cardiovascular risk

Microscopic Colitis Linked With cardiovascular risk

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Microscopic colitis (MC) encompasses lymphocytic and collagenous colitis, with an increasing incidence in Northern Europe. Clinical presentations of MC and irritable bowel syndrome are similar and often overlapping. Diagnosis occurs in 10%-14% of patients with chronic diarrhea and macroscopically normal colonoscopy; a drug-related origin (venotonics, proton pump inhibitors, H2 blockers, and selective serotonin reuptake inhibitors) must be systematically investigated.

Inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis, are associated with an increased risk for major adverse cardiovascular events (MACE). These events include any ischemic heart disease, congestive heart failure, stroke, and cardiovascular mortality; they have been studied less in MC.

Cardiovascular Complication Risk

A Swedish cohort included 11,018 adults with MC that had been proven through biopsies. Participants had no prior cardiovascular disease (CVD). They were matched with 48,371 reference individuals without MC or CVD. Over a median follow-up of 6.6 years, 2181 (19.8%) incident cases of MACE were confirmed in patients with MC and 6661 (13.8%) in reference individuals.

Compared with reference individuals, patients with MC had an overall higher risk for cardiovascular complications (adjusted hazard ratio [aHR], 1.27) and a higher risk for its components: Ischemic heart disease (aHR, 1.38), congestive heart failure (aHR, 1.32), and stroke (aHR, 1.12). But patients with MC did not have a higher risk for cardiovascular mortality (aHR, 1.07). These findings were related more to collagenous colitis than its lymphocytic counterpart.

Multifactorial Causes

The well-known increased risk for MACE in IBD is also present, to a lesser extent, in patients with collagenous colitis despite the usual absence of overt inflammatory biomarkers, which remain intraluminal. The results of the Swedish cohort aligned with those from Danish registries and remained robust after adjusting for cardiovascular risk factors, considering that MC is likely underdiagnosed in the reference population.

However, this Swedish study lacked data on certain MC and cardiovascular risk factors, such as body mass index, alcohol, diet, lipid profiles, and potential surveillance biases that may have influenced the results. Underlying causes of MACE in patients with IBD were multifactorial (eg, metabolic comorbidities, environmental exposures, and lifestyle-related factors) and probably outweighed the inflammatory aspect.

This observation aligns with the lack of efficacy of biologics in severe forms of IBD, which generally respond well to budesonide and thiopurines. This heightened cardiovascular risk is likely triggered by the release of proinflammatory cytokines into the bloodstream, which increases atherosclerotic plaque formation. Nevertheless, it underscores the need to be aware of cardiovascular risk factors in these patients and conduct personalized assessments.

In conclusion, in this extensive national cohort study based on 11,018 patients with biopsy-proven MC, the risk for MACE was 27% higher than in the general population. This translates to one additional case of MACE for every 13 patients with MC followed for 10 years. Beyond discussions about this association, patients with MC could benefit from a personalized cardiovascular risk assessment in the presence of confirmed risk factors.

Nose Breathing May Reduce Cardiovascular Risk: Study

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Breathing through just the nose is more beneficial than breathing through the mouth, affecting blood pressure and other factors that can predict heart disease.

Nose Breathing May Reduce Cardiovascular Risk: Study

Who would have thought that how you breathe makes a difference in your heart health?

According to a new small study, breathing through just the nose is more beneficial than breathing through the mouth, affecting blood pressure and other factors that can predict heart disease.

The study, published in the American Journal of Physiology, notes that common markers for cardiovascular disease, including blood pressure, heart rate variability, blood pressure variability, and changes in arterial pressure, can be affected by the complex dynamics between the body’s cardiovascular and respiratory systems.

In fact, according to the study, breathing through the nose rather than through the mouth can lower a person’s diastolic blood pressure and increase how effectively the parasympathetic nervous system controls the heart’s resting rate.

To determine the relationship between nose breathing and cardiovascular health, the research team gathered 20 participants—13 women and 7 men—from Florida who were between 18 and 30 years old. The participants were required to have a body mass index (BMI) of less than 30, meaning they were not obese. Patients’ seated blood pressure had to be less than 140/90 mmHg. Smokers were excluded.

During the study, participants rested for five minutes and were told to breathe normally. After five minutes, participants breathed in time to a metronome. During different portions of the study with the metronome, participants breathed just through their noses and then only through their mouths. During the mouth-breathing sessions, the participants were fitted with a soft nose clip preventing nasal airflow, so they just inhaled through their mouths. Each time, the researchers measured blood pressure and rate of physical exertion

In the next part of the study, participants cycled on stationary bikes for seven minutes, following the same breathing cues: They breathed normally, then breathed along to a metronome as they would normally, just through the nose, followed by just through the mouth.

After a five- to 10-minute rest, participants cycled again. They were allowed to breathe as they wanted, but every minute, the research team increased the resistance on the bike until participants had reached their capacity, no longer able to sustain 60 revolutions per minute (rpm) pedaling.

