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Research News

 

The importance of gender in CRT device prescribing pattern and mortality outcome

Yanting Wang, MD
 

Heart failure is remains one of the major health problems nationally and globally, with over 5 million patients in the US and 20 million patients worldwide. Cardiac resynchronization therapy (CRT, a established therapy for select patients with heart failure, can be delivered through a CRT pacemaker or a CRT defibrillator. The pacemaker devices are smaller, less expensive, and have a better battery life, but cannot deliver high-energy shocks to terminate potentially lethal arrhythmias. These differences may influence physician prescribing practices and patient preferences. As published guidelines do not distinguish between these devices, we aimed to describe prescribing patterns in elderly women and men with heart failure, and examine whether gender differences are associated with disparate patient outcomes. We examined 512 patients who underwent any CRT device placement between 2002 and 2013 at University of Pittsburgh Medical Center and found that women were more likely to receive the pacemakers than men. Men who received the pacemakers were significantly older than the men or women who received the defibrillator. Women with either device, and in particular the pacemaker, have better overall survival than men. Our study highlights the significant role gender plays in device choice and implantation as well as in mortality outcomes.


   

Wang Y, Sharbugh MS, Munir MB, Adelstein EC, Wang NC, Althouse AD, Saba S. Gender Differences in Cardiac Resynchronization Thearpy Device Choice and Outcomes in Patients ≥75 Years of Age with Heart Failure. Am J Cardiol. 2017 Dec 15;120 (12):2201-2206. doi: 10.1016/j.amjcard.2017.08.044. Epub 2017 Sep 19. PMID: 29050686

   

Wang Y, Sharbaugh MS, Althouse AD, Mulukutla SR, Saba S. Cardiac resynchronization therapy pacemakers versus defibrillators in older non-ischemic cardiomyopathy patients. Indian Pacing Electrophysiol J. 2018 Aug 16. pii: S0972-6292(18)30128-1. doi: 10.1016/j.ipej.2018.08.002. [Epub ahead of print]

   


 
 


Social media engagement may have positive academic impact on cardiovascular research

Amr Barakat, MBBCh
 

Social media outlets, particularly Twitter, have gained interest among the cardiovascular community as a modality for dissemination of cardiovascular research. Online attention scores have emerged as a tool to assess the performance of scholarly articles on Web-based media and social networks. The Altmetric attention score (AAS), a commonly used online attention score, is widely adopted by cardiology journals, providing an objective reflection on how well an article is trending on online platforms. To explore the relationship between AAS and article citations (as a more conventional scholarly metric), we examined 939 original cardiovascular research articles published in 2014 in the 8 highest impact-factor General Internal Medicine and Cardiology journals, and collected AAS and 3-year total citation counts (2015-2017) for each article. Our analysis showed that the online attention as measured by AAS seemed to have a moderate correlation with citation counts at 3 years. The correlation was strong when only clinical trials or meta-analyses were evaluated. Our findings show that social media engagement may have positive academic impact on cardiovascular research, and should encourage academic cardiologists to promote their research on social media and other online platforms.


Barakat AF, Nimri N, Shokr M, Mahtta D, Mansoor H, Mojadidi MK, Mahmoud AN, Senussi M, Masri A, Elgendy IY. Correlation of Altmetric Attention Score With Article Citations in Cardiovascular Research. J Am Coll Cardiol. 2018 Aug 21; 72(8):952-953. doi: 10.1016/j.jacc.2018.05.062.



 
 


Exploring the mechanisms of the racial disparity in drowsy driving

Michael Genuardi, MD
 

Falling asleep while driving is a significant public health problem, leading to tens of thousands of automobile accidents every year in the United States. It has been known that in the US, blacks and Hispanics are at higher risk of drowsy driving than whites, but the reasons for this disparity have not been clear. Using data from over 190,000 drivers, we examined whether impaired access to healthcare, alcohol use, risk-taking behavior, or sleep characteristics explained the drowsy driving difference. We found that after adjustment for age, sex, and medical history, black and Hispanic drivers had a 2-fold increased risk of drowsy driving compared to whites. Adjustment for access to healthcare, alcohol use, and risk-taking behavior did not significantly change the size of the disparity. However, sleep characteristics explained about half of the excess drowsy driving risk in blacks compared to whites. On average, blacks get poorer sleep than whites in the US. Our findings show that this disparity has potentially deadly consequences, and should encourage clinicians and the general public to have increased sensitivity to identifying racial disparities in sleep health.


