by Dr Gard Myrmel

We have known for a while now that the symptoms of acute coronary syndromes can be different for women compared to men. Here, Dr Myrmel discusses how the differences between the sexes also extend to the prognostic value of circulating biomarkers in patients presenting with acute chest pain.

Diagnostic and prognostic challenges associated with patients presenting with acute chest pain

In general, ischemic heart disease and myocardial infarction (MI) is still the leading cause of death worldwide and obviously this involves a lot of patients. Timely diagnosis and intervention is essential to prevent mortality and morbidity, and acute chest pain is one of the most common reasons for hospital admission. One of the main challenges which is relevant for this article is risk stratification, and that includes accurate risk assessment of patients diagnosed with acute coronary syndromes (ACS; for example, who needs urgent revascularization versus who can wait); accurate risk assessment of patients with suspected ACS (for example, who can be ruled out and discharged safely versus who needs admittance and further diagnostic testing, such as serial troponin testing, CT coronary angiography and invasive coronary angiography). One of the problems with the risk scores being used is that they are based on the whole population and may thus overestimate and under-estimate the risk in certain individuals and subpopulations, such as differentiating between men and women. The prognostic value of these risk scores is generally moderate, and there is evidence that clinicians’ use of these risk prediction tools is not optimal, which again can lead to unnecessary and suboptimal diagnostics and treatment, as well placing a large burden on the health-care system – emergency rooms, hospitals and so on.

There are also challenges with diagnostics: patients with MI are usually easy to diagnose because there are fixed criteria based on troponin levels, ECG findings and symptoms. However, very few patients presenting with chest pain actually have myocardial infarction: in our population only 12% of patients presenting with chest pain were diagnosed with MI. Other patients included under the ACS umbrella are those with unstable angina. These patients are more difficult to diagnose as they usually have negative or stable troponin concentrations and they need other diagnostic modalities, such as CT coronary angiography, they require hospital admittance and consume large health resources. Therefore, numerous risk stratification tools and rule-in/rule-out algorithms exist and are used to assess risk and decide who can be safely discharged and who needs to be admitted for further diagnostic testing. Also even if the patient is not diagnosed with any ACS during admission, they may still be at high risk of a cardiovascular event. In our study, in patients without ACS, 12% of men and 11% of women died, suffered an MI or were hospitalized for heart failure during the 4.2 years of follow-up. Hence, this is not a population totally without risk even though ACS is ruled out, and some of these risk calculators can also be used for long-term risk prognostication – identifying those at high risk can be very useful for implementing more strict risk-reduction therapy to try to reduce the risk of a cardiovascular event in these patients.

Biomarkers aid diagnosis as well as risk stratification

Biomarkers are included in all these risk calculators, such as the HEART (History, Electrocardiogram, Age, Risk factors, and Troponin) Score®, the GRACE (Global Registry of Acute Coronary Events) ACS Risk and Mortality calculator, the TIMI (Thrombolysis In Myocardial Infarction) Risk Score for UA/NSTEMI for patients with unstable angina and non-ST elevation MI, and also in the rule-in/rule-out algorithms in patients presenting with acute chest pain. Currently, cardiac troponin is the only biomarker that is used in clinical practice in patients presenting with suspected ACS, and this includes both troponin T and troponin I. The cut-off value for risk stratification can vary: usually the 99th percentile threshold for myocardial injury is used. For instance, in the HeartScore®, troponin concentrations above the normal limit score one point; troponin concentrations more than three times the normal limit score two points. The GRACE and TIMI scores also use the myocardial injury cut-off. However, in the rule-in/rule-out algorithms, different thresholds are used. Also, of course, it depends on the assay that is being used; for instance, in our hospital if the patient has a very low initial troponin T (below 5 ng/L) and it’s been more than 3 hours since the onset of symptoms, this patient can be safely discharged with outpatient follow-up if needed. So ACS can be ruled out with very high accuracy. Biomarkers are very useful not only for the diagnosis of MI but are also essential for risk stratification.

Many researchers argue that cardiac troponin should be used as a continuous variable for risk stratification but we’re not able to implement that into clinical practice yet. The other biomarkers that we analysed in our study are not routinely used for risk stratification in patients presenting with suspected ACS. We analysed the natriuretic peptides, such as NT-proBNP (N-terminal pro-B-type natriuretic peptide), which is mainly released in response to myocardial wall stretch and hemodynamic stress. NT-proBNP is mainly a marker of heart failure but it is also a very good prognostic marker in patients with chest pain. According to the European Society of Cardiology guidelines, it could be measured for risk assessment. As far as I’m aware, there’s no validated prognostic cut-off level, so in our study we decided to use the limit for acute heart failure which is 300 ng/L. Other strong prognostic markers in this population include C-reactive protein (CRP) and growth differentiation factor (GDF)-15. Again, for these markers, I don’t think there’s any validated cut-off values for risk stratification in patients with chest pain, so for CRP we chose a cut-off value of 2 mg/L, based on the American College of Cardiology recommendation in primary prevention. CRP is an inflammatory marker and, in part, reflects cardiovascular inflammation and so is predictive of cardiovascular events. GDF-15 is a more complex biomarker but in this setting it is also mainly a pro-inflammatory cytokine reflecting inflammation but it’s also involved in in many different processes throughout the body, for instance in appetite regulation and so on. So although these are good prognostic markers, other than cardiac troponin, these markers have not really been shown to improve patient management and their added value in risk assessment on top of the current risk scores and troponins appears to be marginal. Therefore, assessment of CRP and GDF-15 is not currently used routinely for prognostic purposes. However, possibly in the future, with the increased use of AI, we may be able to create better risk prediction models that include more biomarkers and multi-marker panels which will improve an individual’s assessment and allow for a more personalized risk stratification score.

