Sickle cell disease and the heart: Awareness increases in cardiology community

Sickle cell disease once carried a life span that ended in the teenage years. As more research is conducted and new treatments become available, patients with sickle cell disease are now living longer — on average, between 40 and 60 years, according to the NIH. However, patients with sickle cell disease who are now living longer appear to have elevated risk for CV conditions.

“What’s happening is our patients with sickle cell are living and are developing chronic damage to their blood vessels and heart.” Mark T. Gladwin, MD, Jack D. Meyers Professor and Chair, chairman of the department of medicine, and director of the Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute at University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, told Cardiology Today.

According to the American Society of Hematology and the NIH, an estimated 70,000 to 100,000 Americans and 8% of black individuals in the United States have sickle cell disease. Most physicians are aware of the CV damage that may occur in patients with sickle cell disease through different CV conditions, but the challenge remains as to the underlying causes.

Collaboration appears to be key. Hematologists and pulmonologists today are working more with cardiologists as patients with sickle cell disease develop CV complications, which can sometimes be confused for the effects of a sickle cell crisis or acute chest syndrome. Knowing how to distinguish the symptoms and to treat them accordingly is what will help these patients live longer, experts told Cardiology Today.

Effects on the heart, vasculature

Abnormal hemoglobin caused by sickle cell disease affects the heart as well as surrounding structures.

“The hemoglobin has a single amino acid substitution that makes it polymerize and bind to other hemoglobin molecules,” Gladwin said. “The polymer in the cell makes the cell more rigid, deformed and subject to both entrapment in the microcirculation and the red cell the hemolyze, causing anemia and producing intravascular cell-free hemoglobin.”

The blockage of blood vessels leads to a sickle crisis, which can manifest in different areas of the body such as the lungs and the heart (see Sidebar on page 11 for list of CV conditions associated with sickle cell disease).

“The effects on the heart and the blood vessels are highly and significantly underrecognized in patients with sickle cell disease,” Ankit A. Desai, MD, FAHA, FACC, assistant professor of medicine and cell and molecular medicine at the Sarver Heart Center at University of Arizona, Tucson, said in an interview.

A chronic anemic state can result from the body’s response of trying to eliminate the sickled cells from the bloodstream.

Patients with sickle cell disease who are anemic may also experience high-output failure, as the heart tries to compensate.

“It’s a very high cardiac output that’s two to three times normal levels,” Vandana Sachdev, MD, director of the NHLBI Echocardiography Laboratory, told Cardiology Today. “The anemia also causes dilation of all cardiac chambers and that can adversely affect the heart in the long run. In addition, occlusion of the microvasculature can lead to ischemia that can affect different organs.”

Pulmonary hypertension caused by both pulmonary vascular disease or from diastolic dysfunction is significantly associated with sickle cell disease. It happens in an estimated 6% to 10% of patients with sickle cell disease. A result of pulmonary hypertension is diastolic HF, or HF with preserved ejection fraction, Gladwin said.

Although HF can occur in patients with sickle cell disease, a recently published research letter in Blood by Natalie A. Bello, MD, MPH, assistant professor of medicine at Columbia University Medical Center in New York, and colleagues found that patients with and without sickle cell trait did not have an elevated risk for developing HF compared to black individuals without sickle cell trait (HR = 1.02; 95% CI, 0.82-1.27).

“Looking at four U.S. cohorts, we saw that individuals with [the sickle cell] trait don’t seem to be at an increased risk of developing HF, which is good news because there are some risks of pulmonary embolism which could lead to right HF if they have thromboembolic disease,” Bello told Cardiology Today.

Hypertension can also occur in patients with sickle cell disease as they age, even though their BP is typically lower compared with the general population. Patients who develop hypertension often exhibit an elevated pulse pressure, related to a high stroke volume and vascular stiffness. Data have not been published regarding the normal curve for distribution for BP in patients with sickle cell disease, but researchers are delving more into this area.

Diastolic dysfunction, in combination with myocardial fibrosis, increases risk for adult mortality and morbidity, Caterina P. Minniti, MD, professor in the departments of medicine (hematology) and pediatrics (pediatric hematology-oncology) at Albert Einstein College of Medicine in New York and director of the Sickle Cell Center for Adults at Montefiore Medical Center in the Bronx, New York, told Cardiology Today.

