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21st March 2023
Levels of the inflammatory marker, high-sensitivity C-reactive protein (CRP) serve as a better predictor for the risk of future cardiovascular events and death in comparison to LDL cholesterol (LDLC), according to an analysis of data from three, large, cardiovascular trials by US researchers.
It has been recognised for many years that high-sensitivity CRP predicts the risk of future myocardial infarction and stroke in healthy men and this relationship also holds true for women. In addition, while hyperlipidaemia is a risk factor for cardiovascular disease, it is also known that addition of drugs with an anti-inflammatory effect, such as colchicine to statin therapy, also significantly reduces the risk of cardiovascular events in patients with chronic cardiac disease.
Given how both inflammation and elevated LDL cholesterol are important cardiovascular risk factors, because patients prescribed statins can still experience an adverse cardiovascular event, an important question is how to deal with this residual risk. In other words, should clinicians treat with additional lipid lowering therapy (to minimise the residual cholesterol risk) or use an anti-inflammatory agent (to lower the residual inflammatory risk)?
Using data from three large statin trials (PROMINENT, REDUCE-IT and STRENGTH) the US researchers compared the highest and lowest quartiles of high-sensitivity CRP and LDLC , to determine the best predictors of future major adverse cardiovascular events, cardiovascular death, and all-cause death.
High-sensitivity CRP and cardiovascular outcomes
A total of 31,245 patients were included and participants aged between 64 and 65 with the proportion of females ranging from 28 to 35%.
Combining data from the three trials showed that the presence of residual inflammatory risk was significantly associated with incident major adverse cardiovascular events (adjusted Hazard Ratio, aHR = 1.31, 95% CI 1.20 – 1.43, p < 0.0001) for the highest vs the lowest high-sensitivity CRP quartiles. This relationship was also true for cardiovascular mortality (aHR = 2.68, p < 0.0001) and all-cause mortality (aHR = 2.42, p < 0.0001).
However, when comparing the highest to lowest quartiles of LDL cholesterol, the relationship was non-significant for major adverse cardiovascular events (aHR = 1.07, p = 0.11) but was significant, albeit smaller, compared to high-sensitivity CRP, for cardiovascular death (aHR = 1.27, p = 0.0086) and all-cause mortality (aHR = 1.16, p = 0.025).
The authors concluded that in those already prescribed a statin, high-sensitivity CRP proved to be a stronger marker for the prediction of future cardiovascular events and death compared to LDL cholesterol levels. They added that their findings suggested that both aggressive lipid-lowering and inflammation-inhibiting therapies might be needed to further reduce atherosclerotic risk.
Ridker PM et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet 2023
9th January 2023
Higher lipoprotein A levels among patients with hypertension, increase their risk of an adverse cardiovascular event according to the findings of a study by US researchers.
Lipoprotein A is a form of low-density lipoprotein (LDL) and an established, genetically determined risk factor for atherosclerosis, coronary artery disease, stroke, thrombosis, and aortic stenosis. It is synthesised in the liver and its plasma concentration ranges from < 1 mg to > 1,000 mg/dL although concentrations above 50 mg/dL are associated with an increased risk for cardiovascular disease including myocardial infarction, stroke, aortic valve stenosis, heart failure, peripheral arterial disease, and all-cause mortality. Levels are largely determined by genetics with up to 90% of the concentration explained by a single gene, the LPA gene. Moreover, concentrations above 50 mg/dL are observed in roughly 20% of the Caucasian population and in an even higher proportion of African-American and Asian-Indian people. It can therefore be assumed that Lp(a) is one of the most important genetically determined risk factors for cardiovascular disease.
Given this relationship with cardiovascular disease risk, in the current study, US researchers used data from the Multi-Ethnic Study of Atherosclerosis (MESA) trial, to examine the longitudinal relationship of Lipoprotein A and hypertension to cardiovascular outcomes in a large multi-ethnic cohort, who were initially free of cardiovascular disease. MESA was designed to include patients from different ethnicities and aimed to include approximately 38% White, 28% African-American, 23% Hispanic and 11% Asian (of Chinese descent) individuals.
