Publications by authors named "David M Systrom"

59 Publications

Persistent Exertional Intolerance After COVID-19: Insights From Invasive Cardiopulmonary Exercise Testing.

Chest 2021 Aug 11. Epub 2021 Aug 11.

Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Background: Some patients with COVID-19 who have recovered from the acute infection after experiencing only mild symptoms continue to exhibit persistent exertional limitation that often is unexplained by conventional investigative studies.

Research Question: What is the pathophysiologic mechanism of exercise intolerance that underlies the post-COVID-19 long-haul syndrome after COVID-19 in patients without cardiopulmonary disease?

Study Design And Methods: This study examined the systemic and pulmonary hemodynamics, ventilation, and gas exchange in 10 patients who recovered from COVID-19 and were without cardiopulmonary disease during invasive cardiopulmonary exercise testing (iCPET) and compared the results with those from 10 age- and sex-matched control participants. These data then were used to define potential reasons for exertional limitation in the cohort of patients who had recovered from COVID-19.

Results: The patients who had recovered from COVID-19 exhibited markedly reduced peak exercise aerobic capacity (oxygen consumption [VO]) compared with control participants (70 ± 11% predicted vs 131 ± 45% predicted; P < .0001). This reduction in peak VO was associated with impaired systemic oxygen extraction (ie, narrow arterial-mixed venous oxygen content difference to arterial oxygen content ratio) compared with control participants (0.49 ± 0.1 vs 0.78 ± 0.1; P < .0001), despite a preserved peak cardiac index (7.8 ± 3.1 L/min vs 8.4±2.3 L/min; P > .05). Additionally, patients who had recovered from COVID-19 demonstrated greater ventilatory inefficiency (ie, abnormal ventilatory efficiency [VE/VCO] slope: 35 ± 5 vs 27 ± 5; P = .01) compared with control participants without an increase in dead space ventilation.

Interpretation: Patients who have recovered from COVID-19 without cardiopulmonary disease demonstrate a marked reduction in peak VO from a peripheral rather than a central cardiac limit, along with an exaggerated hyperventilatory response during exercise.
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http://dx.doi.org/10.1016/j.chest.2021.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354807PMC
August 2021

Postural orthostatic tachycardia syndrome (POTS): Priorities for POTS care and research from a 2019 National Institutes of Health Expert Consensus Meeting - Part 2.

Auton Neurosci 2021 11 30;235:102836. Epub 2021 Jun 30.

Department of Neurology, UT Southwestern Medical Center, Dallas, TX, USA.

The National Institutes of Health hosted a workshop in 2019 to build consensus around the current state of understanding of the pathophysiology of postural orthostatic tachycardia syndrome (POTS) and to identify knowledge gaps that must be addressed to enhance clinical care of POTS patients through research. This second (of two) articles summarizes current knowledge gaps, and outlines the clinical and research priorities for POTS. POTS is a complex, multi-system, chronic disorder of the autonomic nervous system characterized by orthostatic intolerance and orthostatic tachycardia without hypotension. Patients often experience a host of other related disabling symptoms. The functional and economic impacts of this disorder are significant. The pathophysiology remains incompletely understood. Beyond the significant gaps in understanding the disorder itself, there is a paucity of evidence to guide treatment which can contribute to suboptimal care for this patient population. The vast majority of physicians have minimal to no familiarity or training in the assessment and management of POTS. Funding for POTS research remains very low relative to the size of the patient population and impact of the syndrome. In addition to efforts to improve awareness and physician education, an investment in research infrastructure including the development of standardized disease-specific evaluation tools and outcome measures is needed to facilitate effective collaborative research. A national POTS research consortium could facilitate well-controlled multidisciplinary clinical research studies and therapeutic trials. These priorities will require a substantial increase in the number of research investigators and the amount of research funding in this area.
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http://dx.doi.org/10.1016/j.autneu.2021.102836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455430PMC
November 2021

Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting - Part 1.