The team found that mean blood pressure was lower for participants when they breathed just through their noses while resting, but systolic blood pressure was unaffected.

They also found that breathing through the nose versus the mouth did not affect the effectiveness of the cardiovascular system during exercise.

Why Does Nose Breathing Help the Cardiovascular System?

The researchers did not conclude why nasal breathing is better than mouth breathing. They pointed out that breathing through the nose warms, filters, and humidifies the air, which can help relax the airways. Additionally, because using the nose increases the use of the diaphragm and demands less of the chest muscles, the heart may be able to accept oxygen more efficiently.

It is noted that the rates of exertion and breathlessness were noticeably lower in participants when they were breathing through their noses versus breathing through their mouths, indicating that nose breathing could be easier on the cardiovascular system.

The study comes at an important time for cardiovascular research, as heart diseases continue to be the leading cause of death in the United States. Health markers like blood pressure and heart rate can be indicators of heart disease.

“We interpret the collective data to suggest that nasal compared with oral breathing provides modest, but potentially clinically relevant, improvements in prognostic cardiovascular variables at rest, but not during exercise,” the researchers wrote. “This work advances our knowledge of how nasal breathing affects clinically relevant cardiovascular variables and provides foundational acute data in healthy young adults to justify future longer-term studies in other populations.”

Cardiovascular Risk Linked with Severe COVID Risk

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It is well established that cardiovascular disease was associated with more severe outcomes during the first wave of COVID-19, including an increased risk of hospitalisation and death. New research suggests that this may have also applied to people with an elevated 10-year cardiovascular risk score, even in the absence of overt disease. This group has not previously been identified as a risk group for severe COVID-19. 

The observational study, which has not yet been peer reviewed, was led by researchers from the London School of Hygiene and Tropical Medicine (LSHTM), University College London and the University of Bristol, and will be presented at this year’s European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), to be held in Lisbon, Portugal on April 23-26.

Study Details

The team used linked electronic health record data from almost a million adults aged 40-84 years registered at GP practices across England during the first wave of the pandemic in 2020. They calculated the incidence and risk of laboratory-confirmed SARS-CoV-2 and related deaths, intensive care unit admissions, and hospitalisations among adults at raised and low cardiovascular risk based on QRISK3 scores. These scores combine a range of factors, including body mass index, smoking history, blood pressure, cholesterol, age, social deprivation, and ethnicity. A score of 10% or greater, meaning a 10% or higher chance of a heart attack or stroke within the next 10 years, was classed as denoting raised risk, and a score of less than 10% deemed low risk.

Among the initial sample of 949,973 individuals, 113,142 (12%) had existing CVD, 303,558 (32%) were classed as being at raised risk of CVD, and 533,273 (56%) at low risk.

Between March 12 and September 29, 2020, SARS-CoV-2 was confirmed in 4017 participants (average age 58 years, 50% male), giving an adjusted incidence of 5.5 per 1000 (95% CI 5.3 to 5.7). Incidence was similar among the 1144 individuals with raised cardiovascular risk, at 4.9 per 1000 (95% CI 4.6 to 5.1), as among the 1819 people with low cardiovascular risk, at 4.5 per 1000 (95% CI 4.3 to 4.7).

Among those with COVID-19, outcomes included:

  • Hospitalisation 414.4 /1000 (95% CI390.6 to 439.8) (n=1091)
  • ICU admission 60.4/1000 (95% CI 51.7 to 70.6) (n=159)
  • Mortality 218.8 /1000 (95% CI 201.6 to 237.4) (n=576)

Occurrence of Severe Outcomes ‘Far Higher’ in People with Elevated Risk

Rates of all of these adverse outcomes were substantially higher in those with raised cardiovascular risk compared with those at low risk:

  • Hospitalisation 607.2 [552.5 to 667.4] versus 169.3 [149.1 to 192.3]/1000
  • ICU admission 97.4 [77.0 to 123.4] vs 35.7 [27.1 to 47.1]/1000
  • Mortality 310.7 [272.2 to 354.6] vs 23.6 [16.8 to 33.2]/1000

These rates were adjusted for additional sociodemographic and clinical confounders that are not included in the QRISK3 score calculation, including alcohol intake, primary care attendance frequency, prescription of antiplatelets, prescription of anticoagulants, chronic liver disease, chronic respiratory disease, asthma, dementia, chronic neurological disease, cancer, and immunosuppression.

After adjustment, hazard ratios (HR) in those with raised cardiovascular risk were:

  • Hospitalisation HR 2.78 [2.24-3.45]
  • ICU admission HR 2.99 [1.80-4.96]
  • Mortality HR 6.84 [4.18-11.19]

People with elevated cardiovascular risk “showed a substantially greater risk of severe outcomes”, the team concluded.

Author Jennifer Davidson, a PhD student in public health research at the LSHTM said: “Although the risk of contracting COVID-19 infection appears similar among individuals with raised and low cardiovascular risk, the occurrence of severe outcomes is far higher in those at elevated risk.” 