Major signs and symptoms of heart attack in women and men
(Adobe Stock.com)

Factor that affect risk of cardiovascular events

The traditional risk factors for cardiovascular disease and MI include smoking, hypercholesterolemia, hypertension, diabetes, a family history of premature cardiovascular disease, previous MI, peripheral arterial disease, and also age, renal failure and obesity. These risk factors are included in varying degrees in the different risk calculators. The clinical history is important and associated with increased risk of having ACS if the chest pain and other symptoms are suspicious for ACS, which means typical new onset or worsening of angina. Also if the ECG shows signs of myocardial ischemia, then the patient is at increased risk and increased probability of ACS. Also, of course, the biomarker data is useful, which typically includes the lipid biomarkers, LDL and HDL, some also include creatinine and of course troponin, mentioned above.

Differences between males and females

There are differences between the sexes in several aspects of patients presenting with acute chest pain. Women tend to be older when they have an MI and they generally have more comorbidity. We are now pretty familiar with the differences in symptoms between men and women – most often women have typical chest pain but women more often than men can have atypical symptoms, which include signs of autonomic activation, such as nausea, vomiting and sweating as well as fatigue. Shortness of breath is more common in women – they may have shortness of breath even without chest pain, so shortness of breath could be the only symptom. Also referred pain, especially to the back, is more common in women than in men. There are also differences in pathophysiology: women tend to present less often with MI due to coronary plaque rupture but more often have microvascular angina, which is narrowing or constriction of the smaller branches of the coronary vasculature. Women more often have spontaneous coronary artery dissection, which is a dissection or tear in the coronary arteries and also more often have Takotsubo cardiomyopathy or “broken heart syndrome”. Studies from the USA and Australia have shown that female patients are less likely to receive coronary angiography and to undergo early invasive therapy than male patients. Additionally, women may also be undertreated with regards to cardiovascular risk factors, and women are also at increased risk of bleeding events. These sex differences that we know about are generally not reflected or accounted for in any of the risk calculators that are used in clinical practice today – at least not in Norway. The GRACE 3.0 risk stratification model accounts for sex differences in its risk factor profile but I don’t think any guidelines recommend this yet and I don’t know of any places that actually use it, so the sex differences are generally not accounted for in clinical practice.

Sex differences in the prognostic value of circulating biomarkers

We know that the troponin levels tend to be higher in men compared to women – they could be up to 40% higher. Our study showed that increasing concentrations of cardiac troponins, both high-sensitivity cardiac troponin T and troponin I, are associated with a high risk of death and cardiovascular events, including death from all causes, incident MI, and heart failure hospitalization during four years of follow-up in women compared to men. Also, when presenting at the same absolute concentration, for instance if you have troponin results above the myocardial injury cut-off, the risk for death and cardiovascular events is much higher for women. Additionally, troponin concentrations above the 99th percentile  (the myocardial injury cut-off) were associated with an unadjusted hazard ratio of 8.5 in women and 4.6 in men. This is almost twice the risk in women if you use the same cut-off, and if this difference is not accounted for it could lead to an underestimation of risk in women and overestimation in men. The same level of NT-proBNP was also associated with a higher risk in women compared to men; although these findings was not as clear as for troponins, there was a trend towards an increased risk for death and cardiovascular events in women compared to men. For CRP and GDF-15, there were no differences in prognostic value in our study for men and women and seemingly these markers can be used for prognostication without having to adjust for sex.

Benefit of sex-specific cut-off values for biomarkers for prognostication of cardiovascular events

Using the sex-specific cut-off values for cardiac troponins and also for NT-proBNP may lead to less underestimation of risk in women and less overestimation of risk in men and generally a more patient-tailored risk stratification. This again may lessen some of the sex disparities that currently exist, and sex-specific approaches probably should be used to provide an equal risk prediction. Of course, these data have to implemented and used in practice to see if applying these sex-specific cut-off levels actually translate into a real difference in clinical outcomes, but that’s what our study suggests.

The author

Gard M.S. Myrmel MD,
Cardiology Fellow, PhD Candidate Department of Heart Disease,
Haukeland University Hospital, Bergen, Norway

Email address: gard.mikael.sele.myrmel@helse-bergen.no

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