Elevated LDL triglycerides linked to higher risk of atherosclerotic cardiovascular disease

1st February 2023

Higher LDL triglyceride levels are associated with a greater risk of atherosclerotic cardiovascular disease and its components

Danish and UK researchers examining data from the Copenhagen General Population Study, have determined that higher LDL triglyceride levels are linked to an elevated risk of atherosclerotic cardiovascular (ASCV) disease and its components such as myocardial infarction, ischaemic stroke and peripheral artery disease.

It is well recognised that a higher low-density lipoprotein (LDL) level is directly linked with the development of ASCV. Moreover, it has previously been shown that LDL contains a mixture of phospholipids, cholesterol and its esters and around 6% triglycerides. However, the role of triglycerides in ASCV has achieved much less attention in comparison to LDL, possibly because of a lack of randomised, clinical trial evidence.

As a result, in the current study, researchers wanted to better understand the potential role of LDL triglycerides (LDLT) in the development of ASCV and hypothesised that it was likely that higher LDLT levels would in fact be linked to greater risk of ASCV. The team used data obtained in the Copenhagen Population study, in which the lipid levels were measured in nearly 70,000 patients, either by a direct assay or from assessment by nuclear magnetic resonance. The researchers then performed a meta-analysis incorporating their findings from the Copenhagen study with previous studies.

LDL triglycerides and atherosclerotic cardiovascular disease

Levels of LDLT had been measured via a direct assay in 38,081 individuals and by NMR in 30,208 and who were followed for a median of 3 and 9.2 years respectively.

Using the results from measurement of LDLT direct assay, researchers calculated that for every 0.1mmol/l increase in LDLT, there was a 26% higher risk of ASCV (hazard ratio, HR = 1.26, 95% CI 1.17 – 1.35). The risks were similarly elevated for ischaemic heart disease (HR = 1.27), myocardial infarction (HR = 1.28), ischaemic stroke (HR = 1.22) and slightly higher for peripheral artery disease (HR = 1.38). Using the NMR-derived data gave rise to similar elevated risks for ASCV and its components.

When these results were included into the meta-analysis, giving a total participant population in excess of 110,000, a comparison of the highest to lowest LDLT quartile, revealed a risk ratio (RR) for ASCV of 1.5 (95% CI 1.35 – 1.66). Again, the risk ratios were also significantly elevated for ASCV components.

The authors concluded that elevated LDLT were robustly associated with an increased risk of ASCV and its components.

Citation
Balling M et al. Elevated LDL Triglycerides and Atherosclerotic Risk. Am J Coll Cardiol 2023

COVID-19 vaccination reduces infection-related myocardial infarction and stroke risk

9th August 2022

COVID-19 vaccination significantly reduces the risk of both an acute myocardial infarction and stroke among those infected with the virus

COVID-19 vaccination provides individuals with a reduced risk of experiencing an acute myocardial infarction or ischaemic stroke after becoming infected with the virus according to the findings of a study by Korean researchers.

It has now become recognised that following an acute infection with COVID-19, beyond the first 30 days, individuals with COVID-19 have an increased risk of cardiovascular disease and which includes cerebrovascular disorders, dysrhythmias, ischaemic and non-ischaemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. While it is clear that a COVID-19 vaccination is safe and offers protection against severe COVID-19, hospitalisation and death against all current variants of concern, what is less clear is whether vaccination is able to reduce the post-infection cardiovascular sequelae.

As a result, for the present study, the Korean researchers undertook a retrospective cohort study and compared the incidence of acute myocardial infarction and ischaemic stroke in those with and without full COVID-19 vaccination. They linked data from the Korean nationwide COVID-19 registry and the National Health Insurance database and included all adults who were diagnosed with COVID-19 between July 2020 and December 2021.

However, the team excluded several patient groups including: individuals whose data showed that they had a cardiovascular event three months before a COVID-19 infection, cases of re-infection with the virus and patients who were vaccinated but hospitalised with the virus for longer than 30 days.