Among risk factors for cardiovascular disease, hypertension is associated with the strongest evidence for causation. As a result, in the current study, researchers categorised participants into four groups based on both lipoprotein A (Lp(a)) and the presence/absence of hypertension, which was defined by a systolic pressure of 140 mmHg or higher and a diastolic of 90 mmHg or the use of antihypertensive medicines. Group 1 had Lp(a) levels below <50 mg/dL and no hypertension; group 2 had Lp(a) levels ≥50 mg/dL but no hypertension; group 3 had Lp(a) <50 mg/dL and hypertension, whereas participants in group 4 had both an elevated Lp(a) (≥50 mg/dL) and hypertension. Individuals were then followed up until an adverse cardiovascular event.
Lipoprotein A levels, hypertension and adverse cardiovascular events
A total of 6,674 individuals with mean age of 62.1 years (52.8% female) and of whom, 38.6% were White, 27.5% Black, 22.1% Hispanic and 11.9% Chinese American, were followed for a mean of 13.9 years. During this time 809 participants experienced a cardiovascular disease event.
Using group 1 as the reference, those with Lp (a) ≥50 mg/dL and no hypertension (group 2) had no significant increased risk for cardiovascular disease events (Hazard ratio, HR = 1.09, 95% CI 0.79 – 1.50). In contrast, participants in group 3 (i.e., Lp(a) <50 mg/dL and hypertension) had a statistically significant increase in risk (HR = 1.66, 95% CI 1.39 – 1.98). The risk was also significantly elevated for those in group 4 (HR = 2.07, 95% CI 1.63 – 2.62).
In further analysis, the researchers identified that those with an elevated Lp(a) and with hypertension had an increased risk of cardiovascular disease events (HR = 1.24, 95% CI 1.01 – 1.53) relative to those with hypertension but lower Lp(a).
The authors concluded that while hypertension was a major contributor to cardiovascular risk, elevated Lp(a) significantly modified the association of hypertension with cardiovascular disease.
Rikhi R et al. Association of Lp(a) (Lipoprotein[a]) and Hypertension in Primary Prevention of Cardiovascular Disease: The MESA. Hypertension 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
9th June 2022
Utilising time-restricted eating (TRE) in older breast cancer survivor patients with recognised cardiovascular risk factors, appears to reduce their overall risk, according to the findings of a feasibility study by researchers from the University of Toronto, Canada.
The World Health Organization has identified that globally in 2020 there were 2.3 million women diagnosed with breast cancer and which resulted in 685,000 deaths. Fortunately however, the overall 5-year breast cancer survival rate is 85% although this does depend upon the stage at which the cancer was detected and is less for those with later stage disease, for example, 1-year survival for those with stage 4 is only 66%. Despite these high survival rates, it seems that breast survivors are at greater risk of cardiovascular-related mortality compared with those without cancer. In fact, a 2017 systematic review concluded that cardiovascular disease (CVD) is an important cause of death following breast cancer. Consequently, strategies directed at reducing CVD risk among breast cancer survivors are likely to be highly beneficial. One such strategy which has attracted much attention in recent years is time-restricted eating (TRE), a form of intermittent fasting based on the circadian rhythm. For example, one approach, 16:8, allows individuals to eat ad libitum but only during an 8-hour window, e.g., between 12 and 8 pm. TRE could help to reduce CVD risk and in a 2020 systematic review, the authors concluded that TRE is a promising therapeutic strategy for controlling weight and improving metabolic dysfunctions in those who are overweight or obese.
Given the elevated risk of CVD-related mortality among breast cancer survivors, the Canadian team wondered if TRE could reduce this risk, especially among those with pre-existing risk factors such as older age, being over-weight or obese and those who had completed a course of cardio-toxic chemotherapy such as anthracyclines, within 1 to 6 years. The researchers enrolled a group of such women and asked them to eat as much as they wanted, but only between 12 and 8 pm and to only drink water, black tea/coffee outside of this feeding window, for a period of 8 weeks. During the study, participants were given access to behavioural support from a registered dietician. The researchers calculated participants’ 10-year Framingham CVD risk and collected demographic and clinical data e.g., glucose and cholesterol levels as well as blood pressure, waist circumference, visceral adipose tissue (VAT) and whole body fat-free and fat mass.
Time-restricted eating and cardiovascular outcomes
A total of 22 participants with a mean age of 66 years and a mean body mass index (BMI) of 31 were included in the study. Fat-free mass did not change during the study period, although calorie intake was significantly reduced by a median of 450 kcal (p < 0.001).
At baseline, 68% of women were classed as cardio-metabolically unhealthy and this reduced to 53% at the end of the study.