Auton Neurosci 2021 11 5;235:102828. Epub 2021 Jun 5.

Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Autonomic Dysfunction Center, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

Postural orthostatic tachycardia syndrome (POTS) is a chronic and often disabling disorder characterized by orthostatic intolerance with excessive heart rate increase without hypotension during upright posture. Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. A typical patient with POTS is a female of child-bearing age, who often first displays symptoms in adolescence. The onset of POTS may be precipitated by immunological stressors such as a viral infection. A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the pathophysiology of the syndrome is incompletely understood and undoubtedly multifaceted. Clinicians and researchers focused on POTS convened at the National Institutes of Health in July 2019 to discuss the current state of understanding of the pathophysiology of POTS and to identify priorities for POTS research. This article, the first of two articles summarizing the information discussed at this meeting, summarizes the current understanding of this disorder and best practices for clinical care. The evaluation of a patient with suspected POTS should seek to establish the diagnosis, identify co-morbid conditions, and exclude conditions that could cause or mimic the syndrome. Once diagnosed, management typically begins with patient education and non-pharmacologic treatment options. Various medications are often used to address specific symptoms, but there are currently no FDA-approved medications for the treatment of POTS, and evidence for many of the medications used to treat POTS is not robust.
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http://dx.doi.org/10.1016/j.autneu.2021.102828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455420PMC
November 2021

Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Chest 2021 Aug 10;160(2):642-651. Epub 2021 Feb 10.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide; the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia, and objective evidence of small fiber neuropathy (SFN) is reported in approximately 50% of POTS and fibromyalgia patients.

Research Question: Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5-immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN?

Study Design And Methods: We analyzed 1,516 upright invasive iCPETs performed to investigate exertional intolerance. After excluding patients with intrinsic heart or lung disease and selecting those with right atrial pressures (RAP) <6.5 mm Hg, results from 160 patients meeting ME/CFS criteria who had skin biopsy test results were compared with 36 control subjects. Rest-to-peak changes in cardiac output (Qc) were compared with oxygen uptake (Qc/VO slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO tertiles.

Results: During exercise, the 160 ME/CFS patients averaged lower RAP (1.9 ± 2 vs 8.3 ± 1.5; P < .0001) and peak VO (80% ± 21% vs 101.4% ± 17%; P < .0001) than control subjects. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4% ± 19% vs 99.5% ± 23.8% vs 99.9% ± 19.5% predicted; P < .01). In contrast, systemic oxygen extraction was impaired in high-flow vs low- and normal-flow participants (0.74% ± 0.1% vs 0.88 ± 0.11 vs 0.86 ± 0.1; P < .0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% were consistent with SFN (epidermal innervation ≤5.0% of predicted; P < .0001). Denervation severity did not correlate with exertional measures.

Interpretation: These results identify two types of peripheral neurovascular dysregulation that are biologically plausible contributors to ME/CFS exertional intolerance-depressed Qc from impaired venous return, and impaired peripheral oxygen extraction. In patients with small-fiber pathology, neuropathic dysregulation causing microvascular dilation may limit exertion by shunting oxygenated blood from capillary beds and reducing cardiac return.
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http://dx.doi.org/10.1016/j.chest.2021.01.082DOI Listing
August 2021

Impact of right ventricular work and pulmonary arterial compliance on peak exercise oxygen uptake in idiopathic pulmonary arterial hypertension.

Int J Cardiol 2021 05 3;331:230-235. Epub 2021 Feb 3.

Division of Respiratory Diseases, Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.

Background: Pulmonary arterial hypertension (PAH) is associated with increased right ventricular (RV) afterload, RV dysfunction and decreased peak oxygen uptake (pVO). However, the pulmonary hemodynamic mechanisms measured by exercise right heart catheterization (RHC) that contribute to reduced pVO in idiopathic PAH (IPAH) are not completely characterized. Therefore, we sought to evaluate the exercise RHC determinants of pVO in patients with IPAH.