They set the primary outcome of interest as a composite of all hospitalisations for an acute myocardial infarction and ischaemic stroke and which had occurred 31 to 120 days after an individual’s COVID-19 diagnosis. They decided to exclude cardiovascular events within the first 30 days of infection because of the inherent difficulty of differentiating whether the event was related to infection of treatment.

COVID-19 vaccination and cardiovascular outcomes

A total of 231,037 patients were included in the analysis, of whom 62,727 were unvaccinated and with a median age of 42 years (51.5% female). The median age of the vaccinated group was higher (57 years) and had a greater incidence of co-morbidities including diabetes (11.8% vs 7.1%, vaccinated vs unvaccinated) and hypertension (22.1% vs 10.8%). Furthermore, a higher proportion of unvaccinated individuals had severe COVID-19 (3.1% vs 9.8%).

The median period of follow-up was 90 days in the unvaccinated and 84 days in the fully vaccinated group (which was defined as receipt of 2 doses of a vaccine).

The composite outcome occurred in 31 unvaccinated individuals and 74 of those who were fully vaccinated and after adjustment for differences in baseline characteristics, this difference was statistically significant (hazard ratio, HR = 0.42, 95% CI -.29 – 0.62, p < 0.001). This difference was also significant for the individual components of the composite.

The authors concluded that full COVID-19 vaccination was protective against the acute myocardial infarction and an ischaemic stroke that could arise after infection with the virus, compared with individuals who were unvaccinated.

Citation
Kim YE et al. Association Between Vaccination and Acute Myocardial Infarction and Ischemic Stroke After COVID-19 Infection JAMA 2022

Post-MI mortality risk reduced in overweight/obese but higher for underweight individuals

6th June 2022

Post-MI mortality is significantly lower among those with an above normal BMI yet much higher for individuals when their BMI is below normal

The post-myocardial infarction (post-MI) mortality risk has been found to be significantly lower among those who are classed as overweight or obese yet much higher for those with a body mass index (BMI) below the ideal range.

This was the conclusion of a systematic review and meta-analysis by an international team led by researchers from Aberdeen University, Scotland, UK.

Body mass index (BMI) is a measure of nutritional status in adults and defined as a person’s weight in kilograms divided by the square of the person’s height in metres (kg/m2). Based on the BMI, individuals are deemed to be of normal weight when their BMI is being 18.5 and 24.9.

According to the World Health Organization, individuals with a BMI > 25 are classed as overweight, and obese when their BMI is equal to or > 30). According to the American Heart Association, the presence of obesity leads to the development of cardiovascular disease and mortality, independently of other cardiovascular risk factors.

However, there is increasing evidence that patients with an elevated BMI may have better outcomes if they develop cardiovascular or renal disease, which is referred to as the “obesity paradox”.

Despite this, meta-analyses support a J-shaped relationship between mortality and BMI in patients with coronary artery disease, i.e., the risk is highest for underweight and overweight individuals and lowest for those with a normal BMI.

Nevertheless, whether this same J-shaped relationship holds for post-MI mortality is unknown and was subject of the present meta-analysis. The researchers looked for studies in adults with a previous myocardial infarction where the BMI had been measured and which reported on outcomes such as all-cause mortality, recurrence of an adverse cardiovascular event or hospital re-admission.

Hazard ratios (HRs) were used to assess the risk of mortality and the normal BMI (18.5 – 24.9) was used as the reference range for comparative purposes.

Post-MI mortality and BMI

A total of 27 articles with 308,430 participants and with follow-up periods ranging from 6 months to 17 years were included in the analysis.

Among individuals who were classed as overweight (BMI 25 – 29.9) compared to those of normal BMI and based on 8 studies, there as a 15% lower risk of post-MI mortality (HR = 0.85, 95% CI 0.76 – 0.94, p = 0.002).

In 14 studies that reported on odds ratios (ORs) rather than hazard ratios, there was also a reduced mortality risk (OR = 0.72, 95% CI 0.64 – 0.81, p < 0.0001).

