Publications by authors named "Gregory D Lewis"

155 Publications

Association of obesity-related inflammatory pathways with lung function and exercise capacity.

Respir Med 2021 Apr 30;183:106434. Epub 2021 Apr 30.

From the Cardiovascular Research Center, Division of Massachusetts General Hospital, Boston, MA, USA; Cardiology Division of Massachusetts General Hospital, Boston, MA, USA. Electronic address:

Background: Obesity has multifactorial effects on lung function and exercise capacity. The contributions of obesity-related inflammatory pathways to alterations in lung function remain unclear.

Research Question: To examine the association of obesity-related inflammatory pathways with pulmonary function, exercise capacity, and pulmonary-specific contributors to exercise intolerance.

Method: We examined 695 patients who underwent cardiopulmonary exercise testing (CPET) with invasive hemodynamic monitoring at Massachusetts General Hospital between December 2006-June 2017. We investigated the association of adiponectin, leptin, resistin, IL-6, CRP, and insulin resistance (HOMA-IR) with pulmonary function and exercise parameters using multivariable linear regression.

Results: Obesity-related inflammatory pathways were associated with worse lung function. Specifically, higher CRP, IL-6, and HOMA-IR were associated with lower percent predicted FEV and FVC with a preserved FEV/FVC ratio suggesting a restrictive physiology pattern (P ≤ 0.001 for all). For example, a 1-SD higher natural-logged CRP level was associated with a nearly 5% lower percent predicted FEV and FVC (beta -4.8, s.e. 0.9 for FEV1; beta -4.9, s.e. 0.8 for FVC; P < 0.0001 for both). Obesity-related inflammatory pathways were associated with worse pulmonary vascular distensibility (adiponectin, IL-6, and CRP, P < 0.05 for all), as well as lower pulmonary artery compliance (IL-6 and CRP, P ≤ 0.01 for both).

Interpretation: Our findings highlight the importance of obesity-related inflammatory pathways including inflammation and insulin resistance on pulmonary spirometry and pulmonary vascular function. Specifically, systemic inflammation as ascertained by CRP, IL-6 and insulin resistance are associated with restrictive pulmonary physiology independent of BMI. In addition, inflammatory markers were associated with lower exercise capacity and pulmonary vascular dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rmed.2021.106434DOI Listing
April 2021

Heart Failure with preserved ejection fraction according to the HFA-PEFF score in COVID-19 patients: clinical correlates and echocardiographic findings.

Eur J Heart Fail 2021 May 1. Epub 2021 May 1.

Department of Cardiology Charité - Universitätsmedizin Berlin, Campus Benjamin-Franklin, Berlin, Germany.

Aims: Viral-induced cardiac inflammation can induce heart failure with preserved ejection fraction (HFpEF) like syndromes. COVID-19 can lead to myocardial damage and vascular injury. We hypothesised that COVID-19 patients frequently develop a HFpEF-like syndrome, and designed this study to explore this.

Methods And Results: Cardiac function was assessed in 64 consecutive, hospitalized, and clinically stable COVID-19 patients from April - November 2020 with left ventricular ejection fraction (LVEF) ≥50% (age 56±19 years, females: 31%, severe COVID-19 disease: 69%). To investigate likelihood of HFpEF presence, we used the HFA-PEFF score. A low (0-1 points), intermediate (2-4 points), and high (5-6 points) HFA-PEFF score was observed in 42%, 33%, and 25% of patients, respectively. In comparison, 64 subjects of similar age, sex, and comorbidity status without COVID-19, showed these scores in 30%, 66%, and 4%, respectively (between groups: p=0.0002). High HFA-PEFF scores were more frequent in COVID-19 patients than controls (25% vs. 4%, p=0.001). In COVID-19 patients, HFA-PEFF score significantly correlated with age, estimated glomerular filtration rate, high sensitivity troponin T (hsTnT), haemoglobin, QTc interval, LVEF, mitral E/A ratio, and H FPEF score (all p<0.05). In multivariate, ordinal regression analyses, higher age and hsTnT were significant predictors of increased HFA-PEFF scores. Patients with myocardial injury (hsTnT ≥14 ng/L: 31%) vs. patients without myocardial injury, showed higher HFA-PEFF scores (median 5 [IQR 3-6] vs. 1 [0-3], p<0.001) and more often showed LV diastolic dysfunction (75% vs. 27%, p<0.001).

Conclusion: Hospitalised COVID-19 patients frequently show high likelihood of presence of HFpEF that is associated with cardiac structural and functional alterations, and myocardial injury. Detailed cardiac assessments including echocardiographic determination of LV diastolic function and biomarkers should become routine in the care of hospitalised COVID-19 patients. This article is protected by copyright. All rights reserved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ejhf.2210DOI Listing
May 2021

Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial.

JACC Heart Fail 2021 May 7;9(5):360-370. Epub 2021 Apr 7.

Northwestern University, Chicago, Illinois, USA.

Objectives: The purpose of this study was to evaluate the effects of intravenous levosimendan on hemodynamics and 6-min walk distance (6MWD) in patients with pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF).

Background: There are no proven effective treatments for patients with PH-HFpEF.

Methods: Patients with mean pulmonary artery pressure (mPAP) ≥35 mm Hg, pulmonary capillary wedge pressure (PCWP) ≥20 mm Hg, and LVEF ≥40% underwent 6MWD and hemodynamic measurements at rest, during passive leg raise, and supine cycle exercise at baseline and after an open-label 24-h levosimendan infusion (0.1 μg/kg/min). Hemodynamic responders (those with ≥4 mm Hg reduction of exercise-PCWP) were randomized (double blind) to weekly levosimendan infusion (0.075 to 0.1 ug/kg/min for 24 h) or placebo for 5 additional weeks. The primary end point was exercise-PCWP, and key secondary end points included 6MWD and PCWP measured across all exercise stages.

Results: Thirty-seven of 44 patients (84%) met responder criteria and were randomized to levosimendan (n = 18) or placebo (n = 19). Participants were 69 ± 9 years of age, 61% female, and with resting mPAP 41.0 ± 9.3 mm Hg and exercise-PCWP 36.8 ± 11.3 mm Hg. Compared with placebo, levosimendan did not significantly reduce the primary end point of exercise-PCWP at 6 weeks (-1.4 mm Hg; 95% confidence interval [CI]: -7.8 to 4.8; p = 0.65). However, levosimendan reduced PCWP measured across all exercise stages (-3.9 ± 2.0 mm Hg; p = 0.047). Levosimendan treatment resulted in a 29.3 m (95% CI: 2.5 to 56.1; p = 0.033) improvement in 6MWD compared with placebo.

