clearly shows there is potential for delayed diagnosis if ethnic-specific reference ranges are not used and applied. Ultimately, these new reference ranges need to be prospectively linked to clinical outcomes, but it’s intuitive that if clinicians are following clinical guidelines that include linear echo measurements, and are making judgements about pathology based on international reference ranges derived from Europeans, misclassification is likely in Māori and Pacific peoples.

Summary

Abstract

Aim

To develop ethnic-specific echocardiography reference ranges for Aotearoa, and to investigate the impact of indexation to body surface area (BSA). Current reference international ranges are derived from people of mostly NZ European ethnicity and may not be appropriate for Māori and New Zealanders of Pacific ethnicity, who both experience high rates of cardiovascular disease.

Method

Echocardiography was performed in a cross-sectional study of 263 healthy adults (18–50 years): Māori (N=71, 43 female), Pacific (N=53, 28 female), European (N=139, 74 female). Linear measurements of the left heart are reported and indexed to BSA. The upper/lower limit of normal (ULN/LLN) by ethnicity and sex were derived (quantile regression). Ethnic- and sex-specific differences were examined using ANOVA.

Results

The ULN was higher for all un-indexed dimensions in men compared to women, and for most indices the ULN was smallest in NZ Europeans and largest in Māori and Pacific peoples. Indexation reversed these relationships: NZ Europeans had higher ULN for many measurements.

Conclusion

Indexing to BSA introduced bias that preferences the NZ European ethnicity by creating an upper limit reference threshold that far exceeds this sample’s upper range. As a result, this may lead to under-recognition of cardiac enlargement in Māori and Pacific patients, and in particular for women. Unique reference ranges for all ethnic groups and sexes are required to optimally detect and manage cardiovascular diseases (CVD) in Aotearoa.

Author Information

Gillian A Whalley: Department of Medicine and HeartOtago, Otago School of Medicine, The University of Otago, Dunedin, New Zealand; Unitec Institute of Technology, Auckland, New Zealand. Allanah Harrington: Unitec Institute of Technology, Auckland, New Zealand; Dunedin Hospital, Southern District Health Board, Dunedin, New Zealand. Jonathan Christiansen: Waitematā District Health Board, Auckland, New Zealand. Bettina Ikenasio: Unitec Institute of Technology, Auckland, New Zealand Arun Deo: Unitec Institute of Technology, Auckland, New Zealand Greg D Gamble: Department of Medicine, The University of Auckland, Auckland, New Zealand Sue Crengle: Department of Preventive and Social Medicine, Otago School of Medicine, The University of Otago, Dunedin, New Zealand.

Acknowledgements

This study was funded by a Health Research Council of New Zealand Research Partnerships for New Zealand Health Delivery grant (grant number 14/718).

Correspondence

Professor Gillian Whalley: Department of Medicine, Otago Medical School, University of Otago, PO Box 56 Dunedin 9054. P: 021306059.

Correspondence Email

gillian.whalley@otago.ac.nz

Competing Interests

Nil.

1) Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American society of echocardiography and the European association of cardiovascular imaging. Eur Heart J Cardiovasc Imaging. 2015;16(3):233-71.

2) The EchoNoRMAL Collaboration. Ethnic-specific normative reference values for echocardiographic LA and LV Size, LV Mass, and systolic function: The EchoNoRMAL study. JACC Cardiovasc Imaging. 2015;8(6):656-65.

3) Daniels SR, Kimball TR, Morrison JA, et al. Effect of lean body mass, fat mass, blood pressure, and sexual maturation on left ventricular mass in children and adolescents: Statistical, biological, and clinical significance. Circulation. 1995;92(11):3249-54.

4) Whalley GA, Gamble GD, Doughty RN, et al. Left ventricular mass correlates with fat-free mass but not fat mass in adults. J Hypertens. 1999;17(4):569-74.

5) Hull HR, Thornton J, Wang J, et al. Fat-free mass index: Changes and race/ethnic differences in adulthood. Int J Obes. 2011;35(1):121-7.