She added: “Our study is one of the largest population-based studies with a comprehensive measure of cardiovascular risk.”

Expecting Similar Results with Larger Dataset

The authors noted that this is an observational study, so no firm conclusions can be drawn about cause and effect, and they cannot rule out the possibility that other unmeasured factors may have affected the results. However they suggested that investing in strategies to improve cardiovascular health could reduce the severity of COVID-19 across the population.

Senior author Dr Charlotte Warren-Gash, associate professor of epidemiology and honorary consultant in public health at the LSHTM, said: “Because many of the cardiovascular risk factors associated with more severe consequences from COVID-19 are potentially modifiable, clinicians and policy makers should consider that strategies which improve cardiovascular health may also improve outcomes for people following COVID-19.”

The researchers are currently updating their findings with a dataset of over 6 million individuals to confirm the initial results. This will be presented at the meeting and then submitted for a peer-review publication.

Ms Davidson told Medscape UK that their analysis of the larger dataset is still in progress and they do not yet have results to share. However: “At this point we do not anticipate the results of the larger dataset will be materially different to our initial analysis.”

Unlock the power of meal timing to reduce your cardiovascular risk

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Starting your day with a nutritious breakfast is widely emphasized, but here’s a groundbreaking revelation: the timing of your meals, including lunch and dinner, could significantly influence your cardiovascular health.

A recent analysis in Nature Communications underscores this, highlighting that when you eat might be as crucial as what you eat in mitigating cardiovascular risks.

Why “chrononutrition” may soon become the health industry’s new buzzword

Chrononutrition, meaning the strategic timing of meals, will likely be one of the hottest health and nutrition trends in the new year.  We have transitioned from meals at the family dinner table to grabbing unhealthy fast food on the go in less than half a century.  The decline of the family unit combined with the ever-competitive rat race has led to harmful outcomes for too many people throughout the modern world.

The analysis linked above delves into the time at which food is consumed.  The examination aimed to determine if the strategic timing of meals improves human health.  Though it was already known that exposure to light plays a part in circadian rhythms, there was still some debate as to whether chrononutrition had merit.

The scientists who conducted the chrononutrition study analyzed data from 103,389 individuals.  Precisely 79% of the women in the study were women.  The average age of participants was 42.  The research team also accounted for numerous confounding factors ranging from participant sleep cycle to lifestyle, diet quality, and even nuanced demographics such as age.

The data makes the case for timing every meal

The results show timing one’s first meal of the day is especially important.  Consuming breakfast late in the morning or skipping it in favor of lunch is linked to an elevated risk of heart disease.  The researchers determined there was a 6% hike in the risk of cardiovascular disease for each hour that the initial meal was delayed.

For example, an individual who waits until 11 a.m. to eat breakfast has a 6% greater increase in developing cardiovascular disease than someone who consumes breakfast at 10 a.m.

The data shows the timing of the day’s first meal and fasting periods synch the body’s circadian rhythms, affecting cardiometabolic functionality including blood pressure.  Moreover, the study results also provide insight into the importance of the day’s last meal.

Eating food late at night, meaning after 9 in the evening, is linked to a 28% hike in the development of cerebrovascular disease compared to taking the last bite of the evening before 8.  Stroke is a typical example of cerebrovascular disease.  The risk of cerebrovascular disease was higher in female study participants.

The researchers also found the longer one waits when fasting at night, meaning the time difference between the final meal of the day and the first bite in the morning, influences the risk of cerebrovascular disease.

In short, it is in your interest to resist the temptation to enjoy a “fourth meal” late at night.  Instead, build up your hunger after dinner or dessert so you can kick off the next day with a nutritious and fulfilling breakfast.

Tips to strategically time your food intake

Kickstart your metabolism early by eating a balanced breakfast within an hour of waking up.  This sets the tone for your body’s energy utilization throughout the day.

Establish regular meal times and stick to them.  This helps regulate your body’s internal clock, optimizing digestion and nutrient absorption.

Try to finish your dinner at least 2-3 hours before bedtime.  Late-night meals can disrupt sleep patterns and slow down metabolism.

Be mindful of when you consume caffeinated drinks.  Late afternoon or evening consumption can interfere with sleep quality and affect meal timing the next day.

Prepare meals and snacks in advance to ensure you have nutritious options readily available.  This can help prevent impulsive eating and ensure you consume balanced meals at the right times.

If your appetite is lacking early in the morning or afternoon, engage in a light workout before eating.  Use your scheduled meals as positive reinforcement for exercising, and you’ll find eating at designated intervals much easier.

‘Potential cardiovascular risk’ for some on keto-style diet

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Certain traditional risk factors including severe high cholesterol, diabetes, hypertension and smoking may increase CV risk among those following a low-carbohydrate, high-fat “keto-style diet,” a speaker reported here.