Genuardi MV, Althouse AD, Sharbaugh MS, Ogilvie RP, Patel SR. Exploring the mechanisms of the racial disparity in drowsy driving. Sleep Health. In press. Epub 2018 Apr 24. doi: 10.1016/j.sleh.2018.04.003.



 
 


Temporal Associations Between Smoking and Cardiovascular Disease

Smoking has long been a major risk factor for coronary artery disease (CAD). The last 4 decades have seen significant changes to population health and CAD risk factors, including a decline in smoking prevalence, an increase in diabetes and obesity, and the widespread use of potent preventative medications, including statins, which have led to a decline in average cholesterol levels. We sought to investigate if these changes to risk factors and preventative care has altered the magnitude of the risk of developing CAD in smokers compared to non-smokers. To accomplish this, we analyzed over 5,000 participants in the Framingham Heart Study, focusing on three separate 12-year periods from 1971 to 2006. We found that despite recent improvements in preventative cardiac care and the changing prevalence of CAD risk factors, smoking cigarettes continues to confer a 2-fold increase in the risk of developing CAD for men, and a 1.5-fold increase in the risk for women. Our findings point to the continued importance of smoking cessation programs to prevent CAD.


Burke GM, Genuardi M, Shappell H, D'Agostino RB Sr, Magnani JW. Temporal Associations Between Smoking and Cardiovascular Disease, 1971 to 2006 (from the Framingham Heart Study). Am J Cardiol. 2017 Nov 15;120(10):1787-1791. doi: 10.1016/j.amjcard.2017.07.087. Epub 2017 Aug 8. PMID: 28865894.



 
 


New research co-authored by Dr. Sebhat Erqou helps connect the dots between race, pollution and heart disease

Sebhat Erqou, MD, PhD
 

Epidemiological studies have shown that chronic exposure to environmental air pollution is associated with adverse health outcomes, but their role in racial disparities in clinical outocmes has not been fully elucidated. We aimed to assess racial differences in air pollution exposures to ambient fine particulate matter (PM2.5) and their association with cardiovascular disease (CVD) risk factors, arterial endothelial function, incident CVD events and all-cause mortality. We used data from the Heart Strategies Concentrating on Risk Evaluation (HeartSCORE) study to estimate one-year average air pollution exposure to ambient fine particulate matter pollutants (particles with median aerodynamic diameter <2.5 µm [PM2.5]) for approximately1700 participants. We found that PM2.5 exposure was independently associated with elevated blood glucose, worse endothelial function, and incident CVD events and all-cause mortality. Blacks had a 45% higher risk of incident CVD events and all-cause mortality than Whites after adjusting for risk factors. Approximately a quarter of this difference appeared to be explained by differential exposure to PM2.5.


Erqou S, Clougherty JE, Olafiranye O, Magnani JW, Aiyer A, Tripathy S, Kinnee E, Kip KE, Reis SE. Particulate Matter Air Pollution and Racial Differences in Cardiovascular Disease Risk. Arterioscler Thromb Vasc Biol. 2018 Apr; 38(4):935-942. doi: 10.1161/ATVBAHA.117.310305. Epub 2018 Mar 15. PMID: 29545240



 
 


Pitt/HVI Investigators publish largest study yet linking severity of invasively measured pulmonary hypertension to outcomes in heart failure with preserved ejection fraction (HFpEF)

