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18th February 2023
Having autoimmune diseases (AIDs) seems to increase the risk of developing atrial fibrillation according to the findings of a prospective study by Dutch researchers.
Atrial fibrillation (AF) is the most common cardiac arrhythmia and data from 2017 suggests that globally, there were 3.046 million new cases. Although the underlying cause of AF remains uncertain, there is a suggestion of a mechanistic link with inflammatory processes. Moreover, a feature of autoimmune diseases such as rheumatoid arthritis is inflammation and one meta-analysis found a 29% higher risk of AF among those with rheumatoid arthritis. Nevertheless, the link between AF and other autoimmune disorders is less clear. As a result, in the current study, the Dutch team turned to data held in the UK Biobank and looked for those diagnosed rheumatic fever, gastrointestinal AIDs and other AIDs e.g. those affecting the musculoskeletal, connective tissues and neurological systems. Such individuals were monitored over time for the development of AF. In addition, the team collected data on cardiovascular risk factors such as hypertension, type 2 diabetes, body mass index etc and which were adjusted for in regression models.
Autoimmune diseases and development of atrial fibrillation
A total of 494,072 individuals with a median age of 58 (54.8% female) were followed for a median of 12.8 years and during this time 5.5% of the cohort developed AF.
In fully adjusted models, among those with rheumatic fever but no cardiac involvement, there was a 47% higher risk of developing AF (hazard ratio, HR = 1.47, 95% CI 1.26 – 1.72). Similarly, there were elevated risks for those with several autoimmune diseases including Crohn’s disease (HR = 1.23), ulcerative colitis (HR = 1.17), rheumatoid arthritis (HR = 1.39) systemic lupus erythematosus (HR = 1.82) and systemic sclerosis (HR = 2.32).
When analysed by gender, the researchers found that for many of these disorders, there was a higher risk among women although the risk was higher among men but only for ulcerative colitis.
The authors concluded that whilst their data showed how autoimmune diseases were associated with the development of AF, further evidence was need to support the clinical translation of these findings.
Tilly MJ et al. Autoimmune diseases and new-onset atrial fibrillation: a UK Biobank study. Eurospace 2022 (Online ahead of print)
9th January 2023
Infection with herpes zoster is associated with a higher long‐term risk of a major cardiovascular event such as a stroke and the development of coronary heart disease, according to an analysis of three large, prospective studies by researchers from Harvard Medical School, Boston, US.
Herpes zoster (HZ) occurs after reactivation of the varicella-zoster virus which is both persistent and clinically dormant, within spinal ganglia or cranial sensory nerves following an initial infection with varicella. In fact, HZ strikes millions of older adults annually worldwide and disables a substantial number of them via post-herpetic neuralgia. Moreover, in recent years, emerging evidence suggests that HZ infection leads to 1.3 to 4-fold increased risk of cerebrovascular events with a higher risk among adults under 40 years of age and within one year after an HZ episode. However, what remains unclear, is the long‐term association between HZ infection and the risk of adverse cardiovascular events or cardiovascular disease.
In the present study, US researchers investigated the longitudinal association of herpes zoster (or ‘shingles’) and the risk of stroke or coronary heart disease (CHD) among participants in 3 large US cohorts; the NHS (Nurses’ Health Study), NHS II (Nurses’ Health Study II), and HPFS (Health Professionals Follow-Up Study). Within the three cohorts, participants were asked to self-report about clinician‐diagnosed shingles and the year of diagnosis. The primary exposure for the study was categorised according to time (in years) since the participant’s HZ event and those with no history of HZ served as the reference group. The researchers then categorised the time since HZ as never, 1 to 4 years since infection, 5 to 8 years, 9 to 12 years and ≥13 years. In their analysis, adjustment were made for several factors that could potentially be related to HZ and stroke or CHD, including age, race, smoking history, body mass index, waist circumference etc.
Herpes zoster infection and cardiovascular events
The study included data on 79,658 women in the NHS, 93,932 in the NHS II and 31,440 men in the HPFS (2004-2016), without prior stroke or CHD. During >2 million person-years of follow-up, 3603 incident stroke and 8620 incident CHD cases were documented.