Methods: 519 consecutive patients with suspected and/or confirmed pulmonary hypertension were prospectively screened to identify 20 patients with IPAH. All IPAH patients were prospectively evaluated with resting and exercise RHC and cardiopulmonary exercise testing.

Results: 85% of the patients were female; the median age was 34[29-42] years old. At peak exercise, mean pulmonary arterial (PA) pressure was 76 ± 17 mmHg, PA wedge pressure was 14 ± 5 mmHg, cardiac output (CO) was 5.7 ± 1.9 L/min, pulmonary vascular resistance was 959 ± 401 dynes/s/cm and PA compliance was 0.9[0.6-1.2] ml/mmHg. On univariate analysis, pVO2 positively correlated to peak CO, peak cardiac index, peak stroke volume index, peak RV stroke work index (RVSWI) and peak oxygen saturation. There was a negative correlation between pVO and Δ (rest to peak change) PA compliance. In age-adjusted multivariate model, peak RVSWI (Coefficient = 0.15, Beta = 0.63, 95% CI [0.07-0.22], p < 0.01) and ΔPA compliance (Coefficient = -2.51, Beta = -0.43, 95% CI [-4.34-(-0.68)], p = 0.01) had the best performance predicting pVO (R = 0.66).

Conclusions: In conclusion, a load dependent measurement of RV function (RVSWI) and the pulsatile component of RV afterload (ΔPA compliance) significantly influence pVO in IPAH, further highlighting the pivotal role of hemodynamic coupling to IPAH exercise capacity.
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http://dx.doi.org/10.1016/j.ijcard.2021.01.027DOI Listing
May 2021

Sex-Related Differences in Dynamic Right Ventricular-Pulmonary Vascular Coupling in Heart Failure With Preserved Ejection Fraction.

Chest 2021 06 1;159(6):2402-2416. Epub 2021 Jan 1.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. Electronic address:

Background: Right ventricular (RV) dysfunction is associated with poorer outcomes in heart failure with preserved ejection fraction (HFpEF). Although female subjects are more likely to have HFpEF, male subjects have worse prognosis and resting RV function. The contribution of dynamic RV-pulmonary arterial (RV-PA) coupling between sex and its impact on peak exercise capacity (VO) in HFpEF is not known.

Research Question: The goal of this study was to investigate the differential effects of sex on RV-PA coupling during maximum incremental exercise in patients with HFpEF.

Study Design And Methods: This study examined rest and exercise invasive pulmonary hemodynamics in 22 male patients with HFpEF and 27 female patients with HFpEF. To further investigate the discrepancy in RV-PA response between sex, 26 age-matched control subjects (11 male subjects and 15 female subjects) were included. Single beat analysis of RV pressure waveforms was used to determine the end-systolic elastance (Ees) and pulmonary arterial elastance. RV-PA coupling was determined as the ratio of end-systolic elastance/PA elastance.

Results: Both HFpEF groups experienced decreased peak VO (% predicted). However, male patients with HFpEF experienced a greater decrement in peak VO compared with female patients (58 ± 16% vs 70 ± 15%; P < .05). Male patients with HFpEF had a more pronounced increase in RV afterload, Ea (1.8 ± 0.6 mm Hg/mL/m vs 1.3 ± 0.4 mm Hg/mL/m; P < .05) and failed to increase RV contractility during exercise, resulting in dynamic RV-PA uncoupling (0.9 ± 0.4 vs 1.2 ± 0.4; P < .05) and subsequent reduced stroke volume index augmentation. In contrast, female patients with HFpEF were able to augment RV contractility in the face of increasing afterload, preserving RV-PA coupling during exercise.