Conclusions: Six weeks of once-weekly levosimendan infusion did not affect exercise-PCWP but did reduce PCWP incorporating data from rest and exercise, in tandem with increased 6MWD. Further study of levosimendan is warranted as a therapeutic option for PH-HFpEF. (Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF [HELP]; NCT03541603).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jchf.2021.01.015DOI Listing
May 2021

Metabolic Cost of Exercise Initiation in Patients With Heart Failure With Preserved Ejection Fraction vs Community-Dwelling Adults.

JAMA Cardiol 2021 Mar 17. Epub 2021 Mar 17.

Simches Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.

Importance: Heart failure with preserved ejection fraction (HFpEF) is a joint metabolic and cardiovascular disorder with significant noncardiac contributions.

Objective: To define and quantify the metabolic cost of initiating exercise in individuals with and without HFpEF and its functional consequences.

Design, Setting, And Participants: This prospective cohort study included individuals with hemodynamically confirmed HFpEF from the Massachusetts General Hospital Exercise Study (MGH-ExS) and community-dwelling participants from the Framingham Heart Study (FHS). Analysis began April 2016 and ended November 2020.

Exposures: Internal work (IW), a measure of work equivalents required to initiate movement.

Main Outcomes And Measures: Using breath-by-breath oxygen uptake (V̇o2) measurements and V̇o2-work rate associations, cost of initiating exercise (IW) in patients with HFpEF (MGH-ExS) and in community-dwelling individuals (FHS) was quantified. Linear regression was used to estimate associations between IW and clinical/hemodynamic measures.

Results: Of 3231 patients, 184 (5.7%) had HFpEF and were from MGH-ExS, and 3047 (94.3%) were community-dwelling individuals from FHS. In the MGH-ExS cohort, 86 (47%) were women, the median (interquartile range) age was 63 (53-72) years, and the median (interquartile range) peak V̇o2 level was 13.33 (11.77-15.62) mL/kg/min. In the FHS cohort, 1620 (53%) were women, the median (interquartile range) age was 54 (48-60) years, and the median (interquartile range) peak V̇o2 level was 22.2 (17.85-27.35) mL/kg/min. IW was higher in patients with HFpEF and accounted for 27% (interquartile range, 21%-39%) of the total work (IW + measured external workload on the cycle), compared with 15% (interquartile range, 12%-20%) of that in FHS participants. Body mass index accounted for greatest explained variance in patients with HFpEF from MGH-ExS and FHS participants (22% and 18%, respectively), while resting cardiac output and biventricular filling pressures were not significantly associated with variance in IW in patients with HFpEF. A higher IW in patients with HFpEF was associated with a greater increase in left- and right-sided cardiac filing pressure during unloaded exercise, despite similar resting hemodynamic measures across IW.

Conclusions And Relevance: This study found that internal work, a new body mass index-related measure reflecting the metabolic cost of initiating movement, is higher in individuals with HFpEF compared with middle-aged adults in the community and is associated with steep, early increases in cardiac filling pressures. These findings highlight the importance of quantifying heterogeneous responses to exercise initiation when evaluating functional intolerance in individuals at risk for or with HFpEF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamacardio.2021.0292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970388PMC
March 2021

Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Arterial Stiffness and Aabnormal Left Ventricular Hemodynamic Responses During Exercise.

J Card Fail 2021 Feb 26. Epub 2021 Feb 26.

Corrigan Minehan Heart Center, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background: Arterial stiffness is thought to contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). We sought to examine arterial stiffness in HFpEF and hypertension and investigate associations of arterial and left ventricular hemodynamic responses to exercise.

Methods And Results: A total of 385 symptomatic individuals with an EF of ≥50% underwent upright cardiopulmonary exercise testing with invasive hemodynamic assessment of arterial stiffness and load (aortic augmentation pressure, augmentation index, systemic vascular resistance index, total arterial compliance index, effective arterial elastance index, and pulse pressure amplification) at rest and during incremental exercise. An abnormal hemodynamic response to exercise was defined as a steep increase in pulmonary capillary wedge pressure relative to cardiac output (∆PCWP/∆CO > 2 mm Hg/L/min). We compared rest and exercise measures between HFpEF and hypertension in multivariable analyses. Among 188 participants with HFpEF (mean age 61 ± 13 years, 56% women), resting arterial stiffness parameters were worse compared with 94 hypertensive participants (mean age 55 ± 15 years, 52% women); these differences were accentuated during exercise in HFpEF (all P ≤ .0001). Among all participants, exercise measures of arterial stiffness correlated with worse ∆PCWP/∆CO. Specifically, a 1 standard deviation higher exercise augmentation pressure was associated with 2.15-fold greater odds of abnormal LV hemodynamic response (95% confidence interval 1.52-3.05; P < .001). Further, exercise measures of systemic vascular resistance index, elastance index, and pulse pressure amplification correlated with a lower peak oxygen consumption.

Conclusions: Exercise accentuates the increased arterial stiffness found in HFpEF, which in turn correlates with left ventricular hemodynamic responses. Unfavorable ventricular-vascular interactions during exercise in HFpEF may contribute to exertional intolerance and inform future therapeutic interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cardfail.2021.02.011DOI Listing
February 2021

Cardiopulmonary Exercise Testing-Based Risk Stratification in the Modern Era of Advanced Heart Failure Management.

JACC Heart Fail 2021 Mar;9(3):237-240

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jchf.2021.01.003DOI Listing
March 2021

Beyond the stethoscope: managing ambulatory heart failure during the COVID-19 pandemic.

ESC Heart Fail 2021 04 27;8(2):999-1006. Epub 2021 Jan 27.

Cardiology Division, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.