Heart failure is one of the largest public health problems. One type of heart failure, known as heart failure with preserved ejection fraction (HFpEF), is the most common type yet there are no specific therapies, with now multiple negative clinical trials leading to a call for better understanding. Of particular concern is when pulmonary hypertension complicates HFpEF (PH-HFpEF). The prevalence, diagnostic criteria, and outcomes of PH-HFpEF are poorly understood. In this study, Vanderpool et al (Pitt/HVI investigators, or however you want to say this), studied data in all patients undergoing a diagnostic procedure for PH-HFpEF between 1/19/2005 and 9/26/2012 at UPMC Presbyterian, which were linked to data extracted from the UPMC data repository via collaboration with the University of Pittsburgh Department of Medicine Analytics Center (PITT DOM Analytics Center). There were a total of 19,262 procedures performed on 10,023 unique subjects. PH-HFpEF was present in 2587 subjects, (25.8%). This study, which may be the largest of its kind yet to be reported, finds a very high prevalence of PH-HFpEF with poor outcomes and high utilization of the hospital system in terms of hospitalizations. The authors also present detailed outcomes for mortality and hospitalizations which may prove critical for future clinical trial design.


Vanderpool RR, Saul M, Nouraie M, Gladwin MT, Simon MA.
Association Between Hemodynamic Markers of Pulmonary Hypertension and Outcomes in Heart Failure With Preserved Ejection Fraction
. JAMA Cardiol. Published online March 14, 2018. doi:10.1001/jamacardio.2018.0128 PMID: 29541759



 
 


 
  Pol Teekakirikul, MD
   

Dr. Polakit Teekakirikul, a cardiology fellow in the Heart & Vascular Institute, is lead author on an expert opinion article featured on the American College of Cardiology education website. "Mitral valve derangement is increasingly recognized as a fundamental phenotype in hypertrophic cardiomyopathy," said Dr. Teekakirikul, "which must be considered as part of evaluation for any type of invasive therapy to treat outflow tract obstruction." He and senior author, Dr. Timothy Wong, discussed a pragmatic approach to the evaluation of hypertrophic cardiomyopathy (HCM) patients and provided sample imaging data from patients enrolled in a research registry at the UPMC Heart & Vascular Institute. "Hypertrophic cardiomyopathy is a rare disease involving thickening of the heart muscle for which an increasing number of medical and interventional therapies are becoming available - the UPMC HCM Center is excited to be part of such a dynamic field where we can apply cutting edge research and treatments to our patients!" said Dr. Wong.


MR in Patients With Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy
Polakit Teekakirikul, MD; Timothy Wong, MD



 
 


Pitt Researchers Show Importance of Continued Surveillance for Pulmonary Hypertension after Aortic Valve Replacement

In a study published this month in the journal Heart, a team of Pitt researchers performed serial echocardiograms in a cohort of 407 patients that underwent transcatheter aortic valve replacement at UPMC between July 2011 and January 2016. Prior work has shown that an elevated pulmonary arterial pressure, a condition known as pulmonary hypertension, before aortic valve replacement is associated with increased risk of mortality. Pitt researchers measured the pulmonary arterial pressure again after the procedure and determined that it was common for the pulmonary pressure to remain high, and that this also indicated high risk of a poor clinical outcome. Lead author Ahmad Masri, MD notes that "Persistent moderate or severe pulmonary hypertension is not only common after TAVR, but strongly associated with increased risk of all-cause mortality."

Senior author João Cavalcante, MD says, "In contrast, patients whose pulmonary hypertension resolved post-TAVR had survival similar to patients with no evidence of pulmonary hypertension. Therefore, further investigation is required to determine whether persistent PH beyond TAVR is a modifiable target for future therapies. As aortic valve procedures account for an increasingly large share of clinical volume, it will be crucial to identify meaningful therapeutic targets in this population.”