The risk for morbidity and mortality also increases as patients age and develop pulmonary vascular disease, Gladwin said. He added that older patients with sickle cell disease who develop pulmonary vascular disease and diastolic heart disease are also at higher risk for having reduced exercise capacities and death.

Although rare, acute MI can occur in patients with sickle cell disease, often with poor long-term outcomes. A recent study found that among patients with acute MI, those with sickle cell disease had higher rates of in-hospital mortality and were more likely to develop respiratory failure, pneumonia and acute renal failure vs. patients without sickle cell disease.

Treatments for sickle cell conditions can also be associated with CV complications. For example, methadone can increase the QT interval in patients with sickle cell disease, Priscilla Hsue, MD, professor of medicine at the University of California School of Medicine in San Francisco, told Cardiology Today. It can also cause arrhythmias in these patients, Bello said.

“The important takeaway is that patients with sickle cell disease are at risk for many different CV complications and as a clinician to be aware that they can have these different manifestations,” Hsue said.

Identification of CV conditions

Given that patients with sickle cell disease have elevated CV risk, early diagnosis of CV conditions in this population is crucial. Symptoms such as chest pain can denote either a common trait of sickle cell disease or a more significant issue related to the heart. Diagnosing patients using various imaging modalities and blood tests allow cardiologists, hematologists and other health care professionals involved in the care of patients with sickle cell disease to provide the care they need.

Gladwin served on an American Thoracic Society committee that composed a document in the American Journal of Respiratory and Critical Care Medicine in 2014 on the diagnosis and management of pulmonary hypertension in patients with sickle cell disease. “Echocardiography is a noninvasive way to screen [sickle cell disease] patients for structural cardiac abnormalities suggestive of [pulmonary hypertension],” according to the document.

Gladwin and colleagues also published a study in 2004 that alerted clinicians to the benefits of using echocardiograms on patients with sickle cell disease. In this study, “values for pulmonary-artery systolic pressure as estimated by Doppler echocardiography accurately predicted pulmonary-artery systolic pressures measured during right heart catherization (r = 0.77; P < .001).”

A research letter published in JAMA in 2012 by Gladwin and colleagues suggested that a normal echocardiogram can identify patients less likely to have pulmonary hypertension and lower risk for death.

It is recommended that adults with sickle cell disease should be screened with echocardiography every couple of years to screen for pulmonary hypertension, Bello said. Other measurements that can be taken with echocardiography include pulmonary pressure, estimates of right heart dysfunction and tricuspid regurgitation velocity.

“There’s been a nice meta-analysis of 6,000 patients in many trials showing that that value of tricuspid regurgitation velocity can identify patients at highest risk of death,” Gladwin told Cardiology Today.

N-terminal pro-B-type natriuretic peptide is used a lot in patients with sickle cell disease and HF, Sachdev said, as the heart chambers are dilated.

Additional strategies can be utilized to screen patients with sickle cell for other common CV conditions. Brain natriuretic peptide can identify patients at high risk for death, diastolic heart disease or pulmonary hypertension. Patients with renal proteinuria have an increased risk for vasculopathy. Cardiac MRI can be used to screen patients for blood flow abnormalities.

Pulmonary hypertension can be diagnosed with right heart catherization, which is the “gold standard,” Gladwin said, noting it is especially helpful in high-risk patients.

Even with all the different measurements and screening modalities that are used in patients with sickle cell disease, sometimes traditional methods help.

“Everything starts with a good physical examination,” Minniti said. “I have learned to ask questions over the years that are related to the heart, which as a hematologist, I didn’t typically ask, such as shortness of breath ... how many flights of stairs they can [climb] and any kind of nocturnal hypoxia such as obstructive sleep apnea. I used these as a screening tool.”

The risk for MI should be assessed differently in patients with sickle cell disease. Instead of using angiography in the larger vessels, research is being done on using blood flow tests and nuclear and MRI perfusion studies, Sachdev said.