There have been nearly 70 million cases of COVID-19 worldwide, with over 1.5 million deaths at the time of this publication. This global pandemic has mandated dramatic changes in healthcare delivery with a particular focus on social distancing in order to reduce viral transmission. Heart failure patients are among the highest utilizers of health care and are at increased risk for COVID-related vulnerabilities. Effectively managing this complex and resource-intensive patient population from a distance presents new and unique challenges. Here, we review relevant data on telemedicine and remote monitoring strategies for heart failure patients and provide a framework to help providers treat this population during the COVID-19 pandemic. This includes (i) dedicated pre-visit contact and planning (i.e. confirm clinical appropriateness, presence of compatible technology, and patient comfort); (ii) utilization of virtual clinic visits (use of telehealth platforms, a video-assisted exam, self-reported vital signs, and weights); and (iii) use of existing remote heart failure monitoring sensors when applicable (CardioMEMS, Optivol, and HeartLogic). While telemedicine and remote monitoring strategies are not new, these technologies are emerging as an important tool for the effective management of heart failure patients during the COVID-19 pandemic. In general, these strategies appear to be safe; however, additional data will be needed to determine their effectiveness with respect to both process and outcomes measures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ehf2.13201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006709PMC
April 2021

Trends in the use of hepatitis C viremic donor hearts.

J Thorac Cardiovasc Surg 2020 Sep 16. Epub 2020 Sep 16.

Department of Surgery, Massachusetts General Hospital, Boston, Mass; Division of Cardiac Surgery, Massachusetts General Hospital, Boston, Mass. Electronic address:

Objective: To examine trends in utilization of hearts from hepatitis C virus (HCV) viremic donors for transplantation, a strategy to expand organ availability.

Methods: The United Network for Organ Sharing (UNOS) registry was queried for adult patients undergoing heart transplantation between 2015 and 2019. We excluded multiorgan transplants, incomplete data, and loss to follow-up. Nucleic acid testing (NAT) defined HCV status.

Results: Between 2015 and 2019, a total of 11,393 adults underwent heart transplantation: 326 from HCV NAT donors and 11,067 from NAT donors. The use of NAT hearts increased from 1 in 2015 to 137 in 2018 against a static number of NAT organs. The use of NAT hearts varied significantly across regions and individual centers. More than 75% of NAT hearts were transplanted in the Northeast region, leading to further travel (mean, 299 miles vs 173 miles for NAT transplantations; P < .001), with longer ischemic times (mean: 3.52 hours vs 3.10 hours; P < .001). More than one-half of NAT transplantations were performed by 5 individual centers, and a single institution accounted for >20% of all transplantations from viremic donors. Survival in the 2 groups did not differ by Kaplan-Meier analysis (P = .240), and multivariable regression showed no differences in acute rejection (P = .455) or 30-day mortality (P = .490). Of the 326 recipients of NAT hearts, 38 seroconverted and 14 became viremic within 1 year. Survival was 100% in the viremic patients and 97.4% in seroconverted patients at 1 year.

Conclusions: Heart transplantation from HCV viremic donors continues to increase but varies significantly across UNOS regions and individual centers. Short-term outcomes are comparable, but effects of seroconversion and long-term outcomes remain unclear.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtcvs.2020.09.044DOI Listing
September 2020

Free-breathing diffusion tensor MRI of the whole left ventricle using second-order motion compensation and multitasking respiratory motion correction.

Magn Reson Med 2021 05 30;85(5):2634-2648. Epub 2020 Nov 30.

Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Purpose: We aimed to develop a novel free-breathing cardiac diffusion tensor MRI (DT-MRI) approach, M2-MT-MOCO, capable of whole left ventricular coverage that leverages second-order motion compensation (M2) diffusion encoding and multitasking (MT) framework to efficiently correct for respiratory motion (MOCO).

Methods: Imaging was performed in 16 healthy volunteers and 3 heart failure patients with symptomatic dyspnea. The healthy volunteers were scanned to compare the accuracy of interleaved multislice coverage of the entire left ventricle with a single-slice acquisition and the accuracy of the free-breathing conventional MOCO and MT-MOCO approaches with reference breath-hold DT-MRI. Mean diffusivity (MD), fractional anisotropy (FA), helix angle transmurality (HAT), and intrascan repeatability were quantified and compared.

Results: In all subjects, free-breathing M2-MT-MOCO DT-MRI yielded DWI of the entire left ventricle without bulk motion-induced signal loss. No significant differences were seen in the global values of MD, FA, and HAT in the multislice and single-slice acquisitions. Furthermore, global quantification of MD, FA, and HAT were also not significantly different between the MT-MOCO and breath-hold, whereas conventional MOCO yielded significant differences in MD, FA, and HAT with MT-MOCO and FA with breath-hold. In heart failure patients, M2-MT-MOCO DT-MRI was feasible yielding higher MD, lower FA, and lower HAT compared with healthy volunteers. Substantial agreement was found between repeated scans across all subjects for MT-MOCO.

Conclusion: M2-MT-MOCO enables free-breathing DT-MRI of the entire left ventricle in 10 min, while preserving quantification of myocardial microstructure compared to breath-held and single-slice acquisitions and is feasible in heart failure patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mrm.28611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902339PMC
May 2021

Deliberating the Diagnostic Dilemma of Heart Failure With Preserved Ejection Fraction.

Circulation 2020 Nov 2;142(18):1770-1780. Epub 2020 Nov 2.

National Heart Centre Singapore (C.S.P.L.).

There is a lack of consensus on how we define heart failure with preserved ejection fraction (HFpEF), with wide variation in diagnostic criteria across society guidelines. This lack of uniformity in disease definition stems in part from an incomplete understanding of disease pathobiology, phenotypic heterogeneity, and natural history. We review current knowledge gaps and existing diagnostic tools and algorithms. We present a simple approach to implement these tools within the constraints of the current knowledge base, addressing separately (1) hospitalized individuals with rest congestion, where diagnosis is more straightforward; and (2) individuals with exercise intolerance, where diagnosis is more complex. Here, a potential role for advanced or provocative testing, including evaluation of hemodynamic responses to exercise is considered. More importantly, we propose focus areas for future studies to develop accurate and feasible diagnostic tools for HFpEF, including animal models that recapitulate human HFpEF, and human studies that both address a fundamental understanding of HFpEF pathobiology, and new diagnostic approaches and tools, as well. In sum, there is an urgent need to more accurately define the syndrome of HFpEF to inform diagnosis, patient selection for clinical trials, and, ultimately, future therapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.119.041818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805557PMC
November 2020

Feasibility and Consistency of Results with Deployment of an In-Line Filter for Exercise-Based Evaluations of Patients With Heart Failure During the Novel Coronavirus Disease-2019 Pandemic.

J Card Fail 2021 01 21;27(1):105-108. Epub 2020 Oct 21.

Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Pulmonary Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: Exercise testing plays an important role in evaluating heart failure prognosis and selecting patients for advanced therapeutic interventions. However, concern for severe acute respiratory syndrome novel coronavirus-2 transmission during exercise testing has markedly curtailed performance of exercise testing during the novel coronavirus disease-2019 pandemic.

Methods And Results: To examine the feasibility to conducting exercise testing with an in-line filter, 2 healthy volunteer subjects each completed 2 incremental exercise tests, one with discrete stages of increasing resistance and one with a continuous ramp. Each subject performed 1 test with an electrostatic filter in-line with the system measuring gas exchange and air flow, and 1 test without the filter in place. Oxygen uptake and minute ventilation were highly consistent when evaluated with and without use of an electrostatic filter with a >99.9% viral efficiency.

Conclusions: Deployment of a commercially available in-line electrostatic viral filter during cardiopulmonary exercise testing is feasible and provides consistent data compared with testing without a filter.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cardfail.2020.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576320PMC
January 2021

Effect of Praliciguat on Peak Rate of Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: The CAPACITY HFpEF Randomized Clinical Trial.

JAMA 2020 10;324(15):1522-1531

Division of Cardiology and the CardioVascular Center, Tufts Medical Center, Boston, Massachusetts.

Importance: Heart failure with preserved ejection fraction (HFpEF) is often characterized by nitric oxide deficiency.

Objective: To evaluate the efficacy and adverse effects of praliciguat, an oral soluble guanylate cyclase stimulator, in patients with HFpEF.

Design, Setting, And Participants: CAPACITY HFpEF was a randomized, double-blind, placebo-controlled, phase 2 trial. Fifty-nine sites enrolled 196 patients with heart failure and an ejection fraction of at least 40%, impaired peak rate of oxygen consumption (peak V̇o2), and at least 2 conditions associated with nitric oxide deficiency (diabetes, hypertension, obesity, or advanced age). The trial randomized patients to 1 of 3 praliciguat dose groups or a placebo group, but was refocused early to a comparison of the 40-mg praliciguat dose vs placebo. Participants were enrolled from November 15, 2017, to April 30, 2019, with final follow-up on August 19, 2019.

Interventions: Patients were randomized to receive 12 weeks of treatment with 40 mg of praliciguat daily (n = 91) or placebo (n = 90).

Main Outcomes And Measures: The primary efficacy end point was the change from baseline in peak V̇o2 in patients who completed at least 8 weeks of assigned dosing. Secondary end points included the change from baseline in 6-minute walk test distance and in ventilatory efficiency (ventilation/carbon dioxide production slope). The primary adverse event end point was the incidence of treatment-emergent adverse events (TEAEs).

Results: Among 181 patients (mean [SD] age, 70 [9] years; 75 [41%] women), 155 (86%) completed the trial. In the placebo (n = 78) and praliciguat (n = 65) groups, changes in peak V̇o2 were 0.04 mL/kg/min (95% CI, -0.49 to 0.56) and -0.26 mL/kg/min (95% CI, -0.83 to 0.31), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -0.30 mL/kg/min ([95% CI, -0.95 to 0.35]; P = .37). None of the 3 prespecified secondary end points were statistically significant. In the placebo and praliciguat groups, changes in 6-minute walk test distance were 58.1 m (95% CI, 26.1-90.1) and 41.4 m (95% CI, 8.2-74.5), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -16.7 m (95% CI, -47.4 to 13.9). In the placebo and praliciguat groups, the placebo-adjusted least-squares between-group difference in mean change in ventilation/carbon dioxide production slope was -0.3 (95% CI, -1.6 to 1.0). There were more dizziness (9.9% vs 1.1%), hypotension (8.8% vs 0%), and headache (11% vs 6.7%) TEAEs with praliciguat compared with placebo. The frequency of serious TEAEs was similar between the groups (10% in the praliciguat group and 11% in the placebo group).

Conclusions And Relevance: Among patients with HFpEF, the soluble guanylate cyclase stimulator praliciguat, compared with placebo, did not significantly improve peak V̇o2 from baseline to week 12. These findings do not support the use of praliciguat in patients with HFpEF.

Trial Registration: ClinicalTrials.gov Identifier: NCT03254485.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2020.16641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576408PMC
October 2020

Comprehensive Metabolic Phenotyping Refines Cardiovascular Risk in Young Adults.

Circulation 2020 Dec 19;142(22):2110-2127. Epub 2020 Oct 19.

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston (R.K., G.D.L., M.N., R.V.S.).

Background: Whereas cardiovascular disease (CVD) metrics define risk in individuals >40 years of age, the earliest lesions of CVD appear well before this age. Despite the role of metabolism in CVD antecedents, studies in younger, biracial populations to define precise metabolic risk phenotypes are lacking.

Methods: We studied 2330 White and Black young adults (mean age, 32 years; 45% Black) in the CARDIA study (Coronary Artery Risk Development in Young Adults) to identify metabolite profiles associated with an adverse CVD phenome (myocardial structure/function, fitness, vascular calcification), mechanisms, and outcomes over 2 decades. Statistical learning methods (elastic nets/principal components analysis) and Cox regression generated parsimonious, metabolite-based risk scores validated in >1800 individuals in the Framingham Heart Study.

Results: In the CARDIA study, metabolite profiles quantified in early adulthood were associated with subclinical CVD development over 20 years, specifying known and novel pathways of CVD (eg, transcriptional regulation, brain-derived neurotrophic factor, nitric oxide, renin-angiotensin). We found 2 multiparametric, metabolite-based scores linked independently to vascular and myocardial health, with metabolites included in each score specifying microbial metabolism, hepatic steatosis, oxidative stress, nitric oxide modulation, and collagen metabolism. The metabolite-based vascular scores were lower in men, and myocardial scores were lower in Black participants. Over a nearly 25-year median follow-up in CARDIA, the metabolite-based vascular score (hazard ratio, 0.68 per SD [95% CI, 0.50-0.92]; =0.01) and myocardial score (hazard ratio, 0.60 per SD [95% CI, 0.45-0.80]; =0.0005) in the third and fourth decades of life were associated with clinical CVD with a synergistic association with outcome (=0.009). We replicated these findings in 1898 individuals in the Framingham Heart Study over 2 decades, with a similar association with outcome (including interaction), reclassification, and discrimination. In the Framingham Heart Study, the metabolite scores exhibited an age interaction (=0.0004 for a combined myocardial-vascular score with incident CVD), such that young adults with poorer metabolite-based health scores had highest hazard of future CVD.