Interpretation: Male patients with HFpEF were more compromised regarding dynamic RV-PA uncoupling and reduced peak VO compared with female patients. This finding was driven by both RV contractile impairment and afterload mismatch. In contrast, female patients with HFpEF had preserved RV-PA coupling during exercise and better peak exercise VO compared with male patients with HFpEF.
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http://dx.doi.org/10.1016/j.chest.2020.12.028DOI Listing
June 2021

Dynamic right ventricular function response to incremental exercise in pulmonary hypertension.

Pulm Circ 2020 Jul-Sep;10(3):2045894020950187. Epub 2020 Oct 2.

Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Pulmonary hypertension is a progressive disease whose survival is linked to adequate right ventricle adaptation to its afterload. In the current study, we performed an in-depth characterization of right ventricle function during maximum incremental exercise in patients with pulmonary hypertension and how it relates to exercise capacity. A total of 377 pulmonary hypertension patients who completed a maximum symptom-limited invasive cardiopulmonary exercise testing were evaluated to identify 45 patients with heart failure with preserved ejection fraction, 48 with exercise pulmonary hypertension, and 47 with established pulmonary arterial hypertension. These patients were compared to 17 age- and gender-matched normal controls. Load-adjusted right ventricle function was quantified as the ratio of right ventricle stroke work index to pulmonary arterial elastance. All patients with pulmonary hypertension had reduced peak VO %predicted compared to controls. Right ventricle function deteriorated for all pulmonary hypertension groups by 50% of peak VO. Worsening of right ventricle function during freewheeling exercise was associated with greater reduction in peak VO compared to those whose right ventricle function deteriorated at later exercise stages (i.e. min 1, 2, and 3). On multivariate analysis, reduced ratio of right ventricle stroke work index to arterial elastance was an independent predictor of peak VO %predicted (β-Coefficient -5.46, 95% CI: -9.47 to -1.47,  = 0.01). Right ventricle function deteriorates early during incremental exercise in pulmonary hypertension, occurring by 50% of peak oxygen uptake. The current study demonstrates that right ventricle dysfunction is an early phenomenon during incremental exercise in pulmonary hypertension, occurring by 50% of peak oxygen uptake. The threshold at which right ventricle function is compromised during incremental exercise in pulmonary hypertension influences aerobic capacity and may help guide exercise strategies to mitigate dynamic worsening of right ventricle function during exercise training.
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http://dx.doi.org/10.1177/2045894020950187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534091PMC
October 2020

Systemic vascular distensibility relates to exercise capacity in connective tissue disease.

Rheumatology (Oxford) 2021 03;60(3):1429-1434

Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Objective: Exercise intolerance is a common clinical manifestation of CTD. Frequently, CTD patients have associated cardio-pulmonary disease, including pulmonary hypertension or heart failure that impairs aerobic exercise capacity (pVO2). The contribution of the systemic micro-vasculature to reduced exercise capacity in CTD patients without cardiopulmonary disease has not been fully described. In this study, we sought to examine the role of systemic vascular distensibility, α in reducing exercise capacity (i.e. pVO2) in CTD patients.

Methods: Systemic and pulmonary vascular distensibility, α (%/mmHg) was determined from multipoint systemic pressure-flow plots during invasive cardiopulmonary exercise testing with pulmonary and radial arterial catheters in place in 42 CTD patients without cardiopulmonary disease and compared with 24 age and gender matched normal controls.

Results: During exercise, systemic vascular distensibility, α was reduced in CTD patients compared with controls (0.20 ± 0.12%/mmHg vs 0.30 ± 0.13%/mmHg, P =0.01). The reduced systemic vascular distensibility α, was associated with impaired stroke volume augmentation. On multivariate analysis, systemic vascular distensibility, α was associated with a decreased exercise capacity (pVO2) and decreased systemic oxygen extraction.