6) Chan WC, Wright C, Riddell T, et al. Ethnic and socioeconomic disparities in the prevalence of cardiovascular disease in New Zealand. N Z Med J. 2008;121(1285):11-20.

7) Sundborn G, Metcalf PA, Gentles D, et al. Ethnic differences in cardiovascular disease risk factors and diabetes status for Pacific ethnic groups and Europeans in the Diabetes Heart and Health Survey (DHAH) 2002-2003, Auckland New Zealand. N Z Med J. 2008;121(1281):28-39.

8) Rush EC, Freitas I, Plank LD. Body size, body composition and fat distribution: comparative analysis of European, Maori, Pacific Island and Asian Indian adults. Br J Nutr. 2009;102(04):632-41.

9) Whalley GA, Pitama S, Troughton RW, et al. Higher prevalence of left ventricular hypertrophy in two Māori cohorts: Findings from the Hauora Manawa/Community Heart Study. Aust N Z J Public Health. 2015;39(1):26-31.

10) Du Bois, D. and Du Bois EF. A Formula to Estimate the Approximate Surface Area if Height and Weight Be Known. Arch Intern Med. 1916;17(6):863-71.

11) von Elm E, Altman DG, Egger M, et al. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: Guidelines for reporting observational studies. Int J Surg. 2014;12(12):1495-9.

12) Ministry of Health, Health Information Standards Organisation. HISO 10001:2017 Ethnicity Data Protocols. Wellington; 2017.

13) Choi JO, Shin MS, Kim MJ, et al. Normal echocardiographic measurements in a Korean population study: Part I. cardiac chamber and great artery evaluation. J Cardiovasc Ultrasound. 2015;23(3):158-72.

14) Qureshi WT, Leigh JA, Swett K, et al. Comparison of echocardiographic measures in a hispanic/latino population with the 2005 and 2015 American society of echocardiography reference limits (The Echocardiographic Study of Latinos). Circ Cardiovasc Imaging. 2016;9(1):1-8.

15) McDonald-Sundborn G, Metcalf P, Scragg R, et al. Ethnic differences in the prevalence of new and known diabetes mellitus, impaired glucose tolerance, and impaired fasting glucose. Diabetes Heart and Health Survey (DHAH) 2002-2003, Auckland New Zealand. N Z Med J. 2007;120(1257):1-12.

16) Wilson N. Rheumatic Heart Disease in Indigenous Populations—New Zealand Experience. Hear Lung Circ. 2010;19(5–6):282-8.

17) Falk V, Baumgartner H, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur J Cardio-Thoracic Surg. 2017;52(4):616-64.

18) Asch FM, Miyoshi T, Addetia K, et al. Similarities and Differences in Left Ventricular Size and Function among Races and Nationalities: Results of the World Alliance Societies of Echocardiography Normal Values Study. J Am Soc Echocardiogr. 2019 Nov 1;32(11):1396-1406.e2.

19) Swinburn B, Ley S, Carmichael H, Plank L. Body size and composition in Polynesians. Int J Obes. 1999 Nov 11;23(11):1178-83.

20) Rush E, Plank L, Chandu V, et al. Body size, body composition, and fat distribution: A comparison of young New Zealand men of European, Pacific Island, and Asian Indian ethnicities. N Z Med J. 2004;117(1207):1-8.

21) Verbraecken J, Van De Heyning P, De Backer W, Van Gaal L. Body surface area in normal-weight, overweight, and obese adults. A comparison study. Metabolism. 2006;55(4):515-24.

22) Redlarski G, Palkowski A, Krawczuk M. Body surface area formulae: An alarming ambiguity. Sci Rep. 2016;6.