Masri A, Abdelkarim I, Sharbaugh MS, Althouse AD, Xu J, Han W, Chan SY, Katz WE, Crock FW, Harinstein ME, Kliner DE, Navid F, Lee JS, Gleason TG, Schindler JT, Cavalcante JL. Outcomes of persistent pulmonary hypertension following transcatheter aortic valve replacement. Heart. 2017 Sep 29. pii: heartjnl-2017-311978. doi: 10.1136/heartjnl-2017-311978. [Epub ahead of print] PMID: 28970276



 
 


Northwestern Cardiovascular Young Investigators' Forum 2017

   
  Drs. Pol Teekakirikul, Ahmad Masri, and João Cavalante at the Northwestern Cardiovascular Young Investigator Forum; October 2017
(click to enlarge photo)
 
     

The Division of Cardiology was well-represented last week at the prestigious Northwestern Cardiovascular Young Investigators' Forum.

Three presentations hailed from University of Pittsburgh physicians:

Congratulations to all presenters on an excellent showing at the Northwestern Cardiovascular Young Investigators Forum!


 
 


Pitt Researchers Show Potential and Limitations of Working with Big Data in Annals of Internal Medicine

A team of Pitt and UPMC investigators used diagnosis codes from administrative data to identify a large cohort of patients with heart failure. In this study, all hospital encounters with heart failure between 2008 and 2015 were assigned an ICD-9 heart failure code. These were further stratified into three categories: heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, and heart failure of unspecified type. Lead author Dr. Ahmad Masri notes that "using over 20,000 unique encounters of heart failure patients, we found that heart failure coding shifted over time from heart failure of unspecified type toward heart failure with reduced and preserved ejection fraction. While this suggests that coding became more precise and accurate, it also reveals the limitations in using administrative data alone to evaluate our patients."

Senior author Dr. Suresh Mulukutla, says, "In the era of big data, there's a natural excitement to use administrative coding data for analysis, but we must recognize that coding data may change over time and it must be used cautiously. However, our team works closely with the cutting-edge UPMC Clinical Analytics program, led by Dr. Oscar Marroquin, to combine administrative data with clinical and outcome data, with vast potential to better define our patient populations so that we can understand our data and develop effective pathways to deliver patient-centric care."



Masri A, Althouse AD, McKibben J, Lee JS, Mulukutla S. Limitations of Administrative Data for Studying Patients Hospitalized With Heart Failure. Ann Intern Med. 2017 Jun 20;166(12):916-917. doi: 10.7326/L17-0077. PMID: 28462427



 
 


Lung Transplant Can Be Performed Safely in Patients with Coronary Artery Disease

A team of UPMC researchers found that patients with coronary disease can safely undergo lung transplantation, according to a peer-reviewed article in Clinical Transplantation. Of 656 lung transplant recipients in the study, 324 had documented coronary disease, including 106 with obstructive coronary disease; however, outcomes in the patients with coronary disease, even obstructive coronary disease, were not significantly different than outcomes in patients with no trace of coronary disease. “There is a perception that patients with coronary artery disease are poor candidates for a lung transplant,” according to cardiologist Suresh Mulukutla, MD. “Our data suggest that these patients are able to safely undergo lung transplant with reasonably good outcomes, even if they have advanced coronary disease that requires coronary intervention.”



Khandhar SJ, Althouse AD, Mulukutla S, Kormos R, Toma C, Marroquin O, Volz E, Tefera L, Bermudez C. Post-operative Outcomes and Management Strategies for Coronary Artery Disease in Patients in need of a Lung Transplantation. Clin Transplant 2017; 31(9). PMID: 28658533



 
 


Arrival of Delphine Gomez, PhD Completes Recent VMI/HVI Faculty Recruitment Effort

Delphine Gomez, PhD has joined the group of new VMI/HVI faculty members on the recently-renovated 17th floor of the Biomedical Science Tower.  Following her arrival in February, Dr. Gomez has focused on setting up her laboratory, recruiting lab members, and learning the ins and outs of conducting research at Pitt.  Dr. Gomez comes from the University of Virginia Robert M. Berne Cardiovascular Research Center where she completed her postdoctoral fellowship in 2015.  Prior to that, she completed her Bachelor, Master, and Doctoral degrees at University Paris 7, France.  Her current research projects include:  control of smooth muscle cell differentiation and lineage memory; epigenetics/smooth muscle cell plasticity and atherosclerosis; and epigenetic and inflammation in atherosclerosis.  She holds an AHA Scientific Development Grant and has publications in prominent journals such as Circulation Research and Nature Medicine.  She plans to apply for more grants soon and looks forward to collaborating with her colleagues in the VMI and HVI.        



