The incidence of heart failure (HFpEF) with preserved ejection fraction increases with age, and the majority of patients are elderly and female. However, the research progress on the etiology and pathogenesis of HFpEF is slow at present. Common complications of HFPEF include hypertension, obesity, metabolic disorder and so on, and the clinical treatment plan needs to be improved. At the ACC 2021 Conference, Professor Nancy K. Sweitzer of Savile Heart Center in the United States was invited by us to have an in-depth interview on issues related to HFpEF based on our clinical experience.
《International Circulation》:With the aging of the population and the evolution of the human disease spectrum, the proportion of HFpEF in the total number of heart failures has gradually increased. Would you please introduce us what are the HFpEF treatment strategies recommended in the relevant guidelines?
Professor Nancy K. Sweitzer: I think in the next twenty years, we are going to see a lot of this disease as the population ages and the prevalence of the many contributing diseases, particularly hypertension, diabetes and obesity, rises. Right now, as most of your viewers probably know, all of our trials of therapies for heart failure with preserved ejection fraction (HFpEF) have been negative. Some of them were close, but not quite positive. The PARAGON trial was the closest, testing sacubitril/valsartan (Entresto), showing that there was probably benefit in the PARAGON population for patients below the mean ejection fraction in that trial, which was 57%. Interestingly, the drug appeared more beneficial in women than in men, and at higher ejection fractions in women. So I think we still have more to learn about whether that therapy would actually have a role in treatment of this disease. Currently, both the US and European Guidelines are very minimal. They say to use diuretics to control symptoms, and to treat comorbid diseases according to guidelines. In the US Guidelines, that is specified more to be treatment of hypertension according to guidelines, because clearly, blood pressure control to guidelines reduces the development of heart failure with preserved ejection fraction, and probably improves symptoms in heart failure with preserved ejection fraction. Really the guidelines are super-minimal – diuretics and treatment of blood pressure – and then consider detection and treatment of things like coronary artery disease (which is often a contributor) and, especially in the quite elderly, under-recognized. Then, rate and rhythm control strategies of atrial fibrillation are appropriate, because atrial fibrillation is another common comorbidity. We are all eagerly awaiting trials of the SGLT2 inhibitor drugs in this disease to see if they have efficacy. Those bigger trials should be announced hopefully later this year or early next year.
《International Circulation》:Most HFpEF patients have other diseases, such as hypertension, coronary artery disease and atrial fibrillation. What do you think should be done to manage comorbid diseases?
Professor Nancy K. Sweitzer:We do not have any randomized controlled trials that enrolled only HFpEF patients with those comorbidities and looked at management. So basically, we extrapolate from trials of those diseases, where we should treat hypertension according to guidelines in patients with HFpEF. There is debate about what those guidelines should be. The SPRINT trial showed lower cardiovascular complications with quite aggressive blood pressure control to <120mmHg, but some people feel that in this population, such aggressive blood pressure control is not indicated, and there is still debate about that. I don’t think we know the answer, but certainly, blood pressure control to <130mmHg in diabetic patients and to <140mmHg in non-diabetic patients is warranted. In select patients, even more aggressive blood pressure control may be helpful. Coronary artery disease, I think, is under-recognized in this population, and when it is systematically investigated is present in a substantial proportion of patients, as many as 30-50% of them depending on the geography of the population study. But I think an aggressive search for coronary artery disease is warranted. I personally feel that non-invasive testing for ischemia is less helpful in this population, because often they have multivessel disease and ischemia that is not as well detected with non-invasive testing, with the exception of CT angiography. I think this is very useful in this population. It is a non-invasive test, and you can see whether there is in fact significant plaque burden and in how many vessels in the patient. Personally, I am finding CT angiography is very helpful as a screening test to decide whether one should proceed to angiography in HFpEF patients. Then atrial fibrillation is a really complicated topic in HFpEF patients. Many of them have abnormal diastolic function. When relaxation is quite slow, there may be a benefit to heart rate slowing in atrial fibrillation. The rapid rates associated with atrial fibrillation may be quite detrimental. If diastolic function is severely abnormal and the ventricle is very stiff, often all of the filling of the ventricle will occur in early diastole, and in those patients, heart rate control is much less beneficial. In fact, heart rate slowing can be dangerous because it can start to drop cardiac output in the patient. So a sophisticated examination of diastolic properties on echocardiography is often helpful in these patients, and then whether rate or rhythm control strategies are superior is not really well-known. There are ongoing studies right now looking at this question, but I think if a patient presents with decompensated heart failure with preserved ejection fraction and atrial fibrillation, it is worth trying to restore sinus rhythm one time to see if that helps with the symptoms of heart failure. If it does, then probably maintenance of sinus rhythm should be a goal in that particular patient. If you restore sinus rhythm and the symptoms don’t really improve, then maybe rate control is all that is necessary in that patient. And then in some of these patients you just can’t get them back in sinus rhythm, until you treat the heart failure more aggressively sometimes.