In a pooled analyses and compared to those without a history of HZ infection, the multivariable-adjusted hazard ratio (HR) for stroke was non-significant for those with 1 to 4 years since HZ infection (HR = 1.05, 95% CI 0.88 – 1.25). However, the associations became significant as the duration from infection increased. For example, among those with 5 to 8 years since HZ, the hazard ratio was 1.38 (95% CI 1.10 – 1.74) and 1.28 (95% CI 1.03 – 1.59) among those with for 9 to 12 years since HZ. Interestingly, the association became non-significant among those with ≥13 years since HZ (HR = 1.19, 95% CI 0.90 – 1.56).
When considering CHD, the corresponding multivariable-adjusted hazard ratios were similar, e.g. 1.25 (95% CI 1.07 – 1.46) for 9 to 12 years and, as with stroke, the risk of CHD became non-significant after ≥13 years (HR = 1.00, 95% CI 0.83 – 1.21).
The authors concluded that herpes zoster is associated with a higher long-term risk of a major cardiovascular event, underscoring the importance of prevention of infection.
Curhan SG et al. Herpes Zoster and Long-Term Risk of Cardiovascular Disease. J Am Heart Assoc. 2022
8th August 2022
Cancer survivors have a greater risk of subsequent cardiovascular disease (CVD) even after adjustment for traditional CVD risk factors, according to the findings of a prospective study by US researchers.
The number of cancer survivors continues to increase due to advances in early detection and treatment. In fact, one study found that in 2019, more than 16.9 million Americans with a history of cancer were alive and this figure is projected to reach more than 22.1 million by 2030. However, the cardiovascular toxicity of cancer treatment has raised awareness of the importance of heart disease in cancer care leading to the new interdisciplinary field of cardio-oncology. This has been driven in part, due to emerging evidence that risk factors associated with cardiovascular disease are also related to an increased incidence of cancer and excess cancer mortality. It is important therefore, to better understand the burden of CVD among cancer survivors to help improve public health strategies directed towards cardiovascular disease prevention within this patient group.
For the present study, the US researchers undertook a prospective cohort analysis using data from the community-based Atherosclerosis Risk in Communities (ARIC) study, which was designed to investigate the aetiology of atherosclerosis and its clinical sequelae. They set out to examine whether the CVD burden among cancer survivors was independent of traditional CVD risk factors and if this differed between cancers. A subgroup of ARIC patients consented to cancer research and were thus linked to cancer registries. The researchers examined the incidence of coronary heart disease, heart failure, stroke and composite of these conditions as the outcome of interest and used regression analysis to estimate the association of cancer with these CVD outcomes. For the analysis they matched every patient, based on sex, age and race who developed cancer with two participants who did not subsequently develop a cancer.
Cancer survivors and cardiovascular disease
A total of 12,421 individuals with a mean age of 54 years (55% female) were included in the analysis, 3,250 of whom developed cancer after a median of 13.6 years. Among women, breast cancer was the most common form of the disease (35%) whereas prostate cancer was the commonest disease in men (40%).
In fully adjusted regression models (i.e., adjusted for known CVD risk factors such as cholesterol levels, diabetes, hypertension, smoking status), cancer survivors had a 37% higher risk of CVD (hazard ratio, HR = 1.37, 95% CI 1.26 – 1.50). This was also significantly higher for heart failure (HR = 1.52, 95% CI 1.38 – 1.68) and stroke (HR = 1.22) but not for coronary heart disease (HR = 1.11, 95% CI 0.97 – 1.28).
When considering individual cancers, survivors of breast cancer had a 32% higher risk of CVD, whereas lung cancer survivors had a much higher increased risk (HR = 2.37).
The authors concluded that cancer survivors are at a higher risk of CVD in comparison to those without cancer and that this excess risk is not explained by traditional CVD risk factors, highlighting the need for CVD prevention strategies in this group.
Florido R et al. Cardiovascular Disease Risk Among Cancer Survivors. The Atherosclerosis Risk In Communities (ARIC) Study J Am Coll Cardiol 2022
15th June 2022
A higher fish intake appears to be associated with a greater risk of developing both malignant and in situ melanoma according to the results of a prospective cohort study by a group of US researchers.
