Article Information

Sylvain Mathieu^1*, Bruno Pereira², Frédéric Dutheil³, Anne Tournadre¹, Martin Soubrier¹

¹Rheumatology Department, Clermont-Ferrand University Hospital, 58 Rue Montalembert, FR 63003, Clermont-Ferrand, France

²Biostatistics unit (Clinical Research Direction), University Hospital of Clermont-Ferrand (CHU), Clermont-Ferrand, France

³CNRS, LaPSCo, Physiological and Psychosocial Stress, CHU Clermont-Ferrand, University Hospital of Clermont-Ferrand, Occupational and Preventive Medicine, WittyFit, Université Clermont Auvergne, Clermont-Ferrand, France

*Corresponding author: Sylvain Mathieu, Rheumatology Department, Clermont-Ferrand University Hospital, 58 Rue Montalembert, FR 63003, Clermont-Ferrand, France.

Received: 19 September 2024; Accepted: 26 September 2024; Published: 14 October 2024

Citation: Sylvain Mathieu, Bruno Pereira, Frédéric Dutheil, Anne Tournadre, Martin Soubrier. Cardiovascular Risk Profile in Dupuytren’s Disease: A Systematic Review and Meta-Analysis. Cardiology and Cardiovascular Medicine. 8 (2024): 440-454.

Abstract

Keywords

Dupuytren’s disease; Cardiovascular risk, Meta-analysis

Article Details

1. Background

Dupuytren’s disease (DD), characterized by contracture of the fourth and fifth fingers of the hand, is a common disease [1-3], but probably still underestimated. Some patients are completely asymptomatic or hesitate to see their general practitioners because they can considered DD to be shameful due to the supposed frequent association with alcohol consumption [4]. It is true that alcohol intake is a risk factor of occurrence of DD but is not the only one [5,6]. Male patients are at higher risk of DD compared with women [6], although sex predisposition might decrease with age [7]. Grazina et al point out that etiology of DD is still not well known [8]. Heredity has been proposed to be related to the pathogenesis of DD with an autosomal dominant pattern of inherence [9,10]. Diabetes is also recognized to highly increase prevalence of DD. The prevalence of DD is higher in a population of people with diabetes, especially type 1 diabetes [11]. Smoking is another factor that was reported to increase the risk of DD [12]. In summary, patients with DD are more often men, smokers, diabetics and alcohol consumers and therefore might have a higher incidence of cardiovascular (CV) morbidity or mortality. However, few studies are assessed this CV risk and information are lacking on other cardiovascular risk factors (smoking, hypertension, dyslipidemia) in DD patients. Here we performed a meta-analysis to increase the statistical power and accuracy of the available data regarding DD and cardiovascular risk. Our aims were to provide a more accurate assessment of risk of developing cardiovascular events and of CV risk profile in patients with DD.

2. Methods

Literature search: We searched PubMed, Embase and the Cochrane Library to find reports of interest published since 9th June 2023. All observational or case/control studies monitoring death, cardiovascular events such as myocardial infarction (MI) or stroke or cardiovascular risk factors in DD patients were included. The following search terms were used: “(Dupuytren[tiab] AND (cardiovascular OR myocardial OR stroke OR atherosclerosis OR lipid OR diabetes OR glycemia))”. Our search involved articles, or at least abstracts, published in English or French. A hand-search of references was also carried out. We collected data from the electronic abstract databases of the annual scientific meetings of European League Against Rheumatism and American College of Rheumatology from 2009 to 2023 using the term ("Dupuytren").

Trial selection: Two of us (SM and AT) selected potentially relevant articles after reading the title, keywords, abstract and then full-text. Doubts in articles selection were resolved by consensus with other authors.

Inclusion criteria for the full text were: study population of patients with DD; observational and case/control studies; articles published in English or French before June 2023; data giving the number of patients smokers, diabetics, obese or dead especially in case of cardiovascular events or mean and standard deviation of lipid profile parameters, blood pressure, body mass index. The exclusion criteria were: commentary or discussion papers; case reports and studies including fewer than five patients; no data about cardiovascular risk or profile; not DD patients; full-text not available; data not usable for statistical analysis (no standard deviation or no interquartile range).

Data extraction: One reviewer (SM), extracted all data using a standardized data abstraction form. For all extracted data, a central value (mean or median) and variability (standard deviation or interquartile range) or the number of patients with events of interest were obtained.