 
 


Endowed Chair in Amyloidosis and Heart Failure Will Drive New Research Program in VMI

The Pittsburgh Foundation and the University of Pittsburgh have agreed to fund the Richard S. Caliguiri Endowed Chair in Amyloidosis and Heart Failure.  The endowment will allow the VMI to recruit a distinguished amyloidosis investigator who will lead basic science research efforts focused on amyloidosis causes and interventions. 


Initial funding for the chair will come from two funds within the Pittsburgh Foundation:  the Richard S. Caliguiri Fund and the Simeon M. and Katherine Reed Jones Fund.  The Caliguiri Fund was established by the family of the late Richard S. Caliguiri who served as Pittsburgh’s mayor from 1977 until 1988 when he died of amyloidosis at the age of 56.  It is very important to the Caliguiri family that all funds raised go to research conducted in Pittsburgh.  Proceeds from the annual City of Pittsburgh Great Race also benefit the Caliguiri fund.  The Simeon M. and Katherine Reed Jones Fund, which supports research for heart disease, will also contribute a significant amount of money to the endowed chair.  Once annual donations from the two funds total $1 million, Pitt will match with a $1 million contribution.  

To celebrate the establishment of the chair and learn more about the research capabilities at Pitt, the Caliguiri family and current Pittsburgh mayor Bill Peduto toured the VMI and met with researchers and physicians in March.  Dr. Gladwin led the tour and explained the how the incoming amyloidosis investigator will benefit from Pitt’s strong, collaborative heart and vascular research environment and UPMC’s technology to perform advanced, non-invasive imaging scans that show build-up of amyloid proteins in the heart.



 
 


Collaborative Agreement with Bayer Spurs Major Sickle Cell Clinical Trial Study in VMI

In keeping with its strategic goal to partner with industry for translational hemostasis and vascular biology research, the VMI has launched several projects under Pitt’s master collaboration agreement with Bayer.  

The goal of this major new initiative is to advance translational research and therapies for heart, lung, and blood diseases.  Led by a joint steering committee comprised of representatives from both Bayer and Pitt, the collaboration focuses on pre-clinical and early phase clinical trials for drug development and big data analysis, including real-world evidence studies.

Through this collaboration, Bayer has funded several real-world evidence studies led by Pitt scientists as well as a nation-wide sickle cell disease clinical trial initiated and led by VMI Principal Investigator Gregory Kato, MD.  Ten hospitals across the country are currently recruiting or planning to recruit participants for this large phase 2 clinical trial that will assess in patients with sickle cell disease the safety, tolerability, and efficacy of riociguat, a drug currently approved to treat pulmonary hypertension.  The double-blind study will focus on changes in participants’ pain experience and physical function capabilities after twelve weeks in the study.  Dr. Kato is excited to combine the support of Bayer with the VMI’s sickle cell disease research expertise to expedite the development of new therapeutic interventions for patients with this severe disease with limited treatment options.  

As it continues to develop, this partnership will aim to bring together our distinguished scientists with Bayer’s clinical disease experts to better understand patient needs, and to develop novel therapies for heart, lung and blood diseases.



 
 


VMI Researchers Uncover Molecular Origins of Pulmonary Hypertension to Help Speed Treatment

VMI investigators Elena Goncharova, PhD, and Stephen Chan, MD, PhD, study how pulmonary hypertension develops in order to design better therapeutic interventions to prevent, regress, or cure this devastating cardiopulmonary disease.  During the past year, both investigators have made remarkable discoveries in the molecular pathways that cause remodeling of pulmonary vascular tissue and limit blood flow between the heart and lungs.  These discoveries will help identify drug targets that are likely to stop or significantly slow the disease progression.