Melanoma of the skin is the 17th most common cancer worldwide and in 2020, there were an estimated 325 000 new cases and 57 000 deaths. Although a family history and sun exposure have become well recognised as risk factors for the development of a melanoma, dietary factors may also play an important role. For example, caffeine intake may have beneficial and protective effects against cutaneous malignant melanoma, while higher citrus fruit intake and alcohol consumption may have a detrimental effect. Furthermore, while some data point to a diet rich in omega-3 fatty acids as being protective against melanoma, other work has found no such beneficial effect. However, one study has suggested that a higher fish intake is associated with a higher risk of melanoma though the data supporting this was not provided in the paper.
For the present study, the US team used data generated by the US National Institute of Health (NIH)-AARP Diet and Health Study and sought to determine the relationship between a higher fish intake, as well as the type of fish and the risk of melanoma. The NIH-AARP cohort study collected data on fish intake as part of a food-frequency questionnaire and which was differentiated as fried fish, fish sticks, non-fried fish or sea-food and canned tuna. For the present study, the researchers determined the total fish intake as the sum of fried fish, non-fried fish and tuna intake. Using regression analysis, the researchers adjusted for several factors such as body mass index, age, gender, family history of cancer etc and categorised total fish into in quintiles, with the first quintile representing < 5.6 g/fish/day and the fifth > 28.3 g/fish/day.
Higher fish intake and the development of melanoma
A total of 491,367 individuals with a median baseline age of 62 years (59.6% male) were followed for a median of 15.5 years. During the period of follow-up, there were 5,034 cases of malignant melanoma and 3,284 melanoma in situ.
In fully adjusted models, when comparing the lowest to highest intake of fish, there was a significantly increased risk for malignant melanoma (Hazard ratio, HR = 1.22, 95% CI 1.11 – 1.35) and for melanoma in situ (HR = 1.28, 95% CI 1.13 – 1.44).
When analysing the type of fish, the risk of malignant melanoma was elevated for the highest intake of tuna (HR = 1.20) and non-fried fish (HR = 1.18) although there was significantly lower risk for the highest intake fried fish (HR = 0.90, 95% CI 0.83 – 0.98). This pattern was also true for melanoma in situ.
The authors suggested that these results could be explained by the contamination of fish by polychlorinated biphenyls, dioxins etc. While they could not offer any direct proof to support this hypothesis, there is some research which shows a direct association between dietary polychlorinated biphenyls and risk of melanoma.
They concluded that future studies were needed to replicate these findings and to identify the components of fish responsible for the observed associations.
Li Y et al. Fish intake and risk of melanoma in the NIH-AARP diet and health study Cancer Causes Control 2022
20th May 2022
Higher arterial stiffness (AS) rather than the presence of hypertension is a better predictor for the development of diabetes according to the findings of a prospective study by a team of Chinese researchers.
The World Health Organization estimates that there are approximately 422 million people worldwide that have diabetes. The most common form of diabetes is type 2 and in 2017, it was estimated that approximately 462 million individuals were affected by the condition, corresponding to 6.28% of the world’s population. Hypertension is common in those with type 2 diabetes and reportedly affects over two-thirds of patients and a Chinese study has suggested that a higher blood pressure is a risk factor for type 2 diabetes in both middle-aged and elderly patients.
Furthermore, the presence of arterial stiffness, especially in the aorta, has been shown to be an independent predictor of all-cause and cardiovascular mortality in patients with essential hypertension. In addition, other work has suggested that the presence of arterial stiffness is associated with an increased incidence of diabetes, independent of other risk factors and may represent an early risk marker for developing diabetes. However, whether arterial stiffness among hypertensive patients is a useful prognostic marker for the development of diabetes compared with hypertension alone is unclear.
For the present study, the Chinese researchers looked at data obtained from the Kailuan study, which is an ongoing prospective study following patients initially free of hypertension and examines factors associated with development of the condition. In a subgroup of patients, brachial-ankle pulse wave velocity measurements, which is a widely used technique to assess arterial stiffness, were taken. The researchers set the primary outcome as the development of diabetes during the follow-up period. Participants blood pressure and arterial stiffness was categorised as ideal vascular function (IVF) and normotensive, normotensive with AS, hypertensive and with normal AS and hypertensive and with elevated AS (HTAS).