Study location: For each included study, we extracted the country where patients were included and identified the study as a high or low frequency of DD according to the worldwide distribution of DD [13-16]. For example, studies realized in United Kingdom, USA, Scandinavia, India, Japan or Ethiopia are at high prevalence of DD, although studies in France, Turkey, Taiwan, Chile, or Colombia are considered as a low DD prevalence study.

General patients’ characteristics: For each article, we collected, when available, the age and sex of DD patients and controls, the number or percentage of men, smokers, alcohol users and diabetic. In both group, we extracted the number of patients or controls treated for hypertension or dyslipidemia and those having obesity defined by BMI higher than 30.

Extraction of cardiovascular events: In studies, we extracted the number of MI and strokes, both fatal and non-fatal. We also recorded the length of follow-up of the DD patients or controls. We verified that there was no overlap between the included articles and therefore, no event was counted more than once.

Extraction of cardiovascular risk factors: In case/control studies, we collected the recognized cardiovascular risk factors: systolic and diastolic blood pressure, glycaemia, smoking status, lipid profile (total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides), BMI.

Quality of assessment: The two forms of Newcastle-Ottawa Scale (NOS) were used, one for case control studies and one for cohort studies, to check the quality of articles [17].

Statistical analysis: Continuous variables were expressed as weighted mean ± standard deviation (SD). Incidences of diabetics or smokers or men in the DD and control populations were calculated by metaanalysis of proportions (inverse of the variance method). The Mantel-Haenszel procedure was used to determine the odds ratio (OR) of tobacco use, alcohol consumption and other cardiovascular risk factors between DD and controls. This method provided a common odds ratio estimate and 95% confidence interval. For age, blood pressure, total cholesterol (continuous variables), the differences between DD patients and controls were expressed by standardized mean difference (SMD) using inverse of variance method: moderate 0.2-0.8, large > 0.8. Statistical heterogeneity between results was assessed by examining forest plots, confidence intervals and using I², which is the most common metric for measuring the magnitude of between-study heterogeneity and is easily interpretable. I² values range between 0% and 100% and are typically considered low for <25%, modest for 25-50%, and high for >50%. This statistical method generally assumes heterogeneity when the p-value of the I² test is <0.05. Random effects models were used if heterogeneity; otherwise we used a fixed effect model. When sample size was sufficient, meta-regressions were used to study the relationships between our outcome variables (cardiovascular risk factors) and clinically relevant parameters such as the low or high prevalence of DD in the countries where patients were included. Type I-error was fixed at α==0.05. All the items required in the PRISMA checklist were filled in this study. This statistical analysis was conducted using Review Manager software (version 5.0) produced by the Cochrane Collaboration and Stata software (v14, StataCorp., College Station, TX, USA).

3. Results

Eligible studies: Figure 1 shows the flow chart of publications identified by the literature search and those finally retained. A total of 1,002 citations was obtained after research in the data basis. After reading the title, abstract and the full-text, we obtained 79 eligible studies for a total of 114,446 patients with DD. (Figure 1).

Figure 1: Flowchart of Manuscript selection.

Study characteristics: Of the 79 publications, 11 were abstracts, 39 were case/controls studies, 25 were cross-sectional and 4 were longitudinal studies (Supplementary Table 1). Two studies assessed respectively the risk of death and of cardiovascular death in DD patients and controls. Sixty-four studies gave the CV characteristics (gender, tobacco and alcohol use, diabetes, hypertension, dyslipidaemia, body mass index) of DD patients. Twenty-eight studies allowed comparison between DD patients and controls on CV risk profile. The methodological quality of the included studies was pretty good (supplementary Figures 1-3). Forty-one studies (51.9%) were performed in countries with a high prevalence of DD such as United Kingdom, USA, Scandinavia, India, Japan and Ethiopia. The 38 other studies were considered as studies realized in countries with a low prevalence of DD (France, Turkey, Taiwan, Chile, Colombia…) according to the worldwide distribution of DD patients.