《International Circulation》: What are the clinical characteristics of HFpEF patients of different ages? What are the characteristics of the pathogenesis?
Professor Nancy K. Sweitzer: The vast majority of patients with heart failure and preserved ejection fraction are quite elderly. It is most common in patients in their 70s, 80s and 90s. We do see younger patients with HFpEF. Even more than age, I think geography plays a role. In the United States, for example, this population is very obese. In Asia, the HFpEF population is less obese. Clearly, the clinical phenotype in Asia is quite different than in Western Europe and the United States. I don’t think of it so much of an age thing. In each individual patient, it is important to identify the contributing clinical syndromes, whether it is hypertension for instance. In the United States, for example, African-American patients get the disease at a much younger age and it appears to be related, in part at least, to much earlier onset hypertension in that population, as well as diabetes and obesity. In elderly women, it is strongly associated with hypertension, and less strongly associated with coronary disease; while in men, it is associated with coronary disease. I think the Asian phenotype is still being worked out exactly, but hypertension is clearly playing a role, and coronary disease may play a bigger role in Asia with higher rates of cigarette smoking and risk factors for coronary disease. Certainly, in elderly men who present with HFpEF, it is very important to rule out amyloid heart disease, where the wild-type transthyretin amyloid has a 9:1 predilection in men over women. So in elderly men presenting with new HFpEF, it is really important to rule out amyloid. Probably in any patient presenting with unexplained HFpEF, screening for multiple myeloma and AL amyloid is very important, because you don’t want to miss a treatable cancer that is causing the heart disease presentation. So the way I approach this disease when I meet a new patient is try to think of the very broad differential diagnosis of HFpEF and start going through identifying the important contributors that may be treatable, such as AL amyloid or transthyretin amyloid heart disease, thyroid dysfunction, anemia, or renal dysfunction (a very common contributor to this syndrome) and that may have a different treatment. When those things are ruled out and you have what appears to be an isolated disease that involves the cardiovascular system, look at all the comorbidities that are contributing and treat those as aggressively as possible.
《International Circulation》: At this conference, you gave a report on " Futurist View of HFpEF ", Could you share us the specific content?
Professor Nancy K. Sweitzer: I think that we still have some work to do to understand the role of sacubitril/valsartan in this disease. It looks like there is probably benefit in some patients to reduce the risk of hospitalization. There was clearly no mortality benefit with the drug in HFpEF. There is a lot of interest in seeing the results of the SGLT2 inhibitor trials in HFpEF, several of which are drawing to a close. We are hopeful that in the next year we will have some data about those drugs and their role in this disease. There are some device trials. There is a left atrial septal device that produces an ASD from early non-randomized, non-blinded, open label studies in Europe that looked somewhat promising. The PIVOTAL trial has finished enrolment and is in follow-up, so we are awaiting the results of that as well in HFpEF. There is interest in a lot of other new therapies, but I don’t think we have a lot of trials that are very close to completion. We have a lot of interesting trials just beginning, so I think over the next five years, hopefully we will get smarter about phenotyping these patients and enrolling appropriate patients into trials. And there are lots of promising therapies being tested. I have been in this field for a while now, and I am a little bit jaded. I feel as if we have developed a lot of good theories about this disease. We have seen therapies that seemed logical based on pathophysiology that should work, but that haven’t worked. It may be partly because we enroll very heterogeneous populations into our trials and the therapies are only working in a subset of those patients. But it may be that we really don’t understand the disease and don’t characterize the disease sufficiently to do really effective therapeutic trials. We have a lot more to learn still. While we are learning, we are all taking care of these patients, and that’s a real challenge.
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