Conclusion: Systemic vascular distensibility, α is associated with impaired systemic oxygen extraction and decreased aerobic capacity in patients with CTD without cardiopulmonary disease.
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http://dx.doi.org/10.1093/rheumatology/keaa510DOI Listing
March 2021

Fick principle and exercise pulmonary hemodynamic determinants of the six-minute walk distance in pulmonary hypertension.

Pulm Circ 2020 Jul-Sep;10(3):2045894020957576. Epub 2020 Sep 11.

Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA.

The six-minute walk test is widely used to assess the severity and prognosis of pulmonary hypertension. However, the pathophysiology underlying a compromised six-minute walk distance is incompletely characterized. The purpose of this study is to evaluate the Fick principle and pulmonary hemodynamic determinants of the six-minute walk distance in patients with suspected pulmonary hypertension. Twenty-nine patients were retrospectively studied and underwent a right heart catheterization for the evaluation of suspected pulmonary hypertension. With the pulmonary artery catheter in place, patients were moved to a treadmill and completed a six-minute walk test. Fick cardiac output and indices of right heart afterload were calculated using continuous measurements of pulmonary vascular pressures, gas exchange, and mixed venous blood samples. Fifteen subjects who walked ≤ 348 m were compared to 14 subjects who walked > 348 m. Systemic oxygen delivery was impaired in six-minute walk distance ≤ 348 m compared to six-minute walk distance > 348 m (15.2 ± 6.2 vs. 23.2 ± 6.8 mL/kg/min,  < 0.01). Impaired oxygen delivery was due to a depressed cardiac index and decreased cardiac reserve demonstrated by the change in the stroke volume index (3.0 ± 14 vs. 17 ± 15 mL/min/m,  = 0.02). The six-minute walk distance positively correlated with oxygen delivery ( = 0.501,  = 0.006) and inversely correlated with oxygen extraction ( = 0.369,  = 0.049). A decreased six-minute walk distance was associated with an increased total pulmonary resistance ( = 0.502,  = 0.006) and pulmonary vascular resistance ( = 0.530,  = 0.003). In patients with suspected pulmonary hypertension, a decreased six-minute walk distance is due to compromised oxygen delivery, decreased cardiac reserve, and increased right ventricular afterload.
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http://dx.doi.org/10.1177/2045894020957576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502687PMC
September 2020

Pulmonary Vascular and Right Ventricular Burden During Exercise in Interstitial Lung Disease.

Chest 2020 07 12;158(1):350-358. Epub 2020 Mar 12.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Heart & Vascular Center, Brigham and Women's Hospital, Boston, MA. Electronic address:

Background: Pulmonary hypertension (PH) adversely affects patient's exercise capacity in interstitial lung disease (ILD). The impact of pulmonary vascular and right ventricular (RV) dysfunction, however, has traditionally been believed to be mild and clinically relevant principally in advanced lung disease states.

Research Question: The aim of this study was to evaluate the relative contributions of pulmonary mechanics, pulmonary vascular function, and RV function to the ILD exercise limit.

Study Design And Methods: Forty-nine patients with ILD who underwent resting right heart catheterization followed by invasive exercise testing were evaluated. Patients with PH at rest (ILD + rPH) and with PH diagnosed exclusively during exercise (ILD + ePH) were contrasted with ILD patients without PH (ILD non-PH).

Results: Peak oxygen consumption was reduced in ILD + rPH (61 ± 10% predicted) and ILD + ePH (67 ± 13% predicted) compared with ILD non-PH (81 ± 16% predicted; P < .001 and P = .016, respectively). Each ILD hemodynamic phenotype presented distinct patterns of dynamic changes of pulmonary vascular compliance relative to pulmonary vascular resistance from rest to peak exercise. Peak RV stroke work index was increased in ILD + ePH (24.7 ± 8.2 g/m per beat) and ILD + rPH (30.9 ± 6.1 g/m per beat) compared with ILD non-PH (18.3 ± 6.4 g/m per beat; P = .020 and P = .014). Ventilatory reserve was reduced in ILD + rPH compared with the other groups at the anaerobic threshold, but it was similar between ILD + ePH and ILD non-PH at the anaerobic threshold (0.32 ± 0.13 vs 0.30 ± 0.11; P = .921) and at peak exercise (0.70 ± 0.17 vs 0.73 ± 0.24; P = .872).