In a population-based cohort study, regular consumption of a low-carbohydrate, high-fat diet was associated with elevated LDL cholesterol and apolipoprotein B levels, and an increased risk for incident major adverse coronary events (MACE), Iulia Iatan, MD, PhD, FRCPC, postdoctoral fellow in cardiovascular disease prevention, clinical lipidology and cardiometabolic health at the Centre for Heart Lung Innovation at the University of British Columbia, Vancouver, said during a presentation at the American College of Cardiology Scientific Session.

Keto diet foods
Certain traditional risk factors including high cholesterol, diabetes, hypertension and smoking may increase CV risk among those following a low-carbohydrate, high-fat “keto-style diet.”

“Low-carbohydrate, high-fat diets, like ketogenic diets, have become increasingly popular due to the purported health benefits for a variety of conditions, including epilepsy, obesity and glycemic control for diabetes. This can be seen by the number of increasing publications in the last 10 years and monthly Google searches reaching up to 3.3 million results for ‘ketogenic diet.’ In fact, in 2021, approximately 16% of Americans and 14% of Canadians followed a low-carbohydrate dietary pattern in the previous year. These diets are generally characterized by restrictions of carbohydrates and a relative increase in the proportion of fat,” Iatan said.

However, Iatan said, “despite the patients who report subjective improvements in their wellbeing during these diets, a known risk of the diets is that they may trigger or exacerbate hypercholesterolemia.”

Impact on lipids, CV events

There remains limited data on the effect of low-carbohydrate, high-fat diet — or, keto-style diet — on overall lipid profile and risk for atherosclerotic CVD, Iatan said.

The researchers conducted a prospective, population-based cohort study, using the U.K. Biobank database to identify adults aged 40 to 69 years recruited from 2006 to 2010 who completed 24-hour dietary surveys.

The keto-style diet was defined as restricting daily intake of carbohydrates to less than 100 g and/or less than 25% of total daily energy intake and fat more than 45% total daily energy intake. A standard diet was defined as daily dietary parameters not meeting the criteria for the keto-style diet.

Iatan reported results from 305 participants who followed a keto-style diet and 1,220 who followed a standard diet who were not on lipid-lowering therapy. The mean age was 54 years, 73% were women and the majority were white.

At baseline, those following a keto-style diet were more likely to have diabetes, elevated BMI and obesity, according to the results. Based on self-reports, individuals who followed a keto-style diet consumed fewer total kcal per day and fewer carbohydrates, free sugars and plant proteins intake, but elevated intake of animal proteins and animal, plant and saturated fats, compared with those who followed a standard diet.

The primary endpoint was the impact of a keto-style diet on serum lipid levels. Those following a keto-style diet had significantly elevated levels of some lipids and ketone bodies, including:

  • LDL cholesterol (3.8 vs. 3.64 mmol/L; P = .004);
  • ApoB (1.09 vs. 1.04 g/L; P < .001);
  • total cholesterol (6.08 vs. 5.85 mmol/L; P = .002);
  • 3-hydroxybutyrate (0.14 vs. 0.06 mmol/L; P < .001);
  • acetone (0.02 vs. 0.01 mmol/L; P < .001); and
  • acetoacetate (0.02 vs. 0.01 mmol/L; P < .001).

The researchers reported lower levels of lipoprotein(a) (39.43 vs. 46.13 nmol/L; P = .041) and triglycerides (1.34 vs. 1.53 mmol/L; P = .001) with a keto-style diet.

The overall prevalence of severe hypercholesterolemia (> 5 mmol/L) was higher among individuals who followed a keto-style diet (11.1% vs. 6.2%; P < 001), Iatan told Healio.

The impact of a keto-style diet on incident MACE, including angina, MI, CAD, ischemic stroke, peripheral arterial disease, and coronary and carotid revascularization, was the study’s secondary endpoint. The proportion of the cohort that experienced an ASCVD event was higher among those who followed a keto-style (4.3% vs. 9.8%). Following adjustment for diabetes, hypertension, smoking and BMI, the risk for incident ASCVD events was more than twofold among patients following a keto-style diet compared with a standard diet (HR = 2.18; 95% CI, 1.39-3.43; P for all < .001), Iatan told Healio.

In a subgroup analysis, patients who followed a keto-style diet and had an LDL level of 5 mmol/L or more had a nearly sevenfold greater risk for ASCVD compared with those who followed a standard diet and had an LDL level less than 3.5 mmol/L (HR = 6.68; 95% CI, 2.62-17.09; P < .001), according to the results.

Hypercholesterolemia ‘should not be presumed to be benign’

“Based on our results for the primary and secondary endpoints, we show that in this population-based cohort of British descent, habitual consumption of a self-reported low-carb, high-fat diet was associated with increased LDL cholesterol and ApoB levels and increased risk of incident MACE,” Iatan concluded. “These findings highlight the potential CV risk of this dietary pattern and suggest that hypercholesterolemia during this low-carb high-fat diet should not be presumed to be benign.”