The median Framingham CVD risk score reduced from 10.9% at baseline to 8.6% (p = 0.037), although modifiable factors in this score such as total cholesterol and systolic blood pressure were not significantly different. In addition, the mean BMI did not change whereas both VAT and whole body fat mass were significantly lower.
The authors calculated the TRE led to a 2% absolute reduction in CVD mortality risk and suggested that if this was maintained over time, TRE could reduce health costs and improve patient outcomes. They concluded by calling for randomised trials to further evaluate and confirm the value of this intervention.
Kirkham AA et al. Time-Restricted Eating to Reduce Cardiovascular Risk Among Older Breast Cancer Survivors J Am Coll Cardiol CardioOnc. 2022
6th May 2022
Adding coronary artery calcium scores (CACS) to further assess an individual’s cardiovascular risk assessment does not appear to be associated with any clinical benefit. This was the main finding of a systematic review and meta-analysis by a team from the School of Public Health, University of Sydney, Sydney, Australia.
Cardiovascular risk assessment is a critical step in the current approach to primary prevention of heart disease and is calculated using tools such as QRISK. Cardiac computed tomography (CT) imaging is an important tool for cardiovascular risk assessment in observational prospective studies and which provides a measure of subclinical disease such as coronary artery calcium. Moreover, the use of CACS has been shown to be an independent predictor of incident coronary heart disease among those deemed to be at intermediate-risk based on their Framingham risk score. The use of CACS screening has been found to improve medication adherence and provide superior coronary artery disease risk factor control without increasing downstream medical testing. By contrast, however, a study in post-menopausal women concluded that there was no independent benefit of coronary CT imaging in a low-to-moderate risk group.
With some uncertainty over whether addition of CACS derived from CT imaging provides an incremental benefit beyond that obtained from traditional risk assessment methods, in the current study, the Australian team undertook a systematic review and meta-analysis of available studies. They included studies in patients without existing cardiovascular disease, where at least one recognised risk calculator and a CACS had been used. The primary outcome as the change in C statistic for a model which contained the CACS compared to the base model without the CACS.
Coronary artery calcium scores and improvement in CVD risk prediction
A total of 6 studies with 17,961 individuals and 1043 cardiovascular events were included in the analysis. The studies varied in sample size from 470 to 5185 and mean ages ranged from 50 to 75.1 years (38.4 to 59.4% female).
The C statistic for cardiovascular disease (CVD) risk models but without CACS ranged from 0.693 to 0.80. Inclusion of CACS improved the pooled C statistic by 0.036.
When CACS was added, among participants whose risk was reclassified from low to intermediate or high risk, 85.5% to 96.4% did not experience an event during follow-up (ranging from 5.1 to 10 years). Among those who were reclassified from high risk to low risk by CACS, a similarly high proportion, 91.4% to 99.2% did not have a CVD event during follow-up.
The authors suggested that while CACS did appear to provide modest further discriminatory power to traditional risk factor assessments, this additional gain needed to be balanced against the higher costs and radiation risks. They concluded that while there were gains from inclusion of CACS, which patients might benefit remains to be determined and that there is no evidence to suggest that use of CACS offers a clinical benefit.
Bell KJL et al. Evaluation of the Incremental Value of a Coronary Artery Calcium Score Beyond Traditional Cardiovascular Risk Assessment: A Systematic Review and Meta-analysis JAMA Intern Med 2022
24th March 2022
Two cardiac biomarkers, cardiac troponin I and N-terminal pro-brain-type natriuretic peptide (NT-proBNP), although independently associated with an increased risk of incident cardiovascular events (CV) in patients with psoriasis disease, offer no additional benefit when added to cardiovascular risk stratification tools. This was the finding of a longitudinal study by researchers from the Women’s College Hospital, Toronto, Canada.
Patients with both psoriasis and psoriatic arthritis, collectively referred to as psoriasis disease, have an increased risk of cardiovascular disease. For instance, one meta-analysis found that patients with psoriatic arthritis had a 43% increased risk of cardiovascular diseases compared with the general population. Furthermore, among those with psoriasis, but without the inflammatory arthritis, there is also an apparent higher risk of both cardiovascular disease and cardiovascular risk factors, although only among those with more severe disease. While part of the reason behind this increased risk of cardiovascular disease can be explained due to the presence of traditional risk factors such as smoking, physical inactivity etc, patients with psoriasis have been shown to have increased vascular, subcutaneous and hepatic inflammation.