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Echocardiography is used to detect and monitor structural and functional cardiovascular diseases (CVD) by comparing quantitative measurements (such as heart wall thickness and chamber size) to population reference values.[[1]] Recently, the impact of ethnicity upon echo measurements has been raised. The Echocardiographic Normal Ranges Meta-Analysis of the Left heart (EchoNoRMAL),[[2]] an individual person meta-analysis with >20,000 participants, demonstrated important sex and ethnic differences in the normal echocardiographic reference ranges between NZ European, Asian and South Asian cohorts. Overall, the Asian cohorts had smaller hearts compared to the NZ European cohorts; and women had smaller hearts across all ethnic groups.[[2]]

Heart size is closely linked with body size, and guidelines recommend echocardiography measurements are indexed (divided by) by body surface area (BSA)[[1]] to allow comparison between individuals of differing sizes. But BSA is an imperfect indexation variable, and previous research suggests that body composition and fat free mass (FFM) is a better independent predictor of heart size than BSA.[[3,4]] Body composition is also linked to both sex and ethnicity: women have lower FFM than men for the same BMI; and Asian and Indian individuals have lower FFM than Caucasians of similar height and weight, who in turn have less FFM than African American individuals.[[5]] These differences may explain the sex and ethnic differences observed in heart size.

In New Zealand, CVD is a leading cause of mortality, and mortality rates are highest within the indigenous Māori[[6]] and Pacific populations.[[7]] Māori and Pacific individuals also have higher FFM compared with NZ Europeans;[[8]] therefore it is conceivable, indeed likely, that normal heart size is larger in Māori and NZ Pacific peoples. In the Hauora Manawa Heart Study,[[9]] echocardiography revealed that Māori had larger left ventricular (LV) and aortic dimensions, thicker LV walls and higher prevalence of LV hypertrophy (LVH) compared with non-Māori. Whilst this may reflect higher disease burden, it is probable that the true incidence of dilatation and LVH was overestimated by using the international reference values, as they were derived mostly from NZ European individuals.[[1]] At the time there were, and remain, no appropriate reference ranges for clinical application in Māori, nor indeed Pacific peoples.

Our objective was to establish normal reference ranges for echocardiography applicable to both New Zealand and Pacific Islands populations. Our hypothesis was that heart size would be larger in Māori and NZ Pacific peoples and that reference values that include indexation to BSA, which does not account for body composition, may be inappropriate in a cohort of mixed ethnicity. As a result, the echocardiography measurements may not be optimised in these groups, who are also at the higher risk of CVD.

Methods

Study population

This targeted cross-sectional study recruited three age-matched healthy cohorts: Māori, NZ Pacific, NZ European. Between July 2015 and September 2017, participants were recruited through convenience sampling (word of mouth, newspaper articles, primary care practices, workplaces, and recreational sporting groups). Consenting participants attended a single visit at our research facility Awhina Health Campus or at community clinics in various locations (including primary healthcare facilities and workplaces) where demographic data, and clinical and family history were collected, and clinical measurements were taken: height, weight, body composition (Tanita Body Composition Analyzer SC-330), automated blood pressure (BP), point of care total cholesterol and blood glucose (CardioChek PA); and where echocardiography was performed. Body mass index (BMI) was calculated (weight/height[[2]]) and BSA calculated by the DuBois formula.[[10]] Body composition was assessed using sex-specific non-athlete settings, and fat free mass (FFM) was calculated as total weight less fat mass, and included bone mass.

Participants were invited to begin their individual visit with the research team with a karakia, and also offered the remnant of their blood sample to take home. All remaining blood samples were collated in a single medical waste container (separate from general waste) for a cremation ceremony at the study completion. Participants were given a $20 fuel voucher as a koha, as well as pamphlets about reducing the risk of stroke, diabetes and heart disease. These were available in English, te reo Māori, Samoan and Tongan languages. All participants provided signed written consent. The study was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement[[11]] and was approved by the Southern Health and Disability Ethics Committee (approval number 15/STH/96).

Inclusion and exclusion criteria

Participants aged 18–50 years who self-identified as Māori, NZ European, or Pacific Island ethnicity, with good health, were invited. NZ Pacific peoples included participants who identified as either Cook Island Māori, Fijian, Niuean, Samoan, Tahitian or Tongan. Participants who identified as Fijian Indian Pacific were excluded. Other patient exclusion included: random (non-fasting) total cholesterol of >7·0mmol/L or glucose of >10mmol/L; BMI >40; currently or recently (<3 months) pregnant; hypertension (greater than 145/90 on two different automated BP measurements); history of CVD, diabetes, renal failure or other serious conditions (including lung disease or asthma on regular medication (N=2)); taking any cardiovascular medications (except statins); and significant incidental echo findings.