Regardless of the screening tool used, it is important to know when to recommend cardiology care for patients with sickle cell disease. Cardiologists typically become involved in the care of these patients when they develop HF, Kim Allan Williams Sr., MD, professor of cardiovascular disease at Rush University Medical Center in Chicago, past president of the American College of Cardiology and a Cardiology Today Editorial Board member, said in an interview.

The cardiologist may also become involved when evaluating abnormal or borderline ECGs, arrhythmias, high tricuspid regurgitation velocity and significant diastolic dysfunction. Symptoms such as chest pain, exercise tolerance and palpitation should also be monitored by cardiologists, experts said.

Treatments to control CV risk

Once patients with sickle cell disease are identified as having a CV complication, it is important to treat them in a timely manner. These patients have different presentations of CV conditions, so treating them accordingly is crucial. Since the primary problem is sickle cell disease, treating it may alleviate some of the cardiac-related conditions, especially those related to iron overload and hypoxemia.

“The only [medication] that’s really known to be useful in sickle cell is hydroxyurea, which increases hemoglobin levels,” Sachdev said. “Many of the effects ... [such as] the heart being dilated, the high cardiac output, the hemolysis, we think those things get better when a person’s hemoglobin increases with this drug.”

Gladwin said he recommends maximizing the dose of hydroxyurea and adjusting it accordingly based on the patient’s reaction.

The CV manifestations of hydroxyurea have not been thoroughly studied on a large scale. Antihypertensive and antiarrhythmic medications have also not been studied in this patient population, although antihypertensive medications are not frequently used because most patients with sickle cell disease have lower BP levels.

Clinical trials for patients with sickle cell disease and HFpEF are needed, as treatment options for this population are limited, Gladwin said.

The FDA in July approved Endari (Emmaus Medical), an L-glutamine oral powder used for the treatment of patients with sickle cell disease. This is the first medication in 20 years approved to reduce complications related to the disease.

“Glutamine is an amino acid, and that amino acid tends to change the metabolism or the biochemistry of the bloodstream to make it less likely that the red blood cells will sickle,” Williams said. “Having low oxygen tension, dehydration, those are the things that tend to make sickling happen more frequently.”

Patients with sickle cell disease are treated somewhat differently than the general population, especially since they have a severe systemic syndrome that increases their risk for CV manifestations. Statins have been shown not to be very effective in patients with sickle cell disease, Sachdev said, specifically due to them not having high cholesterol or large vessel blockages.

Looking forward, a primary focus is research on new treatment options for patients with sickle cell disease.

“We’re just barely scratching the surface on what the actual problems are in the heart and blood vessels,” Desai said. “Once we have a better grip of the prevalence and all the risk factors to develop the problem, we can begin to address preventable and treatable strategies for those problems.”

Future research, knowledge gaps

Numerous studies have been or are in the process of being conducted on screening, identifying and treating patients with sickle cell disease who also have a CV-related condition.

More than 3 decades ago, young patients with sickle cell disease were shown to have an elevated risk for sudden death with exertion. Since then, the possibility of patients with sickle cell disease being susceptible to the development of fatal cardiac arrhythmias has been considered. Most recently, in addition to a prolonged QTc interval, sickle cell patients have also been reported to have heart fibrosis, both of which are known to increase the risk for fatal heart arrhythmias in patients with HF.

Even much younger participants of a recent study, published in Blood, were assessed by MRI to measure extracellular volume. Those with sickle cell disease and extracellular volume fraction were more likely to have diastolic dysfunction (P = .003). Cardiac fibrosis may be appearing in the youngest of patients with sickle cell disease, Gladwin said.

Other trials are assessing blocking vaso-occlusion and inflammation, in addition to cardiomyopathy of sickle cell disease. Stem cell transplantation is being studied at NIH to determine whether it can cure anemia and sickle cell disease itself, which could mitigate the CV-related conditions these patients may experience, Sachdev said.

Gladwin and colleagues are currently studying riociguat (Adempas, Bayer), which has been approved by the FDA for patients with pulmonary hypertension, but not for hypertension. Researchers are evaluating the efficacy and safety of this medication in patients with sickle cell disease.

“With pulmonary hypertension, there are almost 14 FDA-approved therapies,” Gladwin said. “For sickle cell disease, we only have two FDA-approved therapies available today [glutamine and hydroxyurea]. We need more investment and more clinical research studies evaluating new therapies for sickle cell disease.”