Characteristics of DD patients: The weighted mean age was 63.7 ± 11.2 years (n=32,229), 68.9 % (IC95%: 61.8%-75.7%) of DD patients were men (n=40,324), 37.8 % (IC95%: 28.2%-50.0%) were smokers (n=12,960) and 46.2% (IC95%: 35.3%-57.2%) had alcohol consumption (n=12,852). More than one third of DD patients were manual workers (36.4% (IC95%: 17.7%-57.6%). Nearly 50% of DD patients reported hypertension (46.1% (IC95%: 34.6%-57.8%) (n=21,170) and 29.6% (IC95%: 21.9%-38.0%) dyslipidaemia (n=21,124). In all the 44 studies giving data on diabetes and DD, 15.5% (IC95%: 11.9%-19.5%) of diabetics patients (n=108,807) had DD disease and 43.9% (IC95%: 37.4%-50.5%) of DD patients (n=52,532) were found diabetics.

Risk of death: In three studies, 8,026 deaths were reported in DD patients (n=17,192) over mean follow-up of 24 years: incidence 56.2% [IC95%: 29.1%-81.4%] i.e. 2.3/100 pyrs. In controls incidence of death over 21 years (561 deaths in 1474 controls) was 50.2% [IC95%: 3.5%-96.6%]. Two studies assessed the risk of death in DD compared with controls and meta-analysis of these 2 studies found a higher risk in DD patients (OR=1.72 [IC95%: 1.37-2.16]). By the same way, DD patients had a 33% higher risk of death from cardiovascular disease (Figure 2) compared with controls.

Figure 2: Forest plot for the risk of cardiovascular death between DD and controls.

Comparison of CV risk profile: Twenty-eight case/control studies for diabetes distinguished DD patients (n=19,705) and controls (n=2,054,798). Table 1 and Figure 3 show the comparison of characteristics between DD patients and controls. DD patients were older, more often men and alcohol drinkers.

Figure 3: Comparison of prevalence of cardiovascular risk factors between DD patients and controls.

HBP= high blood pressure

Table 1: Comparison of characteristics between DD patients and controls.

The percentage of smokers was also significantly higher in DD patients compared with controls. On the contrary, DD patients had not more hypertension or high total cholesterol compared with controls. Levels of triglycerides was not different in DD patients and controls. Surprisingly, DD patients were significantly less obese. Metaregression found that the country where the study was located and where DD patients and controls were included had no significant impact on the cardiovascular risk factors (Table 2).

N= number of studies; n=number total of DD patients or controls; OR= odds ratio

Table 2: Comparison of cardiovascular risk factors between DD patients and controls depending the country frequency of DD.

4. Discussion

In this meta-analysis, we found an increased incidence of death and especially of death from cardiovascular origin of 33% in patients with DD. This higher CV risk seemed to be due to a worse cardiovascular profile. DD patients were more often male, smokers and were older with a higher consumption of alcohol, as already reported. Diabetes was found 4-fold more often in DD patients. However, other recognized cardiovascular risk factors were not increased in DD patients in this meta-analysis. We found no difference in level of cholesterol and in blood pressure. Therefore, as diabetes is a well-known higher risk factor of CV mortality and morbidity, we could hypothesize that DD without diabetes might have a lower CV risk, maybe the same CV risk than controls matched for age, sex and alcohol intake. Unfortunately, no study has already be designed like this to answer this interesting question.

Body mass index was lower in DD patients compared with controls and we found no difference in triglycerides levels. This is quite surprising because we could attempt that if there is a higher consumption of alcohol and a higher frequency of diabetes in DD patients, these patients could also have a more frequent prevalence of metabolic syndrome characterized by obesity and higher level of triglycerides [18]. These results might be explained by a higher activity at work in patients with DD patients. A manual work was often reported in DD patients that can be very physical with heavy or repetitive handwork [19-21]. In five studies of this meta-analysis (data not shown), DD patients had a manual work 2-fold more often than controls.

We found a higher frequency of tobacco use in DD patients compared with controls in this meta-analysis, which is in accordance to other references that reported a higher DD risk in smokers [5,22]. Proportion of smokers is important in our study with 50% in DD population and especially 40% in controls in the 6 case-controls studies. These percentages are very important compared to the general population in Europe ou in France respectively 26% and 32% in 2015 [23]. This may suggest that the controls in our meta-analysis are not really healthy controls as those in the general population.