Ethnicity determination

Ethnicity was self-identified, and participants were able to select more than one group, in which case, group allocation was ascribed according to the prioritisation method in the New Zealand Ministry of Health’s ethnicity data protocol: 1) Māori, 2) Pacific, 3) Asian, 4) European.[[12]] This ensured that participants were only counted in one group. For example, if a participant reported both Māori and European ethnicity, they were allocated to the Māori group. If a participant selected Māori and Pacific, they were also allocated to the Māori group.

Echocardiography

Echocardiography was performed by experienced sonographers or cardiology fellows according to a standard research protocol adherent to the ASE Guidelines (Philips CX50 or Siemens SC2000prime). Full echo data are available, but this publication includes linear 2D measurements of the left heart: left ventricular internal end-diastolic dimension (LVIDd); left ventricular internal end-systolic dimension (LVIDs); left ventricular outflow tract (LVOT); and aortic root and proximal ascending aorta. These measurements were made (average of three beats) off-line (Philips Q Station), and by a single reader (GAW) at the conclusion of the study in random order blinded to ethnicity, sex or other clinical information. All measurements were obtained according to recommendations of the American Society of Echocardiography Chamber Quantification Guidelines.[[1]]

Statistical analysis

Exploratory data analysis revealed that all of the variables were normally distributed. Quantile regression was used to determine the 95th and 5th centiles to determine upper limits of normal (ULN) and lower limits of normal (LLN) for each echo measurement. ANOVA was used to determine difference between the three ethnic groups, sex and the interaction of sex and ethnicity. Post hoc analysis was performed using Tukey method.

Results

Study population

After initial screening, 372 participants attended the first visit and 109 were excluded, leaving a final cohort of 263: 71 Māori (43 female, 28 male); 53 NZ Pacific (26 female, 27 male); and 139 NZ European (74 female, 65 male) participants (Figure 1).

The groups were well-matched in terms of age, height, blood pressure and heart rate (Table 1). Significant differences were observed in weight and body composition, with Māori having higher weight, fat mass (FM), fat free mass (FFM) and bone mass than NZ Europeans in both males and females, and with Pacific peoples having the highest. The same pattern was observed in each sex and for calculated BMI and BSA: the NZ European cohort had the lowest, and Pacific the highest, with Māori in between. No significant differences were observed between self-reported physical activity status.

Linear measurements of the left ventricle

For linear LV measurements, the ULN and LLN were higher in men compared to women and varied significantly by ethnicity: the NZ European cohort had the smallest chambers compared to both the Pacific and Māori cohorts (Table 2). Indexation to BSA did not remove the sex differences but did change the order of the ethnic group differences, in such that now the NZ European group had the largest hearts. The only interaction between ethnicity and sex noted was for LVIDs and LVIDs/BSA, which are measures of both size and function.  

Post hoc analyses within these sex groups revealed trends towards the differences noted above, but the only significant difference in unindexed measurements was for LVIDs, where NZ Pacific men had larger LVIDs compared to both NZ European and Māori men (Figure 2). But, when indexed to BSA, these differences in men were eliminated; however, significant differences between ethnicities emerged in women. NZ Pacific women had smaller hearts compared to both the Māori and NZ European women (Figure 2).

Raw unindexed measures of the after larger and before LV. Men had larger LV outflow tract (LVOT), aortic root (AoR) and ascending aortic (AscAo) dimensions than women (Table 2), and significant differences were seen across ethnicities. The relationship was similar to that observed for LV measurements; the European cohort had the smallest compared to both the Pacific and Māori groups. Indexation removed the sex differences for both LVOT and AoR (Table 2) and introduced a significant interaction between ethnicity and sex for LVOT/BSA, and the relationship across the ethnic groups altered such that the European cohort no longer had the smallest measurements: NZ European women now had the largest LVOT/BSA measurements (Figure 3).