Among obese patients (BMI > 30) the HR was 0.86 (95% CI 0.81 – 0.91, p < 0.0001) and for morbidly obese patients, although the HR was reduced, it was not statistically significant (HR = 0.89, 95% CI 0.78 – 1.01, p = 0.08).

In contrast, among those with a BMI < 18.5, there was a 42% higher risk of post-MI mortality (HR = 1.42, 95% CI 1.25 – 1.62, p < 0.0001) and again, where studies reported odds ratios, this was also significantly increased (OR = 2.48, 95% CI 1.77 – 3.47, p < 0.0001).

There were no significant effects when comparing the risk of hospital re-admission for those who were overweight, obese and underweight.

The authors concluded that individuals who have a BMI less than the normal range are at a significantly higher risk of post-MI mortality. They called for future studies to examine the prognostic utility of other markers of nutritional status in MI to better identify those at a higher risk of poor clinical outcomes.

Citation
De Paola L et al. Body Mass Index and Mortality, Recurrence and Readmission after Myocardial Infarction: Systematic Review and Meta-Analysis J Clin Med 2022

Alirocumab and statin therapy leads to plaque regression in acute MI

18th May 2022

Alirocumab combined with high-intensity statin therapy in post-MI patients leads to coronary plaque regression in non-infarct arteries

The PCSK9 inhibitor, alirocumab, given twice weekly in combination with a statin, to patients who underwent urgent percutaneous coronary intervention (PCI) after an acute myocardial infarction (MI) resulted in significantly greater coronary plaque regression in non-infarct-related arteries after 52 weeks compared to placebo.

This was the conclusion of a randomised clinical trial by teams from Switzerland and Denmark.

It has been previously shown that the use of maximal dose statin therapy can produce a significant regression of coronary atherosclerosis when measured by the percent atheroma volume. Patients who have experienced an MI continue to be at risk of a subsequent event, highlighting the continued need for statin therapy.

For example, one study of post-MI patients found how such individuals continue to be at risk of cardiovascular events beyond the first year after their initial MI. A further reason to continue statin therapy and to hopefully see regression of coronary atherosclerosis, comes from a study in those with acute coronary syndrome.

The study revealed that subsequent major adverse cardiovascular events were equally attributable to recurrence at the site of initial or culprit lesions and to non-culprit or non-infarct-related arteries.

It has also been shown that the combination of alirocumab and high dose statins in patients who experienced acute coronary syndrome 1 to 12 months earlier, reduces the risk of recurrent ischaemic cardiovascular events compared to placebo.

Although combining alirocumab with a statin reduces subsequent recurrent adverse cardiovascular events, little is known about how this combination impacts on plaque burden and composition. As a result, for the present study, the researchers undertook the Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction (PACMAN-AMI) randomised trial.

The study recruited adult patients (> 18 years) who underwent urgent percutaneous coronary intervention (PCI) of the culprit lesion for treatment of ST-elevation MI. Patients were randomised 1:1 to biweekly subcutaneous alirocumab (150mg) or placebo and which was started less than 24 hours after the PCI and given in combination with rosuvastatin 20mg daily for a total of 52 weeks.

The availability of various imaging modalities enabled the team to take a closer look at how the combination therapy affected plaques. They used intravascular ultrasonography (IVUS), near-infrared spectroscopy and optical coherence tomography (OCT) on two non-infarct-related coronary arteries both at baseline and at the end of the study.

The IVUS was used to assess changes in percent atheroma volume (PAV), whereas near-infrared provided a measure of the maximum lipid core burden index. This latter metric, provides an assessment of the lipid content of a plaque, such that lower values are associated with a reduced risk of adverse events. OCT can be used to assess minimal fibrous cap thickness with a thicker plaque being more stable and therefore less likely to rupture.

The primary outcome for the study was the change in IVUS PAV from baseline to week 52 and two secondary outcomes were changes in maximum lipid core burden index and OCT-derived minimal fibrous cap thickness.

Alirocumab and changes in percent atheroma volume

A total of 300 patients with a mean age of 58.5 years (18.7% women) and an overall mean LDL cholesterol level of 3.94mmol/l were randomised to alirocumab or placebo.