Editor’s Note: This article was updated on March 6, 2023, to reflect updated data.

Perspective

Alice H. Lichtenstein, DSc)

Alice H. Lichtenstein, DSc

The outcome of long-term consumption of a keto-style diet likely depends on the type of foods — hence, the type of fat — that predominates. If animal fat — meat and milk fat — predominates, high in saturated fat, it is not surprising the researchers reported a positive association with elevated CVD risk. Given LDL cholesterol levels were higher, that is likely the case in this study. If a person decides to follow a keto-style diet and gets their fats predominantly from plant sources, high in unsaturated fat such as plant oils — soybean, canola, corn, olive, nuts and seeds — it is very possible the results will be different.

There is a paper that recently came out in Diabetes Care in patients with type 2 diabetes that supports this premise (Hu Y, et al. Diabetes Care. 2023;doi:10.2337/dc22-2310).

Alice H. Lichtenstein, DSc

Gershoff Professor of Nutrition Science and Policy

Director and Senior Scientist, Cardiovascular Nutrition Laboratory

Tufts University

JM USDA Human Nutrition Research Center on Aging

Androgen Deprivation Therapy and Risk of Cardiovascular Disease in Patients With Prostate Cancer Based on Existence of Cardiovascular Risk

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Background

Because prostate cancer (PCa) is androgen-sensitive, castration by manipulating the hypothalamic-pituitary-gonadal axis to achieve the lowest testosterone levels is an important therapeutic intervention in patients with advanced cancer.1 Yet this comes at a cost, because adverse metabolic changes, notably weight gain, insulin resistance, and dyslipidemia, possibly contribute to a higher risk of cardiovascular disease (CVD).2–5 Current evidence linking androgen deprivation therapy (ADT) and CVD is mixed. As reported by Hu et al,6 3 meta-analyses of observational studies comparing risk of cardiovascular events among patients treated with versus without ADT suggested an increased risk associated with ADT, but none of the meta-analyses of randomized controlled trials (RCTs) found this effect. The discrepancy may lie in the differences in the patient population studied in observational studies and those eligible for randomized trials, with the former including patients with clinically significant cardiovascular comorbidities at baseline who are typically excluded from randomized trials. In addition, study methods for cardiovascular endpoints in these oncology studies were possibly not as refined and specific as in cardiovascular studies. A decade ago, the FDA mandated safety labels of gonadotropin-releasing hormone (GnRH) agonists to include additional warnings about potential increased risks for diabetes and cardiovascular events, and advocated for physicians to closely monitor symptoms suggesting new CVD in patients prescribed GnRH agonists.7

Current literature on the safety profile of different forms of ADT is still not clear, making it difficult to draw any conclusion.1 A meta-analysis pooling data from randomized trials comparing the GnRH antagonist degarelix with GnRH agonists favored the former in terms of cardiovascular safety.8 Notably, the incidence of cardiovascular events was strongly reduced in the subgroup comprising patients with preexisting cardiovascular history at baseline only. These findings further highlighted the need to consider stratifying analyses by baseline preexisting history of CVD when evaluating the cardiovascular safety of these treatments.

In this retrospective study using a Canadian provincial database, the objective was to evaluate the association between ADT type and the risk of CVD in patients newly treated with GnRH agonists or antagonist in both the subgroup with preexisting CVD and the subgroup without preexisting CVD.

Discussion

Since the initial reports linking ADT to cardiac events emerged at the beginning of the 21st century, we witnessed a surge of literature evaluating the cardiovascular risk in patients treated with ADT.18 The association between GnRH agonists and GnRH antagonist and CVD has not yet been clearly defined. Our study is the first of its kind to assess the association between these 2 compounds and CVD using the propensity score technique in a contemporary North American population. Our data suggest that the use of GnRH antagonist compared with GnRH agonists was associated with an increased risk of developing arrhythmia in patients with no prior CVD but was associated with a decreased risk of developing HF in patients with prior CVD and IHD in patients with no prior CVD, respectively. Although not statistically significant, a trend toward a decreased risk in the antagonist group was observed for other CVD, particularly MI independently of prior CVD history.

A French population-based cohort study including 35,118 patients in which 71% received GnRH agonists and 3.6% received the GnRH antagonist also found no significant difference in ischemic events (MI and ischemic stroke) between the 2 groups.19 A recent Italian observational study adjusting for confounders showed a lower tendency of developing MI and stroke among patients receiving GnRH antagonist (degarelix), although not significant, in the overall cohort and the subgroup with no prior CVD.5