Comparison with other reference values

There was general agreement between the ULN seen in this NZ European cohort when compared to both ASE/EACVI and EchoNoRMAL indexed variables[[1,2]] for both men and women (Table 3) and where differences are seen, these are of marginal clinical relevance. However, comparing the distribution of the data for LVIDd with the ASE/EASCVI reference values, a substantial proportion (19% of European men, 26% of European women; 29% of Māori men, 42% of Māori women; and 15% of Pacific men, 27% of Pacific women) fell outside of the reference ranges for raw measurements of LVIDd (Figure 4). In both sexes, the data for Māori and Pacific peoples was shifted to the right for un-indexed LVIDd resulting in higher levels of “abnormal” measurements in Māori men (28.5%) and women (42.3%), but not Pacific participants. Indexation to BSA shifted the distributions to the left and eliminated all abnormal measurements in the Pacific group and a substantial proportion in the Māori groups. In the European group, indexation reduced this from 19–5% in men and 26–6% in women. In both the Māori and Pacific groups, the reduction was even greater: 29–7% in Māori men and 42–3% in Māori women; 15–0% in Pacific Island men and 27–0% in Pacific women.

View Supplementary Figures & Tables.

Discussion

This study has shown, important differences in echocardiographic reference ranges between New Zealanders of European, Māori and Pacific ethnic groups. The results are consistent with previous research showing that echocardiographic heart size, is dependent on sex and ethnicity,[[13,14]] and suggests that current international Caucasian reference values are not applicable in Aotearoa, and worse, will contribute to poorer health outcomes due to misdiagnosis when used in Māori and Pacific peoples. Specifically, we found that heart size is different among these ethnic groups, and that application of the current international guidelines, specifically indexation to BSA, is an imperfect adjustment that may mask the presence of pathological abnormalities.

Indexation to BSA is intended to allow fair comparison of heart size amongst people of different body habitus. But from this data, it is apparent that unintentional preference may be introduced in healthcare delivery, in a way that preferences NZ European ethnicity: for example, among Māori and NZ Pacific peoples using a reference range, derived from a Caucasian population, may result in misclassification of abnormal heart size (such as with cardiomyopathy) as normal with subsequent under-treatment. This is systemic racism and puts Māori and Pacific peoples at higher risk of worse CVD outcomes but could be overcome if ethnic-specific references ranges were adopted in Aotearoa.

Globally, echocardiography is the main tool used to diagnose and monitor pathological cardiac changes, and its use will grow as the size and cost of equipment declines rapidly. However, normal echo reference ranges are yet to be determined for many ethnic groups. Given the dependence upon echocardiography, and in particular LV linear dimensions, to diagnose CVD, and guide interventions, timely and appropriate detection of abnormal heart size is paramount. Similar to other Indigenous populations, Māori and NZ Pacific peoples have the worst cardiovascular outcomes of all New Zealanders,[[6,7]] and are over-represented in almost every type of CVD. Further, CVD risk factors such as diabetes, hypertension and dyslipidaemia, are also more prevalent in Māori and NZ Pacific populations[[7,15]] as is rheumatic heart disease.[[16]] The results of this study indicate that the application of current normal reference indexed values, derived from mostly European individuals, is inappropriate and may lead to delayed diagnosis, especially if indexation to BSA is used.

Optimal identification of disease and provision of appropriate care requires appropriate reference ranges for each ethnic group and for both sexes. This is especially true given that many guidelines for evidence-based interventions incorporate thresholds based on echocardiographic measurements, such as those for valve replacement.[[17]] The impetus for the current study, was the lack of reference echocardiographic data on healthy Māori and Pacific populations. Differences in reference ranges have previously been demonstrated in other ethnicities and confirmed in the EchoNoRMAL study.[[2]] However, being an individual participant meta-analysis, it was limited by potentially different echo methods and analysis across the different countries. The World Alliance of Societies of Echocardiography Normal Values Study (WASE)[[18]] has recently reported a large international dataset (analysed centrally) to answer this question and provided more evidence that echo measurements are different between people of European ethnicity and others, especially Asian people who have smaller hearts. Unfortunately, the WASE study does not include Indigenous populations, nor any Pacific Island populations, nor indeed many populations anticipated to have different body composition than NZ Europeans.