Arterial stiffness and the development of type 2 diabetes
A total of 11,166 participants were enrolled in the study and followed for 6.16 years during which time 768 (6.88%) of incident cases of type 2 diabetes were identified.
After adjustment for covariates (e.g., age, gender, co-morbidities), compared to the IVF group, individuals in the HTAS group had the highest risk developing type 2 diabetes (hazard ratio, HR = 2.42, 95% CI 1.93 – 3.03). This was followed by the normotensive, elevated AS group (HR = 2.11, 95% CI 1.64 – 2.61). Interestingly, the lowest risk was associated with those who were hypertensive and with normal AS (HR = 1.48). These results did not change when further adjusted for mean arterial or diastolic pressure.
The researchers then examined whether an elevated AS or hypertension, or both, increased the predictive power of a conventional model, i.e., with age, sex, BMI, smoking status etc, for the development of diabetes The results showed that the C statistic increased from 0.690 to 0.707 (p = 0.0003), i.e., had more predictive power, after addition of AS. However, the predictive power increased to 0.709 when both hypertension and AS were added, in other words, there was little additional benefit to the model by adding hypertension alone.
The authors concluded that an elevated AS performed better than hypertension for the prediction of type 2 diabetes and suggested that future strategies for the prevention of type 2 diabetes should focus on both hypertension and AS.
Tian X et al. Hypertension, Arterial Stiffness, and Diabetes: a Prospective Cohort Study Hypertension 2022
12th May 2022
A higher level of dairy consumption in Chinese adults has been found to be linked to an increased overall risk of developing cancer and in particular, liver and female breast cancers. This was the key finding of a prospective study by researchers from the UK and China.
Across the globe in 2020, it has been estimated that cancer was responsible for an estimated 19.3 million new cases and almost 10.0 million cancer deaths. Several dietary factors are linked with a reduced risk of developing cancer, including for example, a higher intake of fruit and vegetables, which is associated with a 17% lower cancer mortality. Another food linked with cancer is dairy products and a higher dairy consumption lowers the risk of developing colorectal cancer. However, intake of egg, fish and dairy consumption has remained at a low level among Chinese people with other work finding that dairy consumption was seriously inadequate in Chinese elderly and appears to be reducing. As a result, for the present study, researchers were interested in determining if, despite low levels of intake among the Chinese (compared to Westernised countries), dairy intake was associated with the incidence of cancer.
Turning to data held within the China Kadoorie Biobank, which represents a population-based prospective analysis with over 0.5 million adults across China, the researchers obtained information on the frequency of dairy consumption and which was categorised as daily, 4 – 6 day/week, 1 – 3 days/week, monthly or never/ready and which served as a baseline. The information on dairy intake was re-collected at two follow-up surveys and used to estimate mean intake of dairy foods. Cox regression analysis was used to link incident cancers with dairy consumption and adjusted for several covariates including a family history of cancer, alcohol intake and levels of smoking.
Dairy consumption and incident cancer
Among a population of 510,146 individuals with a mean age of 52 years (59% women), 20.4% reported intake of dairy foods at least once a week (subsequently referred to as ‘regular dairy consumers’) and which was largely for milk. Participants were followed for a mean of 10.8 years, during which time there were 29,277 incident cancer cases recorded. In the fully adjusted models, each 50g/day increase in dairy consumption was associated with a 7% increased risk of total cancer (hazard ratio, HR = 1.07, 95% CI 1.04 – 1.11) when compared to those who never consumed dairy foods. Furthermore, among regular dairy consumers, there was a significant increased risk of liver cancer (HR = 1.12, 95% CI 1.02 – 1.22) and for female breast cancer (HR = 1.17, 95% CI 1.07 – 1.29). There was no significant association for any other form of cancer including colorectal cancer.
The authors concluded that higher dairy consumption was associated with a greater risk of cancer among Chinese individuals even though levels of dairy intake are low compared to Westernised countries.
Kakkoura MG et al. Dairy consumption and risks of total and site-specific cancers in Chinese adults: an 11-year prospective study of 0.5 million people. BMC Med 2022
A higher body fat level in men is associated with an elevated risk of prostate cancer death according to a meta-analysis of prospective studies by researchers from the Nuffield Department of Population Health, Cancer Epidemiology Unit, University of Oxford, Oxford, UK.