Conclusions: Metabolic signatures of myocardial and vascular health in young adulthood specify known/novel pathways of metabolic dysfunction relevant to CVD, associated with outcome in 2 independent cohorts. Efforts to include precision measures of metabolic health in risk stratification to interrupt CVD at its earliest stage are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880553PMC
December 2020

Cardiovascular Functional Changes in Chronic Kidney Disease: Integrative Physiology, Pathophysiology and Applications of Cardiopulmonary Exercise Testing.

Front Physiol 2020 15;11:572355. Epub 2020 Sep 15.

Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States.

The development of cardiovascular disease during renal impairment involves striking multi-tiered, multi-dimensional complex alterations encompassing the entire oxygen transport system. Complex interactions between target organ systems involving alterations of the heart, vascular, musculoskeletal and respiratory systems occur in Chronic Kidney Disease (CKD) and collectively contribute to impairment of cardiovascular function. These systemic changes have challenged our diagnostic and therapeutic efforts, particularly given that imaging cardiac structure at rest, rather than ascertainment under the stress of exercise, may not accurately reflect the risk of premature death in CKD. The multi-systemic nature of cardiovascular disease in CKD patients provides strong rationale for an integrated approach to the assessment of cardiovascular alterations in this population. State-of-the-art cardiopulmonary exercise testing (CPET) is a powerful, dynamic technology that enables the global assessment of cardiovascular functional alterations and reflects the integrative exercise response and complex machinery that form the oxygen transport system. CPET provides a wealth of data from a single assessment with mechanistic, physiological and prognostic utility. It is an underutilized technology in the care of patients with kidney disease with the potential to help advance the field of cardio-nephrology. This article reviews the integrative physiology and pathophysiology of cardio-renal impairment, critical new insights derived from CPET technology, and contemporary evidence for potential applications of CPET technology in patients with kidney disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2020.572355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522507PMC
September 2020

Progress Toward Cardiac Xenotransplantation.

Circulation 2020 Oct 5;142(14):1389-1398. Epub 2020 Oct 5.

Division of Cardiac Surgery, Department of Surgery (R.N.P., D.A.D., M.R.C., L.B., J.C.M., A.M.A.), Massachusetts General Hospital and Harvard University, Boston.

Consistent survival of life-supporting pig heart xenograft recipients beyond 90 days was recently reported using genetically modified pigs and a clinically applicable drug treatment regimen. If this remarkable achievement proves reproducible, published benchmarks for clinical translation of cardiac xenografts appear to be within reach. Key mechanistic insights are summarized here that informed recent pig design and therapeutic choices, which together appear likely to enable early clinical translation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990044PMC
October 2020

Metabolic Architecture of Acute Exercise Response in Middle-Aged Adults in the Community.

Circulation 2020 Nov 15;142(20):1905-1924. Epub 2020 Sep 15.

Cardiology Division and the Simches Cardiovascular Research Center, Department of Medicine, Harvard Medical School (M.N., R.V.S., J.B.B., M.T., R.M., N.E.H., J.E.H., A.L.B., G.D.L.), Massachusetts General Hospital, Boston.

Background: Whereas regular exercise is associated with lower risk of cardiovascular disease and mortality, mechanisms of exercise-mediated health benefits remain less clear. We used metabolite profiling before and after acute exercise to delineate the metabolic architecture of exercise response patterns in humans.

Methods: Cardiopulmonary exercise testing and metabolite profiling was performed on Framingham Heart Study participants (age 53±8 years, 63% women) with blood drawn at rest (n=471) and at peak exercise (n=411).

Results: We observed changes in circulating levels for 502 of 588 measured metabolites from rest to peak exercise (exercise duration 11.9±2.1 minutes) at a 5% false discovery rate. Changes included reductions in metabolites implicated in insulin resistance (glutamate, -29%; =1.5×10; dimethylguanidino valeric acid [DMGV], -18%; =5.8×10) and increases in metabolites associated with lipolysis (1-methylnicotinamide, +33%; =6.1×10), nitric oxide bioavailability (arginine/ornithine + citrulline, +29%; =2.8×10), and adipose browning (12,13-dihydroxy-9Z-octadecenoic acid +26%; =7.4×10), among other pathways relevant to cardiometabolic risk. We assayed 177 metabolites in a separate Framingham Heart Study replication sample (n=783, age 54±8 years, 51% women) and observed concordant changes in 164 metabolites (92.6%) at 5% false discovery rate. Exercise-induced metabolite changes were variably related to the amount of exercise performed (peak workload), sex, and body mass index. There was attenuation of favorable excursions in some metabolites in individuals with higher body mass index and greater excursions in select cardioprotective metabolites in women despite less exercise performed. Distinct preexercise metabolite levels were associated with different physiologic dimensions of fitness (eg, ventilatory efficiency, exercise blood pressure, peak Vo). We identified 4 metabolite signatures of exercise response patterns that were then analyzed in a separate cohort (Framingham Offspring Study; n=2045, age 55±10 years, 51% women), 2 of which were associated with overall mortality over median follow-up of 23.1 years (≤0.003 for both).

Conclusions: In a large sample of community-dwelling individuals, acute exercise elicits widespread changes in the circulating metabolome. Metabolic changes identify pathways central to cardiometabolic health, cardiovascular disease, and long-term outcome. These findings provide a detailed map of the metabolic response to acute exercise in humans and identify potential mechanisms responsible for the beneficial cardiometabolic effects of exercise for future study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049528PMC
November 2020

Characterization of the Progression From Ambulatory to Hospitalized Heart Failure With Preserved Ejection Fraction.

J Card Fail 2020 Nov 19;26(11):919-928. Epub 2020 Aug 19.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address:

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. Some patients develop elevated filling pressures exclusively during exercise and never require hospitalization, whereas others periodically develop congestion that requires inpatient treatment. The features differentiating these cohorts are unclear.

Methods: We performed a secondary analysis of 7 National Institutes of Health-sponsored multicenter trials of HFpEF (EF ≥ 50%, N = 727). Patients were stratified by history of hospitalization because of HF, comparing patients never hospitalized (HFpEF) to those with a prior hospitalization (HFpEF). Currently hospitalized (HFpEF) patients were included to fill the spectrum. Clinical characteristics, cardiac structure, biomarkers, quality of life, functional capacity, activity levels, and outcomes were compared.