Using real-world data from the United Kingdom, an observational study demonstrated decreased risks of any cardiac event and arrhythmia in degarelix users; however, the analyses were not adjusted for potential confounders.20 A hypothesis-generating post hoc analysis of 6 pooled phase III RCTs from 2005 to 2012 with 2,328 patients comparing degarelix (64%) versus GnRH agonists (36%) showed a 40% reduction in cardiac events or death in the degarelix group during the first year of treatment, and an absolute risk reduction of 8.2% in patients with prior CVD. These findings were shown in studies with longer follow-up periods (up to 14 months) only, rendering time an important element in disease manifestation.8 However, the post hoc nature of this analysis and the fact that cardiac events were not the primary endpoints in the individual studies renders it inadequate for drawing definitive conclusions. Similarly, a recently published phase II RCT in men with PCa and prior CVD who were randomized to receive either GnRH agonist or antagonist for 1 year found an absolute risk reduction of 18% of developing new CVD using GnRH antagonist, although it did not show any difference in endovascular function (primary outcome).21 However, the small patient population (n=80) of this trial and reporting of a smaller variety of cardiovascular events (MI and stroke only) as secondary endpoints contribute to its weakness in delivering a clearer picture of this association.

On the contrary, an observational study combining 5 databases demonstrated an increased risk of developing arrhythmia in degarelix users with or without prior CVD, and an increased risk of new MI in those with prior CVD.22 Although this study stratified their analysis by prior history of CVD, it is unclear whether they adjusted for additional potential confounding variables, which is important in this particular context to minimize confounding by indication.

To date, only one RCT (the PRONOUNCE trial) was designed to compare head-to-head the effects of these compounds on cardiovascular health in patients with PCa with prior CVD (ClinicalTrials.gov identifier: NCT02663908). Unfortunately, the trial was stopped prematurely due to low enrollment.23 Data available in the trial are essentially inconclusive given the limited number of patients enrolled generating large imprecision in effect estimates. It is noteworthy that the recently FDA-approved oral GnRH antagonist relugolix had shown a >50% relative risk reduction in the incidence of major adverse cardiovascular events compared with the GnRH agonist leuprolide.24 However, the incidence of cardiovascular events was not the primary endpoint of the trial.

Interestingly, our data demonstrate that an antagonist compared with GnRH agonists was not associated with the risk for MI and stroke, but it was associated with a significant risk reduction of HF, particularly in those with prior CVD, and of IHD in those with no prior CVD. The effects of ADT on metabolic syndrome are unlikely to fully explain the differential effects observed between GnRH antagonist and agonists. Other factors unique to GnRH agonists, namely the testosterone flare, the effects on follicle-stimulating hormone (FSH) release, and the immune system, may provide another explanation. First, testosterone flare associated with GnRH agonists may result in a proinflammatory systemic state.25 Second, users of GnRH antagonist experience a rapid and large (>90%) decrease in FSH levels, whereas users of GnRH agonists only experience a moderate (50%) decline.26 Experimentally, FSH appeared to promote visceral lipogenesis and fat storage both in vitro and in vivo,27 potentially contributing to atherosclerotic plaque development. A preclinical study suggested that mice treated with GnRH agonists accumulated more adipose tissue and atherosclerotic plaque compared with mice treated with a GnRH antagonist, and these differences may be explained by the lower FSH levels attained in the latter group.28 Third, activation of GnRH receptors on T-cell lymphocytes potentially generates an inflammatory immune response. Preclinical studies have shown that GnRH agonists led to atherosclerotic plaque destabilization, whereas the GnRH antagonist did not.29 However, clinical data showed no difference in endovascular function.21

Moreover, our data showed an arrhythmogenic activity associated with the use of GnRH antagonist, especially in patients with no prior CVD. An observational study similarly found an increased risk of arrhythmia in GnRH antagonist users with or without prior CVD.22 GnRH agonists were also found to elevate the risk of arrhythmia in patients with PCa, although only in those with prior CVD.30 More recently, a longitudinal observational study showed subclinical derangements in cardiac parameters in patients with PCa receiving ADT with prolongation of QTc segment.31 Both GnRH agonists and antagonists were shown to potentially induce torsades de pointes through testosterone reduction leading to QT prolongation.32–34 The proposed mechanism may reside in the interaction between testosterone and cardiac ion channels delaying ventricular repolarization. This finding led the FDA to issue warnings of QT prolongation for both GnRH agonists and antagonists.32 However, this cannot explain the difference we observed in our study between the 2 groups. In a brief report using the European pharmacovigilance data, the GnRH antagonist was more likely to be reported for drug-induced long QT syndrome compared with GnRH agonists.35 Overall, our observation is in contrast to the safety findings from the RCTs comparing GnRH antagonist and agonists in which rates of QT prolongation were similar between groups, though the number of events was very low.26,36 Nonetheless, given the complexity of the matter, our finding warrants further studies to elucidate the underlying mechanisms.