Prostate cancer is the second most frequent cancer diagnosis made in men and the fifth leading cause of death worldwide and in 2020 there were more than 1.4 million new cases of prostate cancer. Prior evidence indicates that there is a positive association between height and the risk of prostate cancer, with taller men being at a greater risk but also that those with greater adiposity, have an elevated risk of high-grade prostate cancer and prostate cancer death. Moreover, other work suggests that a higher body fat level, based on central adiposity is a more relevant factor and that a higher waist circumference was an important risk factor for prostate cancer.
For the present study, the Oxford team use data from the UK Biobank and focused on men who had originally undergone anthropometric measurements (e.g., height, weight, waist and hip circumference). A subgroup of these men also underwent abdominal MRI and a dual-energy X-ray absorptiometry (DXA) scan and for whom body mass index (BMI), waist and hip circumferences were re-assessed. The primary outcome of interest was prostate cancer as the underlying cause of death. In addition, the researchers combined their Biobank data with other published prospective studies to undertake a dose response meta-analysis.
Higher body fat levels and prostate cancer death
Among a cohort of 21,8237 men with a mean age at recruitment of 56.5 years, over a follow-up period of 11.6 years, 661 men (mean age = 63.1 years), died of prostate cancer.
In a multivariable-adjusted model, there was no statistically significant association of BMI, body fat percentage and waist circumference and prostate cancer mortality. However, for the waist to hip ratio (WHR), this association was significant per 0.05 unit increase (hazard ratio, HR = 1.07, 95% CI 1.01 – 1.14, P for trend = 0.028) when comparing the highest to lowest WHR quartiles.
In the meta-analysis, the hazard ratio was 1.10 (95% CI 1.07 – 1.12) for every 5kg/m2 increase in BMI, 1.03 for every 5% increase in body fat percentage, and 1.06 for every 0.05 increase in WHR.
Using the estimate for the effect of BMI from the meta-analysis, the authors estimated that as approximately 11,900 men died from prostate cancer each year (averaged between 2016 – 2018) and if their estimate was accurate, a reduction in mean BMI of 5kg/m2 would potentially lead to 1309 fewer prostate cancer deaths every year in the UK.
They concluded that men with higher body fat (both total and central) were at a higher risk of death from prostate cancer and that these findings provided a reason for men to maintain a healthy weight.
Perez‐Cornago A et al. Adiposity and risk of prostate cancer death: a prospective analysis in UK Biobank and meta-analysis of published studies BMC Med 2022
7th April 2022
Metformin use by fathers with diabetes, three months before conception, is linked to an increased risk of birth defects among their offspring. This was the main finding of a study by Danish researchers from the Department of Epidemiology, Biostatistics and Bio-demography, and Interdisciplinary Center on Population Dynamics, University of Southern Denmark, Denmark.
It is already known that diabetic men have a significantly higher percentage of sperm with nuclear DNA damage and which is a factor associated with compromised fertility and increased miscarriage rates. Furthermore, other research suggests that there is a relationship between male and female diabetes and fecundity (i.e., their ability to produce live offspring) and that early evaluation and treatment may be warranted for diabetics prior to attempting to conceive. However, as well as men, data also shows that among pregnant women with type 1 diabetes, increasingly worse glycaemic control in the three months before or after estimated conception was associated with a progressively increased risk of major cardiac defects in their offspring.
In men, the entire spermatogenic process is thought to require approximately 74 days and for the present study, the Danish team looked at fathers who had a prescription for any diabetic medication, including insulin, metformin and sulfonylureas, during the three months before conception, which they termed the sperm development period (sDev). Since diabetes is known to affect sperm, their primary interest was to examine if the use of diabetic medicines might prevent damage to paternal sperm. They used a national patient registry to extract individual-level data and excluded mothers who were diabetic and using diabetic medication at any time prior to birth. The primary outcome of interest was the diagnosis of 1 or more major birth defects in the first year of life. The authors calculated odds ratios and adjusted for several factors birth year, paternal age, income, education, maternal age and smoking status.
