What are the causes and consequences of sex-specific differences in heart failure?
You know, I think biologic sex is such an important variable that is often overlooked in medical research and in medical practice. And I think heart failure is a perfect example of how biologic sex really influences everything from pathophysiology to risk factors, diagnosis and outcomes.
Heart failure really is fundamentally different in men and women. We know, for example, that risk factors for heart failure are different in men and women. For example, in men, the most common risk factor is by and large epicardial coronary artery disease. By contrast, in women, heart failure really seems to represent a culmination of systemic inflammation triggered by a number of comorbidities, and is really thought to be really a systemic disorder.
And then similarly, that sort of translates to sex differences in pathophysiology. For example, in men, we know that apoptosis or just loss of cardiomyocytes seems to be the driving factor in heart failure development, whereas in women epicardial coronary disease seems to be a lesser risk factor, whereas coronary microvascular dysfunction and downstream sequelae related to coronary microvascular dysfunction seems to be a primary culprit.
And then this again, translates to differences in phenotypes; heart failure with reduced ejection fraction is far more common in men, whereas heart failure with preserved ejection fraction is much more prevalent among women. Interestingly, women with heart failure seem to do worse overall with respect to quality of life and exercise intolerance, and other parameters. But overall prognosis is better in women compared with men.
And then finally, I think really interestingly, we’ve seen recently, in large randomized trials specifically related to Sacubitril/Valsartan, there seems to be potential preferential benefit of Sacubitril/Valsartan in women with HFpEF compared with men.
So every step along the way from disease pathogenesis all the way to response to therapy really seems to differ in men and women. And yet we are treating this…we treat heart failure as one condition, but I argue that there are really, they are really different disease conditions in men and women.
How do sex-specific differences in natriuretic peptide levels impact heart failure diagnosis and risk stratification?
So there are numerous sex differences related to natriuretic peptides and other biomarkers, and I’d like to point out one important distinction, which is that sex differences really can affect biomarkers in two ways. The first is that baseline differences in circulating levels can differ in men and women. I think this is what we commonly think about when we consider sex differences in biomarkers. And the second and a little bit more complicated concept is that the effect of a given biomarker may actually predict or be associated with disease outcome differently in men and women. Both effects are true in the case of natriuretic peptides. So we know very well that natriuretic peptide levels are higher in women compared with men in healthy populations. In the heart failure population, it seems to be that these differences are attenuated between men and women.
And then… but secondly, what’s interesting also to note is that the effect of natriuretic peptides on predicting incident outcomes seems to be potentially greater in men versus women, although the data are somewhat conflicted, conflicting. And then the prognostic value of natriuretic peptides in men and women seem to be similar. And I think these are… it’s important to recognize that there are differences both in circulating levels and effect modification of natriuretic peptides in men and women. For one, right now, there are no differences in cutoffs based on sex related baseline levels for natriuretic peptides for the diagnosis of heart failure. That’s something to think about. We know, for example, in myocardial infarction that there are sex differences, sex differences in cutoffs for the diagnosis of myocardial infarction for troponin assays, for example. So that’s one thing certainly that I think the community is contending with. And then the second is, should we be thinking about using natriuretic peptides to predict and to prognosticate differently in our male and female patient populations?
How do hormone status and menopause influence biomarker levels and how does this impact clinical practice?
Such an exceptional question. I think the role of menopause and sex hormones really remains the central question in all of women’s health. We know that the story is really far more complicated than simply presence or absence of estrogen or other sex hormones. But we recognize also that there is an important influence of sex hormones, specifically estrogen, progesterone and testosterone on cardiovascular biology.
If I would take an example of natriuretic peptides, for example, we know that when comparing across different menopausal states, hormone status states, and between men and women, that men actually seem to have the lowest levels of natriuretic peptides, whereas premenopausal women on hormonal contraception appear to have the highest levels of natriuretic peptides.
Now, in a study that we recently conducted looking at a large panel of biomarkers of 71 cardiovascular related protein biomarkers, we also saw an influence of menopause and hormone status on circulating levels of biomarkers. What was interesting though was that a subset of biomarkers seem to be influenced by hormone status and menopause status, whereas another subset did not seem to be influenced whatsoever by hormone and menopause status.
I think these are all…these all sort of give us clues that hormone and menopause status are important in the pathophysiologic processes of cardiovascular disease, but that the story is really nuanced. And I would say that we’re still at a quite rudimentary level of trying to understand these complexities. And so none of this has really been translated to clinical practice. And at this stage, I would say that really trying to better understand the influence of sex hormones, menopause status is where we’re at, so that we can someday hope to translate those findings into clinical practice.
How can future research enable personalised therapy approaches, especially considering sex-specific heart failure treatment?
Yeah, I think every, you know, I think what’s so exciting about being part of the cardiovascular research community these days is sort of the move toward precision medicine. The role of biologic sex is one element of personalized and precision medicine. Right now we really treat our male and female patients the same, but we recognize actually that there are certain biomarkers that seem to be, first of all, there are differences in baseline levels of circulating biomarkers. There are certain biomarkers that seem to be more prognostic or predictive in men versus women or vice versa. Yet we are sort of using the same standard biomarkers and really the same cutoffs for both men and women. So I think there’s a lot of work for us to better identify how we might be able to more precisely tailor these diagnostic tools as well as predictive and prognostic tools to our male and female patients. And then I think from there, even being able to tailor to the individual person is sort of the dream for all of us here.
I gave the example of Sacubitril/Valsartan, and we saw that in heart failure with preserved ejection fraction, that women seem to derive preferential benefit. And this is really important because first, we have very few therapies for HFpEF. Second, we know that HFpEF is more common or more prevalent among women. So that sort of represents this therapeutic gap where more women have HFpEF, we have fewer therapies available for this condition. So in fact, if there is a specific therapy, targeted therapy that seems to derive greater benefit in women versus men, should we be thinking about preferentially treating our female patients with these therapies? Now, of course, that was one randomized trial, a huge randomized trial, but we still don’t quite understand the mechanisms as to why we see this preferential benefit by sex. And that’s something that I’m really interested in, so that we can ultimate… the hope really is to ultimately improve outcomes for our women patients, who we know systematically are undertreated, have worse outcomes really across all cardiovascular endpoints.
What are your hopes for cardiovascular care in the future?
So I hope that in the future we are recognizing that greater than 50% of our population should be… that we should be tailoring our therapies, our guidelines to taking care of women more uniquely.