DD is associated with diabetes and alcohol consumption that play an important role in the physiopathology of Dupuytren’s disease. Management of CV risk in DD patients with an assessment of 10 year CV risk using SCORE (Systematic Coronary Risk Estimation) calculation or ASCVD (atherosclerotic cardiovascular diseaseatherosclerotic cardiovascular diseaseatherosclerotic cardiovascular diseaseAtherosclerotic Cardiovascular Disease) risk for example seems important in global evaluation of patients with DD, especially those with diabetes. SCORE calculation using gender, level of cholesterol total and HDL, systolic blood pressure, tobacco use gives an estimation of global CV risk at 10 years and indication to start healthy lifestyle and/or statins to reach the target of LDL-cholesterol [24-27]. A good control of diabetes with a low glycated hemoglobin was reported to permit to decrease CV risk [28,29]. Moreno et al. [30] reported that hemoglobin glycated was an independent predictor of flow mediated dilation, a non invasive marker of endothelial dysfunction in atheroma [30]. A good control of diabetes seems also interesting to decrease the prevalence of DD. Ganesan et al. [31] found that the prevalence of DD varied depending on HbA1c levels. The prevalence was of 0.463% in patients having levels within the diabetic range, while lower prevalence of 0.392% and 0.416% were found in patients with prediabetes or uncontrolled diabetes, respectively [31]. Kang et al. [32] confirmed that diabetes and poor glycemic controls are major risk factors for DD, which present an opportunity for prevention [32]. By the same way, discussion on alcohol consumption are important in everyday management of DD, by general practitioners for example. Alcohol consumption and cardiovascular risk is still debated [33]. Dose of alcohol intake seems important. It is well known that chronic heavy drinking occasions detrimentally impact on most major cardiovascular diseases but the cardiovascular benefits of low-moderate alcohol consumption are still being questioned and perhaps might have been overestimated [34]. Less is best could be the good message given to DD patients on alcohol consumption.

We found no impact on CV risk factors results between DD patients and controls of the country where the study was realized. DD patients were more often men, diabetic and alcohol users whether the study took place in a country with a high or low frequency of DD and differences between OR were not significantly different. No difference was also found between countries for the impact of smoking on CV risk factors between DD and controls. These results mean that the ethnic origin of DD patients or genetic factors seem not to have a significant role in the excess CV risk found in DD. Therefore, the country where DD patients come from should not be taken into account in the assessment of CV risk. All DD patients are concerned by the research and treatment of CV risk factors.

Our study has some limitations. First, the number of studies assessing CV events occurrence in DD included in this meta-analysis is low. Association between diabetes and DD is well-known with many references in the medical literature. But consequences of diabetes such as occurrence of myocardial infarctions or strokes are not sufficiently studied in DD population. The two included studies represented nearly 1000 DD patients and 4000 controls. This was insufficient to draw strong conclusions on CV risk in DD but it is however not negligible. Another limitation is related to the publication bias. We cannot exclude that some investigations were not published because of insufficient interesting results or insufficient included patients. However, we searched relevant abstracts in European and American congresses, and trial registries, such as PROSPERO (international prospective register of systematic reviews), and found no other references.

5. Conclusion

DD patients have higher CV risk most likely due to a higher frequency of established independent CV risk factors including diabetes. This study does not provide evidence of a significant role of genetic factors or the country of origin of DD patients. The issue of CV risk evaluation, especially the search of diabetes, tobacco and alcohol use, should be more addressed in the management of DD patients during medical consultation. All cardiovascular risk factors should be assessed and targeted in DD patients, whatever the country they come from. This point is even more important as the incidence of DD is increasing [35].

Funding:

This study did not receive any financial support.

Data Availability Statement:

Data are available from the corresponding author upon reasonable request.

Conflict of Interest:

Authors declare no conflict of interest. Sylvain Mathieu has received personal fees from Bristol Myers Squibb, Pfizer, Abbvie, Novartis, Roche, Chugai, Merck, Sharp, and Dohme, Tilman but not related to the submitted work. Anne Tournadre has received personal fees from Abbvie, Lilly, Novartis, Fresenius-Kabi, Pfizer, Sanofi, Janssen, MSD, but not related to the submitted work. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Supplementary File:

Table 1: Characteristics of the included publications.

Supplementary Figure 1: Quality of cohort studies.

Supplementary Figure 2: Quality of cross-sectional studies.

Supplementary Figure 3: Quality of case-controls studies.