After 52 weeks of therapy, the mean LDL cholesterol level was 1.91mmol/l in the placebo group and 0.60mmol/l in the alirocumab group (p < 0.001).

For the primary endpoint, the change in mean PAV was significantly greater for alirocumab compared to placebo (-2.13% vs -0.92%, p < 0.001). The lipid core burden was also significantly reduced with alirocumab (mean change -79.4 vs -37.60, alirocumab vs placebo, p = 0.006). Finally, fibrous cap thickness also significantly increased with alirocumab compared to placebo (p = 0.01).

Based on these findings, the authors concluded by calling for future studies to examine whether the changes observed with alirocumab would lead to an improvement of clinical outcomes for patients.

Citation
Räber L et al. Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction: The PACMAN-AMI Randomized Clinical Trial. JAMA 2022

Sacubitril-valsartan provides no mortality benefit compared with ramipril in acute MI with reduced ejection fraction

26th November 2021

Sacubitril-valsartan offers no mortality advantage in acute MI patients and a reduced ejection fraction compared with ramipril alone

Using sacubitril-valsartan in those experiencing an acute myocardial infarction (MI) and an ejection fraction lower then 40% appears to offer no mortality benefit over the use of ramipril alone. This was the conclusion of a trial by the PARADISE-MI researchers at the Cardiovascular Division, Brigham and Women’s Hospital, Boston, US.

The mortality benefits achieved from the use of angiotensin converting enzyme (ACE) inhibitors in randomised, placebo-controlled trials among patients with left-ventricular dysfunction or heart failure, is well established and is independent of age, sex, and baseline use of diuretics, aspirin, and beta-blockers. Moreover, the beneficial effects of ACE inhibitors also extents to the angiotensin-receptor blocker drugs such as valsartan.

Neprilysin is an enzyme that contributes to the breakdown of the biologically active natriuretic peptides and several other vasoactive compounds which have a favourable effect on the pathogenesis of heart failure. Inhibition of neprilysin with sacubitril, therefore maintains natriuretic peptides and the combination of sacubitril-valsartan has been approved for the management of patients with chronic heart failure and a reduced ejection fraction.

Nevertheless, whether this combination would be effective among patients suffering an acute MI without prior heart failure but with a reduced ejection fraction was the subject of the present study by the US team. They conducted the Prospective ARNI versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events after Myocardial Infarction (PARADISE-MI), which was an international, randomised, double-blind, active comparator trial, comparing sacubitril-valsartan with ramipril alone. The trial recruited patients with a spontaneous MI within 0.5 to 7 days before presentation in association with a reduced ejection fraction (< 40%), pulmonary congestion or both. Included patients were randomised 1:1 to sacubitril-valsartan or ramipril 5mg, both given twice daily in addition to any recommended therapy. The composite primary outcome was death from cardiovascular causes or incident heart failure.

Findings

A total of 5661 patients with an average age of 63.7 years (24.1% women) and a mean ejection fraction of 36%, were randomised to either therapy and followed up for a median duration of 22 months. There were 338 (11.9%) primary outcome events in the sacubitril-valsartan group and 373 (13.2%)in the ramipril group and this difference was non-significant (hazard ratio, HR = 0.90, 95% CI 0.78 – 1.04, p = 0.17). Similarly, death due to cardiovascular causes was also not different (HR = 0.91, 95% CI 0.78 – 1.07), as was hospitalisation for heart failure or outpatient heart failure (HR = 0.84, 95% CI 0.70 – 1.02) and death due to any cause (HR = 0.88, 95% CI 0.73 – 1.05).

The authors concluded that sacubitril-valsartan offered no benefit survival benefit among those with an acute MI and a reduced ejection fraction.

Citation

Pfeffer MA. et al. Angiotensin Receptor–Neprilysin Inhibition in Acute Myocardial Infarction. N Eng J Med 2021

Early influenza vaccination after MI reduces cardiovascular mortality

6th September 2021

Influenza vaccination given within 72 hours of a myocardial infarction (MI) reduced all-cause and cardiovascular mortality at 12 months.

