Acute MI Symptom Clustering Differs in Men and Women: VIRGO

Women presenting to the hospital with acute myocardial infarction have greater variation in their clustering of symptoms, a broader distribution of unique symptom phenotypes, and tend to present with more symptoms per patient when compared with men.

The findings might explain why acute MI is missed more often in women than in men, say investigators, and should encourage physicians to expand their thinking when it comes to potential diagnoses in their female patients.

“Women are different in some way,” said lead investigator John Brush Jr, MD (Sentara Healthcare and Eastern Virginia Medical School, Norfolk). “Women have more phenotypes, and the reason they have more phenotypes is that they have more uncommon phenotypes. That could potentially create confusion for someone trying to recognize a diagnosis. If you have a woman who is having an acute MI, but the phenotype is not what you’d expect, then you’re more likely to miss the diagnosis.”

In terms of the clinical message, Brush emphasized teaching physicians to be more expansive in their thinking about presenting acute MI symptoms and how those symptoms combine in an individual patient. “I’m hoping our paper gets people thinking along those lines,” said Brush. “This is a ‘think different’ kind of study. It’s a new idea about how to look at the diagnosis of acute myocardial infarction.”

Missing Acute MIs in Women

Published online February 17, 2020, ahead of print in Circulation: Cardiovascular Quality and Outcomes, the new study is an analysis of the Variation in Recovery: Role of Gender on Outcomes of Young Acute MI Patients (VIRGO) multicenter registry. To TCTMD, Brush noted that the diagnosis of acute MI is missed more often in women than in men, particularly in women 55 years or younger, but the reason why this occurs is unknown. As an author of a textbook on medical reasoning, Brush said that physicians typically begin their diagnosis by generating a short list of potential diagnoses.

“When we recognize a possible diagnosis, we’re using the same mental processes we use to identify a chair, or dog, or cat,” he said. “We look at something and know what it is because we’ve seen it a gazillion times before.”

Brush said an experienced clinician has a “filing cabinet of exemplars,” which are memories of individual phenotypes, so that when they see a patient, they’re able to recognize a condition, which in turn leads to further testing to confirm the diagnosis. “The various phenotypes that we see and encounter—all those variable combinations of symptoms—become exemplars that can be used going forward,” said Brush.

In VIRGO, which included 3,501 young adults hospitalized with acute MI between 2008 and 2012, data on the presenting symptoms were collected with standardized interviews during the index admission. In the interview, patients were asked if they had chest pain, pain in the jaw, neck, arm, or back, dizziness, indigestion, nausea, palpitations, shortness of breath, sweating, weakness/fatigue, or confusion. These 10 symptoms could be combined in individual patients as unique symptom phenotypes. Data from medical records were also used to identify the clustering of symptoms in men and women. 

Using the symptoms derived from the interviews, women presented with 426 different combinations of symptoms compared with 280 phenotypes in men. The difference remained significant even after adjustment for the larger number of women enrolled in the VIRGO registry. Additionally, there was a broader distribution of symptom clustering in women. For example, 40% of women had one of the top 25 interview-derived symptom phenotypes compared with 46% of men (P < 0.001). The two most common acute MI phenotypes in men and women were chest pain alone and chest pain with jaw, neck, arm, or back pain.

Similar findings were observed when investigators used the symptoms extracted from medical records. In women, there were 244 symptom clusters identified compared with 154 combinations in men. Half of the women (50%) had one of the 10 most common acute MI phenotypes compared with 59% of men (P < 0.001).

‘Prototypical’ Acute MI Phenotype is Rare

In the registry, women were more likely to have an NSTEMI, were less likely to receive emergent or urgent PCI, and were more likely to have a delay in diagnosis (> 6 hours after symptom onset). Overall, there were a larger number of interview-derived symptom phenotypes in women than in men who had a STEMI, who underwent PCI, and who didn’t delay in presenting to the hospital. To TCTMD, Brush said it’s also likely that women, or their immediate caregivers, aren’t recognizing their acute MI symptoms.  

“Any time you have a source of ambiguity or confusion, it can diminish the ability to generate the idea this person may be having an acute myocardial infarction,” he said.   

The prototypical description of acute MI is a patient with chest pain radiating down the arm accompanied by shortness of breath and diaphoresis. Each one of those four symptoms is common at the population level, said Brush, but that specific combination of symptoms occurred as a phenotype in just 1% of acute MI patients in VIRGO. “If you’re looking for the prototype, you’re actually looking for something that’s rare,” he said. Also, if the prototype has been developed from a population compromised primarily of men, “you could potentially be teaching a stereotype,” he added.

In an editorial, Nakela Cook, MD, MPH (National Heart, Lung, and Blood Institute, Bethesda, MD), notes that among those who delayed before presenting to the hospital, there was no significant difference in the number of symptom phenotypes between men and women despite it being a potential mediator of outcomes.

“Thus, there remains a unique opportunity to further elucidate drivers of delays in time to diagnosis that are attributable to patient factors versus clinical care factors (eg, hospital/setting, physician/care team, etc) to inform effective interventions to improve acute MI outcomes for women,” she writes.

Cook states that one of the reasons it’s important to examine the differences in acute MI phenotypes is that it might help shed light on the underlying causes. “Studies have demonstrated sex differences in the pathophysiology of acute MI with plaque erosion, MI with nonobstructive coronary arteries, and spontaneous coronary artery dissection—all more common causes of acute MI in women as compared with men,” she writes. “An association between individual symptom phenotypes and pathophysiology could enhance diagnosis to appropriate treatment management.”

Cook also notes that the study shouldn’t diminish the fact that chest pain remains the most common acute MI symptom for men and women.