Metformin use and birth defects
A total of 1,116,779 offspring were included in the analysis, of whom, 3.3% had one or more birth defects. A total of 7,029 offspring were exposed to paternal diabetic medication including insulins (5,298), metformin (1,451) and sulfonylureas (647). The main birth defects observed among metformin-exposed offspring were genital defects, all of which occurred in boys.
In regression analysis, the adjusted odds ratio (aOR) for birth defects during the sDev period for insulins was 0.98 (95% CI 0.85 – 1.14), 1.40 (95% CI 1.08 – 1.82, p = 0.012) for metformin and 1.34 (95% CI 0.94 – 1.92) for sulfonylureas.
Interestingly, the frequency of birth defects varied among paternal metformin users at different time points in comparison to the sDev period. For example, longer than 1 year before the sDev, the frequency was 4% but this increased to 4.4% one year before sDev before peaking at 5.2% during sDev. Moreover, the frequency declined thereafter to 3.3% more than one year after sDev. However, the birth defect frequency was non-significant and no higher than non-metformin users, at all time points other than during sDev.
The authors concluded that preconception use of metformin is associated with major birth defects, particularly genital birth defects in boys, although added that further work was required to confirm these findings.
Wensink MJ et al. Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring. A Nationwide Cohort Study Ann Intern Med 2022
30th March 2022
The consumption of foods and beverages which contain artificial sweeteners has been found to be associated with a slight increased risk of cancer according to the results of a large, French cohort study by researchers from the Sorbonne Paris Nord University, University of Paris, France.
The World Health Organization recommends that both adults and children should reduce their intake of free sugars to less than 10% of total energy intake. Consequently, manufacturers developed alternatives to sugar and artificial sweeteners were developed, one of which is aspartame, that has been used since 1981 and is present in more than 6,000 products. Although aspartame contains the same number of calories as sugar, it is around 200 times sweeter than sugar. The potential carcinogenicity of artificial sweeteners like aspartame has always been controversial and one review in 2014 suggested that the studies performed in the 1970s did not provide adequate scientific support for the safety of aspartame and that more recent life-span carcinogenicity data undertaken with rodents provide consistent evidence of aspartame’s carcinogenic potential. Moreover, a 2021 review of aspartame and cancer concluded that new findings confirm that aspartame is a chemical carcinogen in rodents. Nevertheless, it has been unclear from studies in humans whether artificial sweeteners are associated with an increased risk of cancer. For example, one 2012 prospective study that evaluated whether the consumption of aspartame- and sugar-containing soda is associated with risk of haematopoietic cancers, concluded that the apparent cancer risk in individuals who consume regular soda do not permit the ruling out of chance as an explanation. In contrast, a second study concluded that higher levels of aspartame intake were not associated with the risk of overall hematopoietic cancer.
With some uncertainty over the association between cancer and intake of artificial sweeteners, for the present study, the French team prospectively followed participants in the NutriNet-Sante study. This prospective trial was designed to determine, among adults, any associations between nutrition and health. Nutritional intake information is collected at baseline and every year on various factors such as health status, physical activity, smoking status and diet using 24-hour dietary recall questionnaires through which the intake of artificial sweeteners can be assessed.
Artificial sweeteners and cancer risk
A total of 102,865 participants with a baseline mean age of 42.2 years (78.5% female) were followed for a median of 7.8 years and consumption of artificial sweeteners was recorded for 36.9% of participants.
A total of 3,358 incident cancers developed during the follow-up period. Compared those who did not consume artificial sweeteners, among high consumers, there was an increased risk of cancer development (hazard ratio, HR = 1.13, 95% CI 1.03 – 1.25, p-trend = 0.002). Two sweeteners in particular, aspartame (HR = 1.15, p = 0.002) and acesulfame-K (HR = 1.13, p = 0.007) were associated with higher cancer risks. In addition, aspartame was associated with an increased risk of breast cancer (HR = 1.22, 95% CI 1.01 – 1.48, p = 0.036).
Based on these findings, the authors concluded that while the study could not establish causal links, their findings did not support the use of artificial sweeteners as a safe alternative to sugar in food and beverages.
Debras C et al. Artificial sweeteners and cancer risk: Results from the NutriNet-Santé population-based cohort study PLoS Med 2022