Coronary heart diseases are the leading global cause of death and responsible for an estimated 17.9 million lives lost each year. The idea that influenza might contribute to the development of myocardial infarction (MI) and subsequent death, comes from autopsy studies of patients who died during influenza epidemics. In fact, a recent analysis of 364 hospitalisations for acute MI, confirmed a significant association between respiratory infections, especially influenza and MIs. It is therefore possible that administration of an influenza vaccination as both a primary or secondary preventative measure, could improve cardiovascular disease outcomes. However, a Cochrane review from 2015, concluded that among those with cardiovascular disease, influenza vaccination may reduce mortality and combined cardiovascular events but that more and higher-quality evidence is necessary to confirm these findings.

This need for more high-quality evidence was the reason for the Influenza vaccination After Myocardial Infarction (IAMI) trial undertaken by researchers from the Faculty of Health, Department of Cardiology, Orebro University, Sweden. The team hypothesised that influenza vaccination would reduce the incidence of death, further MIs and stent thrombosis, in patients with a recent MI or with high-risk coronary disease, which included those with stable coronary artery disease and 75 years of age or older with additional risk factors. Eligible patients for the trial were those with either ST-elevation myocardial infarction (STEMI) or non-STEMI. Patients were excluded if they had received an influenza vaccination during the previous 12 months. Participants were then randomised 1:1 to either influenza vaccine or placebo (saline) within 72 hours of their MI. The primary endpoint of interest was a composite of all-cause death, MI, or stent thrombosis at 12 months.

Findings
There were 2571 individuals with a mean age of 59.9 years (81% male) randomised to either arm. Overall, 54.5% of participants were admitted with STEMI and 45.2% with non-STEMI and 8 with stable coronary artery disease. Over the following 12 months, the primary outcome occurred in 5.3% of those vaccinated and 7.2% of those in the placebo group (hazard ratio, HR = 0.72, 95% CI 0.52 – 0.99, p = 0.04). The mortality rates were 2.9% (influenza vaccine) and 4.9% placebo (HR = 0.59, 95% CI 0.39 – 0.90, p = 0.014). In addition, within the influenza vaccination group, 2% experienced a subsequent MI compared to 2.4% in the placebo group (p = 0.57). None of the patients with stable coronary artery disease died.
Discussing their findings, the authors noted how the early administration of influenza vaccination led to a reduced risk of death compared to placebo. They concluded that the provision of influenza vaccination should form part of the in-hospital treatment received by patients following a myocardial infarction.

Citation

Frobert O et al. Influenza Vaccination after Myocardial Infarction:
A randomised, Double-Blind, Placebo-Controlled, multi-center Trial. Circulation 2021

COVID-19 an independent risk factor for myocardial infarction and ischaemic stroke

23rd August 2021

A swedish population-based study has shown infection COVID-19 to be an risk factor for both myocardial infarction and ischaemic stroke.

Although COVID-19 is a considered to be predominately respiratory infection, a review from the end of 2020, established that infection can also result in adverse cardiovascular outcomes. For example, one study of 3,334 COVID-19 patients in the US, found a 1.6% incidence of ischaemic strokes, and an 8.9% incidence of myocardial infarction. This rate was much higher than in a Danish observational study of 5119 patients, of whom, only 0.3% experienced an acute myocardial infarction. However, many of the adverse cardiovascular outcomes have reported among those hospitalised with COVID-19 and there is a lack of data on this disease burden following infection with the virus at the population level.

This was the reason for a study led by a team from the Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden. The researchers sought to quantify the relative risk of both ischaemic stroke and myocardial infarction following infection with COVID-19 using a large, nationwide register within Sweden. The team used two methods of study; the self-controlled case series (SCCS) method and a matched control cohort. In the SCCS method, an individual acts as their own control, so that only those who experience an event are included and serves as an alternative to the cohort or case-controlled study design. For comparative purposes, the researchers also used a more traditional matched cohort study. The period of study was February to September 2020 and the researchers calculated the incidence rate ratio (IRR) of both cardiovascular events following onset of COVID-19. Since an adverse cardiovascular event could have occurred on the same day as infection with COVID-19, it is possible that the event occurred independently of infection with the virus and the team therefore performed two separate analyses using either day 0 (i.e., day of exposure to COVID-19) and one excluding day 0.