Results: As expected, HFpEF (n = 338) displayed the greatest severity of congestion, as assessed by N-terminal pro B-type natriuretic peptide levels, edema and orthopnea. As compared to HFpEF (n = 109), HFpEF (n = 280) displayed greater comorbidity burden, with more lung disease, renal dysfunction and anemia, along with lower activity levels (accelerometry), poorer exercise capacity (6-minute walk distance and peak exercise capacity), and more orthopnea. Patients with current or prior hospitalization displayed higher rates of future HF hospitalization, but quality of life was similarly impaired in all patients with HFpEF, regardless of hospitalization history.

Conclusions: A greater burden of noncardiac organ dysfunction, sedentariness, functional impairment, and higher event rates distinguish patients with HFpEF and prior HF hospitalization from those never hospitalized. Despite lower event rates, quality of life is severely and similarly limited in patients with no history of hospitalization. These data suggest that the 2 clinical profiles of HFpEF may require different treatment strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cardfail.2020.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704788PMC
November 2020

Proteomic Signatures During Treatment in Different Stages of Heart Failure.

Circ Heart Fail 2020 08 29;13(8):e006794. Epub 2020 Jul 29.

Massachusetts General Hospital, Boston (S.A.M., A.C., N.E.I., H.G., D.D., E.C., G.D.L., J.L.J.).

Background: Proteomics have already provided novel insights into the pathophysiology of heart failure (HF) with reduced ejection fraction. Previous studies have evaluated cross-sectional protein signatures of HF, but few have characterized proteomic changes following HF with reduced ejection fraction treatment with ARNI (angiotensin receptor/neprilysin inhibitor) therapy or left ventricular assist devices.

Methods: In this retrospective omics study, we performed targeted proteomics (N=625) of whole blood sera from patients with American College of Cardiology/American Heart Association stage D (N=29) and stage C (N=12) HF using proximity extension assays. Samples were obtained before and after (median=82 days) left ventricular assist device implantation (stage D; primary analysis) and ARNI therapy initiation (stage C; matched reference). Oblique principal component analysis and point biserial correlations were used for feature extraction and selection; standardized mean differences were used to assess within and between-group differences; and enrichment analysis was used to generate and cluster Gene Ontology terms.

Results: Core sets of proteins were identified for stage C (N=9 proteins) and stage D (N=18) HF; additionally, a core set of 5 shared HF proteins (NT-proBNP [N-terminal pro-B type natriuretic peptide], ESM [endothelial cell-specific molecule]-1, cathepsin L1, osteopontin, and MCSF-1) was also identified. For patients with stage D HF, moderate (δ, 0.40-0.60) and moderate-to-large (δ, 0.60-0.80) sized differences were observed in 8 of their 18 core proteins after left ventricular assist devices implantation. Additionally, specific protein groups reached concentration levels equivalent (<0.10) to stage C HF after initiation on ARNI therapy.

Conclusions: HF with reduced ejection fraction severity associates with distinct proteomic signatures that reflect underlying disease attributes; these core signatures may be useful for monitoring changes in cardiac function following initiation on ARNI or left ventricular assist device implantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006794DOI Listing
August 2020

Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial.

JACC Heart Fail 2020 10 10;8(10):789-799. Epub 2020 Jun 10.

Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jchf.2020.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286640PMC
October 2020

Impaired Exercise Tolerance in Heart Failure With Preserved Ejection Fraction: Quantification of Multiorgan System Reserve Capacity.

JACC Heart Fail 2020 08 10;8(8):605-617. Epub 2020 Jun 10.

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Pulmonary Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Exercise intolerance is a principal feature of heart failure with preserved ejection fraction (HFpEF), whether or not there is evidence of congestion at rest. The degree of functional limitation observed in HFpEF is comparable to patients with advanced heart failure and reduced ejection fraction. Exercise intolerance in HFpEF is characterized by impairments in the physiological reserve capacity of multiple organ systems, but the relative cardiac and extracardiac deficits vary among individuals. Detailed measurements made during exercise are necessary to identify and rank-order the multiorgan system limitations in reserve capacity that culminate in exertional intolerance in a given person. We use a case-based approach to comprehensively review mechanisms of exercise intolerance and optimal approaches to evaluate exercise capacity in HFpEF. We also summarize recent and ongoing trials of novel devices, drugs, and behavioral interventions that aim to improve specific exercise measures such as peak oxygen uptake, 6-min walk distance, heart rate, and hemodynamic profiles in HFpEF. Evaluation during the clinically relevant physiological perturbation of exercise holds promise to improve the precision with which HFpEF is defined and therapeutically targeted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jchf.2020.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395858PMC
August 2020

Survival After Heart Transplantation in Patients Bridged With Mechanical Circulatory Support.

J Am Coll Cardiol 2020 06;75(23):2892-2905

Division of Cardiac Surgery, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.

Background: The United Network of Organ Sharing (UNOS) heart allocation policy designates patients on ECMO or with nondischargeable, surgically implanted, nonendovascular support devices (TCS-VAD) to higher listing statuses.

Objectives: This study aimed to explore whether temporary circulatory support-ventricular assist devices (TCS-VAD) have a survival advantage over extracorporeal membrane oxygenation (ECMO) as a bridge to transplant.

Methods: The UNOS database was used to conduct a retrospective analysis of adult heart transplants performed in the United States between 2005 and 2017. Survival analysis was performed to compare patients bridged to transplant with different modalities.

Results: Of the 24,905 adult transplants performed, 7,904 (32%) were bridged with durable left ventricular assist devices (LVADs), 177 (0.7%) with ECMO, 203 (0.8%) with TCS-VAD, 44 (0.2%) with percutaneous endovascular devices, and 8 (0.03%) with TandemHeart (LivaNova, London, United Kingdom). Unadjusted survival at 1 and 5 years post-transplant was 90 ± 0.4% and 77 ± 0.7% for durable LVAD, 84 ± 3% and 71 ± 4% for all TCS-VAD types, 79 ± 9% and 73 ± 14% for biventricular TCS-VAD, and 68 ± 3% and 61 ± 8% for ECMO. After propensity-matched pairwise comparisons were made, survival after all TCS-VAD types continued to be superior to ECMO (p = 0.019) and similar to LVAD (p = 0.380). ECMO was a predictor of post-transplant mortality in the Cox analysis compared with TCS-VAD (hazard ratio 2.40; 95% confidence interval: 1.44 to 4.01; p = 0.001).