Our study is not without limitations. There are inherent biases associated with the use of a database, possibly introducing information biases (misclassification due to miscoding). Due to the use of administrative healthcare claims data, confounding factors related to ADT and CVD, such as like lifestyle characteristics (eg, alcohol use, smoking), pathologic data (eg, Gleason score, disease stage), and laboratory results (prostate-specific antigen level), were not measured. Despite accounting for other confounding variables through appropriate statistical methods using propensity scores, other unknown or unmeasured factors linking CVD to ADT might have been missed. These might lead to potential residual confounding even after using the IPTW method, because this does not account for these factors. Some of the changes observed between crude and IPTW adjusted hazard ratios might be explained by this. Our study has its strengths, however. First, large provincial administrative databases portray the effects of these treatments in actual clinical practice, unlike RCTs including highly selected individuals under strict protocols. Second, we evaluated a variety of cardiovascular events combined as a composite outcome and separately as individual components to allow for a more distinctive examination of the association between the type of ADT and specific types of CVD. Last, use of the IPTW method reduced the confounding bias by using balanced groups in terms of baseline variables.

Conclusions

Compared with GnRH agonists, the GnRH antagonist was found to be associated with a decreased risk of developing HF and an increased risk of developing arrhythmia in patients with PCa. Risk of IHD was also lower in patients with no prior CVD receiving GnRH antagonist. Consistent with the joint statement from the American Heart Association, American Cancer Society, and American Urological Association, the cardiovascular profiles of patients should be optimized before initiating ADT, and close follow-ups with primary care physicians or cardiologists should be arranged to monitor for CVD signs and symptoms.

Mammograms may help reveal cardiovascular risk.

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https://www.health.harvard.edu/womens-health/mammograms-may-help-reveal-cardiovascular-risk?utm_content=buffer20cd5&utm_medium=social&utm_source=linkedin&utm_campaign=hhp

Lipid-lowering drugs more effective in adults with high cardiovascular risk

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Zetia and proprotein convertase subtilisin/kexin type 9 inhibitors may reduce nonfatal myocardial infarction and stroke in adults with high or very high cardiovascular risk, according to findings published in The BMJ.

These adults must also be receiving maximally tolerated statin therapy or are statin-intolerant, according to Safi U. Khan, MD, MS, a cardiovascular outcome researcher and cardiology fellow at Houston Methodist Hospital, and colleagues.

herat consultation, Shutterstock
Ezetimibe and PCSK9 inhibitors may benefit patients with high cardiovascular risk. Source: Adobe Stock.

“The absolute cardiovascular benefits of the therapies depend on individuals’ baseline cardiovascular risk,” Khan and colleagues wrote.

As part of a multiprofessional BMJ Rapid Recommendations panel, the researchers conducted a network meta-analysis of 14 randomized controlled trials that assessed Zetia (ezetimibe, Merck) and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The trials included 83,660 adults on statins. Khan and colleagues evaluated the patients’ level of risk, values and preferences by performing frequentist fixed-effects analyses and grading of recommendations, assessment, development and evaluation (GRADE). This information was used to ascertain the certainty of evidence in the 14 trials. The panel included cardiologists, general practitioners, general internists, endocrinologists, a geriatrician, methodologists and three patient partners. The four effective critical outcomes the panel selected were nonfatal myocardial infarction (MI), nonfatal stroke, all-cause mortality and cardiovascular mortality.

Risk reductions

Overall, evidence from the 14 trials indicated that ezetimibe and PCSK9 inhibitors may benefit high-risk patients. However, the treatments yielded little or no benefit among patients with moderate or low cardiovascular risk, according to Khan and colleagues.

Specifically, adding ezetimibe to statins reduced MI (RR = 0.87; 95% CI, 0.8-0.94) and stroke (RR = 0.82; 95% CI, 0.71-0.96) but not all-cause mortality (RR = 0.99; 95% CI, 0.92-1.06) or cardiovascular mortality (RR = 0.97; 95% CI, 0.87-1.09).

The researchers also reported that adding a PCSK9 inhibitor to statins reduced MI (RR = 0.81; 95% CI, 0.76-0.87) and stroke (RR = 0.74; 95% CI, 0.64-0.85) but not all-cause mortality (RR = 0.95; 95% CI, 0.87-1.03) or cardiovascular mortality (RR = 0.95; 95% CI, 0.87-1.03).

Likely reductions in MI and stroke

Among adults with very high cardiovascular risk, the researchers reported with moderate to high certainty that adding a PCSK9 inhibitor to statins was likely to reduce MI by 16 incidences per 1,000 and stroke by 21 incidences per 1,000. Meanwhile, adding ezetimibe was likely to reduce stroke by 14 incidences per 1,000, and adding ezetimibe to a PCSK9 inhibitor and statins may reduce stroke by 11 incidences per 1,000, according to Khan and colleagues.

The researchers reported with lower certainty that adding a PCSK9 inhibitor to statins and ezetimibe may reduce MI by 14 incidences per 1,000 and stroke by 17 incidences per 1,000 among adults with very high cardiovascular risk.

Among those with high cardiovascular risk, adding a PCSK9 inhibitor probably reduced MI by 12 incidences per 1,000 and stroke by 16 incidences per 1,000 (moderate certainty), the researchers reported. Also, adding a PCSK9 inhibitor to ezetimibe and statins may reduce stroke by 13 incidences per 1,000 (low certainty). These findings were consistent in statin-intolerant patients.