Treatment options such as gene editing and bone marrow transplantation are other approaches that researchers are studying to treat sickle cell disease.

Although many studies are in progress looking at potential treatment and screening options, there is a dearth of large studies to evaluate the benefits of different modalities and medications.

“We have several trials [in sickle cell disease] looking at stroke and how to prevent stroke, which have been fantastically helpful, but we have not had a large study looking at just cardiac dysfunction,” Minniti said.

Although knowledge gaps remain, research in patients with sickle cell disease has come a long way.

“We are beginning to see a lot more researchers who are interested in it, which is great,” Desai said. “Researchers are studying not just important patient-level information about the manifestations, but also researchers are beginning to now explore underlying genetic and molecular influences that might help explain some of these findings and maybe even help develop therapeutics that might be novel.”

Collaborative care

As more effects of sickle cell disease and how to treat them are discovered, having access to all of the resources needed to do so, whether they be screening modalities, treatment options and even clinical care.

“[We need to] advocate for hematologists, cardiologists and pulmonary vascular experts partnering together and developing programs to screen for these cardiac complications and to participate in clinical trials or using the best available treatment strategies to try to take care of these really at-risk patients,” Gladwin said. – by Darlene Dobkowski

• References:
• Bello NA, et al. Blood. 2017;doi:10.1182/blood-2016-08-705541.
• Desai AA, et al. Circ Cardiovasc Imaging. 2014;doi:10.1161/CIRCIMAGING.113.001420.
• FDA. FDA approves new treatment for sickle cell disease. July 7, 2017. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm566084.htm. Accessed Aug. 8, 2017.
• Gladwin MT, et al. N Engl J Med. 2004;doi:10.1056/NEJMoa035477.
• Gladwin MT, et al. J Am Coll Cardiol. 2012;doi:10.1016/j.jacc.2011.10.900.
• Indik JH, et al. PLoS One. 2016;doi:10.1371/journal.pone.0164526.
• Klings ES, et al. Am J Respir Crit Care Med. 2014;doi:10.1164/rccm.201401-0065ST.
• Liem RI, et al. Blood. 2017;doi:10.1182/blood-2016-07-727719.
• Mehari A, et al. JAMA. 2012;doi:10.1001/jama.2012.358.
• Niss O, et al. Blood. 2017;doi:10.1182/blood-2017-02-767624.
• Ogunbayo GO, et al. Am J Cardiol. 2017;doi:10.1016/j.amjcard.2017.07.108.

• For more information:
• Natalie A. Bello, MD, MPH, can be reached at Columbia University Medical Center, 51 Audubon Ave., Room 4-401, New York, NY 10032; email: nb338@cumc.columbia.edu.
• Ankit A. Desai, MD, FAHA, FACC, can be reached at University of Arizona, 1656 E. Mabel St., Medical Research Building, Room #319, Mailstop #245217, Tucson, AZ 85724; email: adesai@shc.arizona.edu.
• Mark T. Gladwin, MD, can be reached at University of Pittsburgh Department of Medicine, 1218 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261; email: gladwinmt@upmc.edu.
• Priscilla Hsue, MD, can be reached at University of California, San Francisco, Zuckerberg San Francisco General, 1001 Potrero Ave., San Francisco, CA 94110; email: priscilla.hsue@ucsf.edu.
• Caterina P. Minniti, MD, can be reached at Montefiore Medical Center, 3411 Wayne Ave., Bronx, NY 10467; email: cminniti@montefiore.org.
• Vandana Sachdev, MD, can be reached at NIH Clinical Center, 10 Center Drive, Bethesda, MD 20814; email: sachdevv@nhlbi.nih.gov.
• Kim Allan Williams Sr., MD, can be reached at Rush University Medical Center, 1653 W. Congress Parkway, Chicago, IL 60612; email: kim_a_williams@rush.edu.

Disclosures: Bello, Hsue, Minniti, Sachdev and Williams report no relevant financial disclosures. Desai reports receiving grant support from the NIH. Gladwin reports a research collaboration with Bayer Pharmaceuticals.