The use of population-based risk algorithms like the Framingham Risk Score (FRS) are widely used in risk stratification for the development of CV events, such algorithms may underestimate long term risk of major adverse cardiac events in psoriasis patients.
Elevated levels in the general population of the cardiac biomarker high cardiac troponin is associated with increased CVD risk. In addition, among older people with type 2 diabetes, NT-proBNP was strongly associated with subsequent risk of all cardiovascular disease events. Moreover, elevated NT-proBNP levels have a mortality predictive value in patients with rheumatoid arthritis. While both cardiac troponin I and NT-proBNP are useful cardiac biomarkers in the general population, whether the two markers add value for the risk stratification of patients with psoriasis disease is uncertain.
For the present study, the researchers evaluated the association between cardiac troponin I and NT-proBNP and a marker of CV risk, the presence and progression of carotid atherosclerosis, assessed by the carotid total plaque area (TPA). They recruited patients with psoriasis disease and a cohort who had undertaken a baseline and subsequent carotid ultrasound assessment of atherosclerosis. For all participants, Framingham risk scores, which includes several factors such as age, gender, smoking status, systolic blood pressure, diabetes etc were calculated, to estimate their 10-year risk of CV. The researchers set the primary end point as the occurrence of the first CV event which was a composite outcome including angina, myocardial infarction, ischaemic cerebrovascular accident and cardiovascular death.
Cardiac biomarkers and CV events
A carotid ultrasound was performed on 358 individuals and the mean duration of follow-up was 3.69 years. After adjustment for CV risk factors, the association between baseline TPA and cardiac troponin I remained significant but not for NT-proBNP. However, this association was no longer significant for atherosclerosis progression.
During a follow-up of 7.1 years there were 64 incident CV events, giving a rate of 0.90 events per 100 person-years. Both cardiac troponin I (hazard ratio, HR = 3.02, 95% CI 1.12 – 8.16) and NT-proBNP (HR = 2.02, 95% CI 1.28 – 3.18) were significantly associated with CV events per one standard deviation increase.
However, inclusion of both biomarkers into the FRS this did not improve the diagnostic accuracy of the score. In other words, while cardiac troponin I was associated with atherosclerotic burden, it had no subsequent predictive value as the level of atherosclerosis increased. Furthermore, while it was clear that the two biomarkers were associated with a higher risk of a CV event, adding these into the FRS did not improve the overall diagnostic accuracy for predicting CV events.
They concluded that the use of both biomarkers while predictive of CV events in the general population, did not aid CV risk stratification in patients with psoriasis disease.
Colaco K et al. Association of Cardiac Biomarkers with Cardiovascular Outcomes in Patients with Psoriatic Arthritis and Psoriasis: A Longitudinal Cohort Study Arthritis Rheumatol 2022
10th March 2022
A higher sodium intake from the use of soluble paracetamol tablets has been found to increase the risk of both cardiovascular disease (CVD) and mortality in patients, irrespective of their hypertensive status. This was the conclusion of a study by researchers from the Department of Orthopaedics, Xiangya Hospital, Changsha, China.
It has been known for some time that a higher sodium intake increases blood pressure and is therefore a risk factor for cardiovascular disease. Furthermore, an increased intake of the mineral has also been linked to an additional 1.65 million deaths from cardiovascular causes above a reference level intake of 2.0 g per day. In addition, studies suggest that in comparison to a moderate intake of sodium, higher intakes are associated with an increased risk of cardiovascular events and death among those with hypertensive but not form normotensive patients.
While lowering intake of sodium is known to be associated with a reduced risk of stroke and fatal coronary heart disease in adults, it would be unethical to examine the impact of a greater intake on CVD and mortality risk, given the benefits of reducing intake. While dietary sodium is a major source of intake, sodium is also contained within several medicines, in particular, soluble paracetamol. For the present study, the Chinese team compared the risks of incident CVD and all-cause mortality associated with the intake of sodium-containing soluble paracetamol (acetaminophen) compared to intake of non-sodium containing formulations according to patient’s hypertension status.
The team turned to the Health Improvement Network which is an electronic medical record database in the UK containing anonymised data for approximately 17 million patients as their source of information. They extracted data for two separate cohorts. The first included patients aged 60 – 90 years of age and with a diagnosis of hypertension and prescribed either a sodium and non-containing paracetamol formulation. The second cohort was similar although this time included patients without a diagnosis of hypertension. Socio-demographic data including gender, age, body mass index and various lifestyle factors were recorded and used as covariates in their analysis. The primary outcomes of interest were incident CVD which included myocardial infarction, stroke and heart failure, and all-cause mortality.