Conclusions: Post-transplant survival with TCS-VAD is superior to ECMO and similar to LVAD in a national database.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2020.04.037DOI Listing
June 2020

Clinical and Hemodynamic Associations and Prognostic Implications of Ventilatory Efficiency in Patients With Preserved Left Ventricular Systolic Function.

Circ Heart Fail 2020 05 4;13(5):e006729. Epub 2020 May 4.

Cardiology Division, Department of Medicine (M.N., M.T., J.B.B., R.V.S., M.S., J.S., R.F., R.M., N.E.H., A.L.B., J.E.H., G.D.L.), Massachusetts General Hospital, Harvard Medical School, Boston.

Background: Ventilatory efficiency (minute ventilation required to eliminate carbon dioxide, VE/VCO2) during exercise potently predicts outcomes in advanced heart failure with reduced ejection fraction, but its prognostic significance for at-risk individuals with preserved left ventricular systolic function is unclear. We aimed to characterize mechanistic determinants and prognostic implications of VE/VCO2 in a single-center dyspneic referral cohort (MGH-ExS [Massachusetts General Hospital Exercise Study]) and in a large sample of community-dwelling participants in the FHS (Framingham Heart Study).

Methods: Maximum incremental cardiopulmonary exercise tests were performed. VE/VCO2 was assessed as the slope pre- and post-ventilatory anaerobic threshold (VE/VCO2, VE/VCO2), the slope throughout exercise (VE/VCO2), and as the lowest 30-second value (VE/VCO2).

Results: In the MGH-ExS (N=493, age 56±15 years, 61% women, left ventricular ejection fraction 64±8%), higher VE/VCO2 was associated with lower peak exercise cardiac output and steeper increases in exercise pulmonary capillary wedge pressure (both <0.0001). VE/VCO2 (hazard ratio, 1.34 per 1-SD unit [95% CI, 1.10-1.62] =0.003) was associated with future cardiovascular hospitalization/death and outperformed classical VE/VCO2 measures used in heart failure with reduced ejection fraction (VE/VCO2). In FHS (N=1936, age 54±9 years, 53% women), VE/VCO2 measures taken in low-to-moderate intensity exercise (including VE/VCO2, VE/VCO2) were directly associated with cardiovascular risk factor burden (smoking, Framingham cardiovascular disease risk score, and lower fitness; all <0.001).

Conclusions: Impaired ventilatory efficiency is associated with cardiovascular risk in the community and with adverse hemodynamic profiles and future hospitalizations/death in a referral population, highlighting the prognostic importance of easily acquired submaximum exercise ventilatory gas exchange measurements in broad populations with preserved left ventricular systolic function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224335PMC
May 2020

Intravascular Ultrasound Pulmonary Artery Denervation to Treat Pulmonary Arterial Hypertension (TROPHY1): Multicenter, Early Feasibility Study.

JACC Cardiovasc Interv 2020 04;13(8):989-999

University of California, San Diego, San Diego, California.

Objectives: The aim of this study was to investigate whether therapeutic intravascular ultrasound pulmonary artery denervation (PDN) is safe and reduces pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH) on a minimum of dual oral therapy.

Background: Early studies have suggested that PDN can reduce PVR in patients with PAH.

Methods: TROPHY1 (Treatment of Pulmonary Hypertension 1) was a multicenter, international, open-label trial undertaken at 8 specialist centers. Patients 18 to 75 years of age with PAH were eligible if taking dual oral or triple nonparenteral therapy and not responsive to acute vasodilator testing. Eligible patients underwent PDN (TIVUS System). The primary safety endpoint was procedure-related adverse events at 30 days. Secondary endpoints included procedure-related adverse events, disease worsening and death to 12 months, and efficacy endpoints that included change in pulmonary hemodynamic status, 6-min walk distance, and quality of life from baseline to 4 or 6 months. Patients were to remain on disease-specific medication for the duration of the study.

Results: Twenty-three patients underwent PDN, with no procedure-related serious adverse events reported. The reduction in PVR at 4- or 6-month follow-up was 94 ± 151 dyn·s·cm (p = 0.001) or 17.8%, which was associated with a 42 ± 63 m (p = 0.02) increase in 6-min walk distance and a 671 ± 1,555 step (p = 0.04) increase in daily activity.

Conclusions: In this multicenter early feasibility study, PDN with an intravascular ultrasound catheter was performed without procedure-related adverse events and was associated with a reduction in PVR and increases in 6-min walk distance and daily activity in patients with PAH on background dual or triple therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcin.2019.12.027DOI Listing
April 2020

Pig-to-human heart transplantation: Who goes first?

Am J Transplant 2020 10 25;20(10):2669-2674. Epub 2020 May 25.

Division of Cardiac Surgery, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA.

Cardiac xenotransplantation has recently taken an important step towards clinical reality. In anticipation of the "first-in-human" heart xenotransplantation trial, we propose a set of patient characteristics that define potential candidates. Our premise is that, to be ethically justified, the risks posed by current state-of-the-art options must outweigh the anticipated risks of a pioneering xenotransplant procedure. Suitable candidates include patients who are at high immunologic risk because of sensitization to alloantigens, including those who have exhibited early onset or accelerated cardiac allograft vasculopathy. In addition, patients should be considered (1) for whom mechanical circulatory support would be prohibitively risky due to a hypercoagulable state, a contraindication to anticoagulation, or restrictive physiology; (2) with severe biventricular dysfunction predicting unsuccessful univentricular left heart support; and (3) adults with complex congenital heart disease. In conclusion, because the published preclinical benchmark for clinical translation of heart xenotransplantation appears within reach, carefully and deliberately defining appropriate trial participants is timely as the basis for ethical clinical trial design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajt.15916DOI Listing
October 2020

Does Chronotropic Incompetence in HFpEF Cause or Result From Exercise Intolerance?

Circ Heart Fail 2020 03 13;13(3):e006872. Epub 2020 Mar 13.

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (V.-K.T., G.D.L.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.006872DOI Listing
March 2020

Quality of life in heart failure with preserved ejection fraction: importance of obesity, functional capacity, and physical inactivity.