Findings
Using the national registry, a total of 86,742 individuals were diagnosed with COVID-19 during the period of study with a median age of 48 years (43% male). In the SCCS study there were 186 acute myocardial infarctions, of whom 39 patients died. When day 0 was excluded, the IIR for acute myocardial infarction was 2.89 (95% CI 1.51 – 5.55) for the first week, 2.53 (95% CI 1.29 – 4.94) for the second week, although not significant for weeks 3 and 4 (IIR = 1.60, 95% CI 0.84 – 3.04). However, when day 0 was included, the IIR was significantly higher (IIR = 8.44, 95% CI 5.45 – 13.08) for the first and second weeks, but again, not significant for the third and fourth weeks. The corresponding values for ischaemic stroke were also significantly increased during the first week when day 0 was excluded (IIR = 2.97, 95% CI 1.71 – 5.15) and when day 0 was included (IIR = 6.18, 95% CI 4.06 – 9.42). In the matched cohort analysis, similar, significant increased risk were observed for both acute myocardial infarction and ischaemic stroke, irrespective of whether day 0 was included.
Based on these findings from two independent methods, the authors concluded that COVID-19 is an independent risk factor for both acute myocardial infarction and ischaemic stroke.

Citation
Katsoularis I et al. Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: a self-controlled case series and matched cohort study. Lancet 2021

MicroRNAs can distinguish between myocarditis and myocardial infarction

11th June 2021

Myocarditis can mimic myocardial infarction but a unique biomarker provides clinicians an opportunity to distinguish the two conditions.

Acute myocarditis (aMC) has many different causes but the prevalence is unclear because the condition has similar clinical symptoms to an acute myocardial infarction (aMI). Although the diagnosis of myocarditis can be confirmed with cardiac magnetic resonance imaging, this technique is not always available. However, one approach to resolve the diagnosis involves the use of microRNAs (miRNAs), which are small, non-coding RNAs that play an important role in gene expression. Several miRNAs have been identified in the infarcted heart and this led a team from the Vascular Pathophysiology Area, Madrid, to try and identify a unique miRNA which could be used to distinguish between myocarditis and myocardial infarction. The team focused on circulating T cells, in particular T helper 17 (Th17) cells, which were confirmed as being a characteristic of myocardial injury in the acute phase of myocarditis. They performed a miRNA microarray analysis and quantitative polymerase chain reaction (qPCR) assays in Th17 cells after experimentally inducing myocarditis and myocardial infarction in mice to identify unique biomarkers.

Findings
The researchers identified the miRNA, mmu-miR-721, produced by Th17 cells in mice which was only produced in response to either autoimmune or viral myocarditis and which was absent from those with aMI. Using four patient cohorts with myocarditis, they subsequently identified a human homologue to mmu-miR-721, termed has-miR-Chr8:96. The researchers found that plasma levels of has-miR-Chr8:96 were considerably higher among myocarditis patients compared to both those with a myocardial infarction and in healthy controls. The area under the receiver-operating characteristics curve for has-miR-Chr8:96 was 0.927 (i.e., 92.7%) for distinguishing between aMC and aMI and this diagnostic value was retained even after adjusting for age, ejection fraction, and serum troponin levels.

Although the authors accepted that more work is needed to validate this biomarker in other cardiac disorders such as dilated cardiomyopathy, their preliminary findings suggest that raised plasma levels of has-miR-Chr8:96 are unique to those with myocarditis and have sufficient discriminatory power from myocardial infarction.

Citation
Blanco-Dominguez R et al. A Novel Circulating MicroRNA for the Detection of Acute Myocarditis. N Engl J Med 2021;384:2014-27