“Prescribing these lipid-lowering agents should be considered among appropriate candidates with very high or high cardiovascular risk patients to achieve desired cardiovascular benefits,” the researchers wrote.

Major cardiovascular risk factors common yet undertreated in patients with COPD

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Among patients with COPD, major cardiovascular risk factors were common but inadequately monitored, treated and controlled, researchers reported in the Annals of the American Thoracic Society.

“COPD inherently conveys high cardiovascular risk due to cumulative smoking burden, advanced population age and clustering of additional risk factors, intertwined with socioeconomic deprivation, impaired health literacy and reduced physical activity,”Nathaniel M. Hawkins, MD, MPH, assistant professor in the division of cardiology at the University of British Columbia, Vancouver, and colleagues wrote. “Risk factors were very common in our cohort, with one-quarter having diabetes, > 50% hypertension, > 60% dyslipidemia, > 70% overweight and > 80% smoking history.”

Common CVD risk factors in patients with COPD
Data were derived from Hawkins NM, et al. Ann Am Thorac Soc. 2022;doi:10.1513/AnnalsATS.202104-463OC.

The cross-sectional analysis evaluated medical records of 32,695 patients with COPD (mean age, 68.4 years; 50.7% women) in the Canadian Primary Care Sentinel Surveillance Network from 2013 to 2018. These patients were matched for age, sex and rural residence with 32,638 control participants (mean age, 68.4 years; 50.7% women). Researchers identified five CV risk factors in the cohort: hypertension, dyslipidemia, diabetes, obesity and smoking.

The mean Framingham Risk Score was 20.6% among patients with COPD compared with 18.6% among controls.

Nearly 54% of patients with COPD were categorized as having high CV risk. All five CVD risk factors were more common among patients with COPD compared with controls:

  • hypertension (52.3% vs. 44.9%);
  • dyslipidemia (62% vs. 57.8%);
  • diabetes (25% vs. 20.2%);
  • obesity (40.8% vs. 36.8%); and
  • smoking (40.9% vs. 11.4%).

According to the researchers, risk factor monitoring among patients with COPD in the previous year was suboptimal, at 71.8% for hypertension, 39.4% for dyslipidemia, 74.5% for diabetes and 52.3% for obesity. Further, smoking status was infrequently reported in electronic medical records. Among monitored patients, guideline-recommended targets were achieved in 60.8% of patients for hypertension, 46.6% for dyslipidemia, 57.4% for diabetes, 10.6% for obesity and 12% for smoking.

In addition, CV therapies were underutilized in patients with COPD. Angiotensin-converting enzyme inhibitors were used in 69%, statins in 69% and smoking-cessation therapies in 27%.

“Strategies are needed to improve risk factor control and increase uptake of simple, affordable cardiovascular therapies to reduce morbidity and mortality in this high-risk group of patients,” the researchers wrote.

Repeat Measures of Lipoprotein(a) Molar Concentration and Cardiovascular Risk

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Abstract

Background

When indicated, guidelines recommend measurement of lipoprotein(a) for cardiovascular risk assessment. However, temporal variability in lipoprotein(a) is not well understood, and it is unclear if repeat testing may help refine risk prediction of coronary artery disease (CAD).

Objectives

The authors examined the stability of repeat lipoprotein(a) measurements and the association between instability in lipoprotein(a) molar concentration with incident CAD.

Methods

The authors assessed the correlation between baseline and first follow-up measurements of lipoprotein(a) in the UK Biobank (n = 16,017 unrelated individuals). The association between change in lipoprotein(a) molar concentration and incident CAD was assessed among 15,432 participants using Cox proportional hazards models.

Results

Baseline and follow-up lipoprotein(a) molar concentration were significantly correlated over a median of 4.42 years (IQR: 3.69-4.93 years; Spearman rho = 0.96; P < 0.0001). The correlation between baseline and follow-up lipoprotein(a) molar concentration were stable across time between measurements of ❤ (rho = 0.96), 3-4 (rho = 0.97), 4-5 (rho = 0.96), and >5 years (rho = 0.96). Although there were negligible-to-modest associations between statin use and changes in lipoprotein(a) molar concentration, statin usage was associated with a significant increase in lipoprotein(a) among individuals with baseline levels ≥70 nmol/L. Follow-up lipoprotein(a) molar concentration was significantly associated with risk of incident CAD (HR per 120 nmol/L: 1.32 [95% CI: 1.16-1.50]; P = 0.0002). However, the delta between follow-up and baseline lipoprotein(a) molar concentration was not significantly associated with incident CAD independent of follow-up lipoprotein(a) (P = 0.98).

Conclusions

These findings suggest that, in the absence of therapies substantially altering lipoprotein(a), a single accurate measurement of lipoprotein(a) molar concentration is an efficient method to inform CAD risk.