Eur J Heart Fail 2020 06 9;22(6):1009-1018. Epub 2020 Mar 9.

Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.

Aims: Patient-reported quality of life (QOL) is a highly prognostic and clinically relevant endpoint in patients with heart failure (HF) with preserved ejection fraction (HFpEF). The relationships between QOL and different markers of HF severity remain unclear, particularly as they relate to functional capacity and directly measured activity levels. We hypothesized that QOL would demonstrate a stronger relationship with measures of exercise capacity and adiposity compared to other disease measures.

Methods And Results: This is a secondary analysis of the National Heart, Lung, and Blood Institute-sponsored RELAX, NEAT-HFpEF and INDIE-HFpEF trials to determine the relationships between QOL (assessed by the Kansas City Cardiomyopathy Questionnaire and Minnesota Living with Heart Failure Questionnaire) and different domains reflecting HF severity, including maximal aerobic capacity (peak oxygen consumption), submaximal exercise capacity (6-min walk distance), volume of daily activity (accelerometry), physician-estimated functional class, resting echocardiography, and plasma natriuretic peptide levels. A total of 408 unique patients with chronic HFpEF were split into tertiles of QOL scores defined as QOL QOL , QOL . The QOL HFpEF group was youngest, with a higher body mass index, greater prevalence of class II obesity and diabetes, and the lowest N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. After adjustment for age, sex and body mass index, poorer QOL was associated with worse physical capacity and activity levels, assessed by peak oxygen consumption, 6-min walk distance and actigraphy, but was not associated with NT-proBNP or indices from resting echocardiography. QOL was similarly reduced in patients with and without prior HF hospitalization.

Conclusions: Quality of life in HFpEF is poorest in patients who are young, obese and have diabetes, and is more robustly tied to measures reflecting functional capacity and daily activity levels rather than elevations in NT-proBNP or prior HF hospitalization. These findings have major implications for the understanding of QOL in HFpEF and for the design of future clinical trials targeting symptom improvement in HFpEF.

Clinical Trial Registration: RELAX, NCT00763867; NEAT-HFpEF, NCT02053493; INDIE-HFpEF, NCT02742129.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ejhf.1788DOI Listing
June 2020

Rationale and design for a multicenter, randomized, double-blind, placebo-controlled, phase 2 study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator praliciguat over 12 weeks in patients with heart failure with preserved ejection fraction (CAPACITY HFpEF).

Am Heart J 2020 04 21;222:183-190. Epub 2020 Jan 21.

Division of Cardiology and the CardioVascular Center, Tufts Medical Center, Boston, MA.

Background: Heart failure with preserved ejection fraction (HFpEF) is a significant cause of morbidity and mortality worldwide. Exercise intolerance is the main symptom of HFpEF and is associated with a poor quality of life and increased mortality. Currently, there are no approved medications for the treatment of HFpEF. Praliciguat (IW-1973), a novel soluble guanylate cyclase stimulator that may help restore deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine 3',5'-monophosphate signaling, is being investigated for the treatment of patients with HFpEF.

Methods: CAPACITY HFpEF is a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial designed to evaluate the safety and efficacy of praliciguat over 12 weeks in approximately 184 patients with HFpEF. Eligible patients must have evidence supporting clinical HFpEF and at least 2 of the following 4 conditions associated with NO deficiency: diabetes/prediabetes, hypertension, obesity, and age >70 years. The primary efficacy end point is the change from baseline in peak VO by cardiopulmonary exercise test (CPET). Secondary end points include the change from baseline in 6-minute walk test distance and the change in ventilatory efficiency on CPET, as well as number of CPET responders. Other exploratory end points include changes in echocardiographic parameters, New York Heart Association functional classification, cardiac events, blood and urine biomarkers pathophysiologically relevant to heart failure, and patient-reported outcomes including Kansas City Cardiomyopathy Questionnaire.

Conclusions: The CAPACITY HFpEF trial will provide data on short-term safety and efficacy of praliciguat on peak exercise capacity, as well as multiple secondary end points of submaximal functional capacity, patient-reported outcomes, and biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ahj.2020.01.009DOI Listing
April 2020

Association of Ascending Aortic Dilatation and Long-term Endurance Exercise Among Older Masters-Level Athletes.

JAMA Cardiol 2020 05;5(5):522-531

Cardiovascular Performance Program, Massachusetts General Hospital, Boston.

Importance: Aortic dilatation is frequently encountered in clinical practice among aging endurance athletes, but the distribution of aortic sizes in this population is unknown. It is additionally uncertain whether this may represent aortic adaptation to long-term exercise, similar to the well-established process of ventricular remodeling.

Objective: To assess the prevalence of aortic dilatation among long-term masters-level male and female athletes with about 2 decades of exercise exposure.

Design, Setting, And Participants: This cross-sectional study evaluated aortic size in veteran endurance athletes. Masters-level rowers and runners aged 50 to 75 years were enrolled from competitive athletic events across the United States from February to October 2018. Analysis began January 2019.

Exposures: Long-term endurance exercise.

Main Outcomes And Measures: The primary outcome was aortic size at the sinuses of Valsalva and the ascending aorta, measured using transthoracic echocardiography in accordance with contemporary guidelines. Aortic dimensions were compared with age, sex, and body size-adjusted predictions from published nomograms, and z scores were calculated where applicable.

Results: Among 442 athletes (mean [SD] age, 61 [6] years; 267 men [60%]; 228 rowers [52%]; 214 runners [48%]), clinically relevant aortic dilatation, defined by a diameter at sinuses of Valsalva or ascending aorta of 40 mm or larger, was found in 21% (n = 94) of all participants (83 men [31%] and 11 women [6%]). When compared with published nomograms, the distribution of measured aortic size displayed a rightward shift with a rightward tail (all P < .001). Overall, 105 individuals (24%) had at least 1 z score of 2 or more, indicating an aortic measurement greater than 2 SDs above the population mean. In multivariate models adjusting for age, sex, body size, hypertension, and statin use, both elite competitor status (rowing participation in world championships or Olympics or marathon time under 2 hours and 45 minutes) and sport type (rowing) were independently associated with aortic size.

Conclusions And Relevance: Clinically relevant aortic dilatation is common among aging endurance athletes, raising the possibility of vascular remodeling in response to long-term exercise. Longitudinal follow-up is warranted to establish corollary clinical outcomes in this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamacardio.2020.0054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240353PMC
May 2020