It is likely that body composition is a key contributor to the ethnic differences in echocardiographic measurements observed in the current study and others since FFM has previously been linked to heart size.[[3,4]] Several studies have shown that for the same body mass index (BMI), Māori and Pacific people have a higher proportion of FFM for a given BMI than NZ Europeans of similar size.[[8,19,20]] Therefore, Māori and Pacific individuals could be expected to have larger hearts. However, if this is so, it is because of increased FFM, not increased BSA. Because BSA is a crude measure of body size, it is impossible to differentiate whether two people of similar BSA have the same body composition and using it as an indexing variable to minimise differences between individuals is flawed. Furthermore, a measurement that is essentially a surrogate for the surface, are of the skin that was derived initially from nine individuals over 100 years ago, and may have little relevance to modern humans. Verbraecken et al[[21]] have recently shown that the DuBois & DuBois BSA calculator underestimates BSA in traditionally-defined obese individuals by up to 5%, and they point out that differences in nutrition and exercise may have led to changes in body composition. However, this problem may not be limited to the DuBois & DuBois calculation. In a comparison of 25 BSA formulae an alarming discrepancy was noted such that the authors noted: “Differences among calculations made by the formulae are so great that, in certain cases, they may considerably affect patients’ mortality, especially for people with an abnormal physique or for children.”[[22]] To our knowledge, there have been no BSA derivation cohorts based in Aotearoa, nor indeed, any that included Māori and Pacific people who have different body composition. It is what the skin is covering that matters, and specifically how much fat free mass.

Historically, indexation to BSA was believed to remove the differences in heart size between men and women, but we now understand this not to be the case and the current guidelines provide different indexed values for men and women.[[1]] These differences in men and women can be explained by differences in body composition also. We believe that the difference between ethnicities can also be explained by differences in body composition. And by indexing echo measurements to BSA, the ability to detect structural abnormalities is reduced in Māori and Pacific peoples. The differences seen in this study could also be explained by small differences in blood pressure observed between the ethnic groups in women (both systolic and diastolic) and men (diastolic only). But if the differences are linked to higher blood pressure in Māori and Pacific peoples, this provides even more compelling reason to not minimise the structural changes by dividing by BSA. It is unacceptable to apply reference ranges derived from one population to all other populations. Without appropriate reference ranges, timely and appropriate diagnosis and management is potentially compromised. In children, a different approach is used that measures the deviation from the mean (using standard deviations), and although FFM has also been shown to be the best predictor of heart size in children,[[3]] there is a paucity of data with regard to ethnicity and normal heart size in children and certainly none in Aotearoa.

Limitations

This study restricted the entry to adults 18–50 years because the risk of silent CVD increases with age, and careful (and potentially invasive) steps would have been needed to rule out CVD in older participants. This is an area for future research.

The results may have been influenced by the inclusion of overweight individuals. Initially we planned to exclude participants with BMI >35, but this would have excluded the majority of Pacific and some Māori participants. Therefore, a pragmatic decision was made to exclude participants with BMI >40. This also reflects the uncertainty of the use of BMI cutoffs in people of different ethnicity and different body composition, such as both the Māori and Pacific cohorts in the study, making the definition of obesity challenging. Furthermore, this population reflects a real-world cohort of healthy, younger individuals. Similarly, the results may have been influenced by physical activity, but self-reported activity was not different. Nevertheless, it would be useful to incorporate an objective measurement of physical fitness in future research to determine whether the increase in heart size seen in this cohort is linked to increased physical activity, as it has been in athletes in the past.

The study may be underpowered for some measurements and the smaller Māori and Pacific cohorts might have resulted in a failure to detect small, but clinically meaningful, differences for some variables. Nevertheless, the testing of our primary hypothesis remains robust. Furthermore, the number of observations over the age range presented is at least the same, if not greater than, reported in the WASE study.[[18]]

Another potential limitation is that measurements were made by one investigator (GAW), but this investigator is highly experienced and has led CORE lab analysis in several large trials. Measurements were made in random order, blinded to the participants’ age, sex and ethnicity. Any measurement bias that remains applies to all three groups. We are also reassured by the similarity between our NZ European cohort reference limits and those published in the ASE/EACVI guidelines,[[1]] and the EchoNoRMAL Collaboration.[[2]]

Lastly, it is unclear what the impact of using these new ranges will impact on clinical management and outcomes: longitudinal data are needed. However, it is likely that under-recognition of pathology (by “indexing out” abnormalities using BSA) has occurred and to avoid this, indexed measurements should be used cautiously until we have longitudinal data.