Sodium intake and CVD/mortality outcomes
For the first cohort, a total of 151,398 individuals with a mean age of 78.3 years (65.8% female) and a history of hypertension were included and of whom, 4532 were given a sodium-containing paracetamol. These were matched with a total of 147,299 without hypertension and a mean age of 71.4 (63.3% female), of whom 5,351 were given a sodium-containing paracetamol formulation.
Among those with hypertension, there were 122 cases of CVD among those given the mineral and 3051 cases among the non-sodium group over a median follow-up period of 0.89 and 0,93 years respectively. This gave a 59% higher risk of incident CVD among those taking a sodium-containing paracetamol formulation (Hazard ratio, HR = 1.59, 95% CI 1.32 – 1.92). Furthermore, the risk of all-cause mortality was more than double (HR = 2.05, 95% CI 1.92 – 2.19).
Among those given a sodium-containing paracetamol formulation but without hypertension, there was a 45% increased risk of CVD (HR = 1.45, 95% CI 1.18 – 1.79) and a 87% increased mortality risk (HR = 1.87, 95% CI 1.74 – 2.00).
Commenting on these results, the authors noted that sodium-containing drugs are an important but often overlooked source of the mineral. They concluded that individuals should avoid unnecessary excessive sodium intake through sodium-containing paracetamol use.
Zeng C et al. Sodium-containing acetaminophen and cardiovascular outcomes in individuals with and without hypertension Eur Heart J 2022
28th January 2022
Breastfeeding mothers have a lower risk of subsequent cardiovascular disease in later life according to a meta-analysis by researchers from the Department of Neurology, Clinical Epidemiology Team, Medical University of Innsbruck, Innsbruck, Austria.
The World Health Organization has decreed that ‘breastfeeding is one of the most effective ways to ensure child health and survival‘ adding how breastmilk is an ideal food for infants as it is safe, clean and contains antibodies which help protect against many common childhood illnesses. Despite this perceived value, a 2019 analysis of breastfeeding in low and middle incomes countries, revealed how only 37% of children under 6 months of age are exclusively breastfed.
While there are clear benefits to children, breastfeeding also appears to benefit the health of lactating mothers, with one review identifying how breastfeeding for longer than 12 months was associated with a 26% reduced risk of breast cancer and a 32% reduced risk of ovarian cancer. In 2021, a statement from the American Heart Association, suggested that ‘lactation and breastfeeding may lower a woman’s later cardiometabolic risk‘. Furthermore, an umbrella review of the association between maternal health and cardiovascular disease in later life, also suggested an inverse association between length of lactation and morbidity or mortality from cardiovascular disease but did not provide a pooled estimate of this association.
For the present study, the Austrian team undertook a systematic literature review and meta-analysis to more precisely characterise the association between breastfeeding and the development of maternal cardiovascular events. They compared ‘ever’ versus ‘never’ breastfeeding in relation to cardiovascular disease (CVD), coronary heart disease (CHD), stroke or fatal CVD and calculated hazard ratios for each of these outcomes.
The team identified 8 relevant prospective studies which included 1,192,700 women with a mean age of 51.3 years, of whom 82% reported having ever breastfed for a mean duration of 15.6 months.
There was a significant 11% reduced risk of maternal CVD among those breastfeeding compared to who did not (Hazard ratio, HR = 0.89, 95% CI 0.83 – 0.95). Similarly, significant reductions were also observed among those breastfeeding for CHD (HR = 0.86), stoke (HR = 0.88) and fatal CVD (HR = 0.83).
The authors calculated that each additional year of breastfeeding resulted in significant reduced risk, based on hazard ratios, for CVD (HR = 0.91) and CHD (HR = 0.89) and although the risk for stroke was reduced (HR = 0.91) this was non-significant.
Commenting on these results, the authors noted how the relationship between breastfeeding and cardiovascular risk had been overlooked for a long time and that in general, the maternal health benefits are less well known. They suggested that interventions to promote and facilitate breastfeeding should be reinforced.
Tschiderer L et al. Breastfeeding Is Associated With a Reduced Maternal Cardiovascular Risk: Systematic Review and Meta‐Analysis Involving Data From 8 Studies and 1 192 700 Parous Women. J Am Heart Assoc 2022