Dr. Goncharova and her laboratory discovered a new mechanism that drives pathogenic proliferation and impairs apoptosis of vascular smooth muscle cells in small pulmonary arteries. They found that HIPPO, a key growth suppressor cassette that prevents organ overgrowth, is dysfunctional in small pulmonary arteries of patients with pulmonary arterial hypertension. This results in activation of transcriptional co-activators Yap and Taz, unleash other pro-proliferative pro-survival signaling pathways and increases cell proliferation and survival. The researchers identified ILK1 as a key molecule that “locks” HIPPO in inactive state and showed that pharmacological inhibition of ILK1 restores HIPPO function and stops the cyclical process of molecular activations that causes dangerous cell proliferation and apoptosis resistance in pulmonary hypertension patients’ arteries.  Selective ILK inhibitors can now be further explored as a promising strategy for therapeutic intervention to reverse pulmonary hypertension.

Dr. Chan and his laboratory discovered a novel link between pulmonary vessel wall stiffening and the way that these blood vessels create energy and biomass. Dr. Chan’s group found that this link is primarily controlled by the activation of YAP and TAZ which in turn control an enzyme called glutaminase.  Activation of glutaminase sets in motion a metabolic process that ends in dangerous cell proliferation in the arteries of pulmonary hypertension patients.  The Chan lab identified the YAP inhibitor verteporfin and the glutaminase inhibitor CB-839 as therapeutic drug candidates when used, either singly or together, can impede the molecular pathways driving this deadly disease.        

VISIT the Center for Pulmonary Vascular Biology and Medicine website to learn more about the exciting discoveries and innovations in PH research happening in the VMI.



 
 


Gladwin Lab Develops Potential Carbon Monoxide Antidote

VMI Director Mark Gladwin, MD and his lab have engineered a carbon monoxide-scavenging protein that reverses carbon monoxide (CO) poisoning in mice.  This protein, or a similar one, may lead to the creation of the first antidote in humans to the often deadly poisoning.

When inhaled, CO binds to hemoglobin in blood, preventing oxygen from being adequately circulated throughout the body.  CO also inhibits the process of respiration in mitochondria, which is crucial to cellular function and survival.  Current treatments for CO poisoning attempt to replace CO in blood with oxygen as quickly as possible. They are only moderately effective.  CO exposure results in debilitating effects on the body and the brain, including cognitive deficits that can persist months or years after a poisoning event.  The poisoning is responsible for more than 50,000 emergency room visits in the United States annually, and is one of the leading global causes of poisoning death. 

Gladwin and his team discovered that neuroglobin (Ngb), a hemoglobin-like protein present in the brain, binds CO with an unusually high affinity. The team engineered a mutant version of the protein, called Ngb H64Q, that is 1,200 times faster at forcing CO to release itself from being bound to hemoglobin than just air alone.  

When tested in a mouse model of CO poisoning, they found that Ngb H64Q was significantly better at removing CO from hemoglobin than existing treatments.  Importantly, CO bound to Ngb H64Q was detected in the urine of mice shortly after treatment, which indicated that the rodents were able to excrete the antidote from the body without any major toxic effects.  Researchers plan to scale up their safety and efficacy testing in animal models and hope to advance to clinical trials within the next few years.

Related publication:
Azarov I, Wang L, Rose JJ, Xu Q, Huang XN, Belanger A, Wang Y, Guo L, Liu C, Ucer KB, McTiernan CF, O'Donnell CP, Shiva S, Tejero J, Kim-Shapiro DB, Gladwin MT. (2016) Five-coordinate H64Q neuroglobin as a ligand-trap antidote for carbon monoxide poisoning. Sci Transl Med. 8(368):368ra173. PMID 27928027. PMC5206801. DOI 10.1126/scitranslmed.aah6571.