Conclusion

Applying the current international echocardiography reference ranges indexed to BSA in Aotearoa will under-diagnose cardiac enlargement in some Māori and Pacific Island patients, and introduce unintentional bias that preferences the detection of pathology in NZ Europeans. In other words, the application of reference ranges developed in Caucasian to Māori and Pacific patients is an example of systemic racism. This study highlights the need for ethnic-specific normal ranges and highlights the unintended consequences that arise from using a one-size approach derived from European cohorts in different ethnic groups. Whilst it may seem ideal to index measurements to a measure of body size to enable comparison across people of different sizes, this study clearly shows there is potential for delayed diagnosis if ethnic-specific reference ranges are not used and applied. Ultimately, these new reference ranges need to be prospectively linked to clinical outcomes, but it’s intuitive that if clinicians are following clinical guidelines that include linear echo measurements, and are making judgements about pathology based on international reference ranges derived from Europeans, misclassification is likely in Māori and Pacific peoples.

Summary

Abstract

Aim

To develop ethnic-specific echocardiography reference ranges for Aotearoa, and to investigate the impact of indexation to body surface area (BSA). Current reference international ranges are derived from people of mostly NZ European ethnicity and may not be appropriate for Māori and New Zealanders of Pacific ethnicity, who both experience high rates of cardiovascular disease.

Method

Echocardiography was performed in a cross-sectional study of 263 healthy adults (18–50 years): Māori (N=71, 43 female), Pacific (N=53, 28 female), European (N=139, 74 female). Linear measurements of the left heart are reported and indexed to BSA. The upper/lower limit of normal (ULN/LLN) by ethnicity and sex were derived (quantile regression). Ethnic- and sex-specific differences were examined using ANOVA.

Results

The ULN was higher for all un-indexed dimensions in men compared to women, and for most indices the ULN was smallest in NZ Europeans and largest in Māori and Pacific peoples. Indexation reversed these relationships: NZ Europeans had higher ULN for many measurements.

Conclusion

Indexing to BSA introduced bias that preferences the NZ European ethnicity by creating an upper limit reference threshold that far exceeds this sample’s upper range. As a result, this may lead to under-recognition of cardiac enlargement in Māori and Pacific patients, and in particular for women. Unique reference ranges for all ethnic groups and sexes are required to optimally detect and manage cardiovascular diseases (CVD) in Aotearoa.

Author Information

Gillian A Whalley: Department of Medicine and HeartOtago, Otago School of Medicine, The University of Otago, Dunedin, New Zealand; Unitec Institute of Technology, Auckland, New Zealand. Allanah Harrington: Unitec Institute of Technology, Auckland, New Zealand; Dunedin Hospital, Southern District Health Board, Dunedin, New Zealand. Jonathan Christiansen: Waitematā District Health Board, Auckland, New Zealand. Bettina Ikenasio: Unitec Institute of Technology, Auckland, New Zealand Arun Deo: Unitec Institute of Technology, Auckland, New Zealand Greg D Gamble: Department of Medicine, The University of Auckland, Auckland, New Zealand Sue Crengle: Department of Preventive and Social Medicine, Otago School of Medicine, The University of Otago, Dunedin, New Zealand.

Acknowledgements

This study was funded by a Health Research Council of New Zealand Research Partnerships for New Zealand Health Delivery grant (grant number 14/718).

Correspondence

Professor Gillian Whalley: Department of Medicine, Otago Medical School, University of Otago, PO Box 56 Dunedin 9054. P: 021306059.

Correspondence Email

gillian.whalley@otago.ac.nz

Competing Interests

Nil.

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