Interpretation: ILD with resting and exercise PH is associated with increased exercise RV work, reduced pulmonary vascular reserve, and reduced peak oxygen consumption. The findings highlight the role of pulmonary vascular and RV burden to ILD exercise limit.
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http://dx.doi.org/10.1016/j.chest.2020.02.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173767PMC
July 2020

Comprehensive Diagnostic Evaluation of Cardiovascular Physiology in Patients With Pulmonary Vascular Disease: Insights From the PVDOMICS Program.

Circ Heart Fail 2020 03 24;13(3):e006363. Epub 2020 Feb 24.

Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Department of Medicine (F.P.R.).

Background: Invasive hemodynamic evaluation through right heart catheterization plays an essential role in the diagnosis, categorization, and risk stratification of patients with pulmonary hypertension.

Methods: Subjects enrolled in the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) program undergo an extensive invasive hemodynamic evaluation that includes repeated measurements at rest and during several provocative physiological challenges. It is a National Institutes of Health/National Heart, Lung, and Blood Institute initiative to reclassify pulmonary hypertension groups based on clustered phenotypic and phenomic characteristics. At a subset of centers, participants also undergo an invasive cardiopulmonary exercise test to assess changes in hemodynamics and gas exchange during exercise.

Conclusions: When coupled with other physiological testing and blood -omic analyses involved in the PVDOMICS study, the comprehensive right heart catheterization protocol described here holds promise to clarify the diagnosis and clustering of pulmonary hypertension patients into cohorts beyond the traditional 5 World Symposium on Pulmonary Hypertension groups. This article will describe the methods applied for invasive hemodynamic characterization in the PVDOMICS program. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02980887.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046052PMC
March 2020

Metabolomics of exercise pulmonary hypertension are intermediate between controls and patients with pulmonary arterial hypertension.

Pulm Circ 2019 Oct-Dec;9(4):2045894019882623. Epub 2019 Oct 30.

Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Mechanisms underlying pulmonary arterial hypertension (PAH) remain elusive. Pulmonary arterial hypertension and exercise PH share similar physiologic consequences; it is debated whether they share biologic mechanisms and if exercise PH represents an early phase of pulmonary arterial hypertension. We conducted an observational study to test if there is a graded metabolic disturbance along the severity of PH, which may indicate shared or disparate pathophysiology. Individuals referred to an academic medical dyspnea center with unexplained exertional intolerance underwent invasive cardiopulmonary exercise testing. We identified controls with no hemodynamic exercise limitation, individuals with exercise PH (mean pulmonary arterial pressure (mPAP) < 25 mmHg at rest but ≥ 30 mmHg during exercise without pulmonary venous hypertension) and pulmonary arterial hypertension (mPAP > 25 mmHg at rest without pulmonary venous hypertension) ( = 26 in each group). Unbiased metabolomics with chromatography mass spectrometry was performed on pulmonary arterial blood at rest and peak exercise. Random forest analysis and hierarchical clustering were used to quantify metabolite prediction of group membership and rank metabolites which were significantly different between groups. Compared to controls, pulmonary arterial hypertension subjects exhibited perturbations in pathways involving glycolysis, TCA cycle, fatty acid and complex lipid oxidation, collagen deposition and fibrosis, nucleotide metabolism, and others. The metabolic signature of exercise PH was uniquely between that of control and pulmonary arterial hypertension subjects. Accuracy predicting control, exercise PH, and pulmonary arterial hypertension group was 96%, 90%, and 88%, respectively, using paired rest-exercise metabolic changes. Our data suggest the metabolic profile of exercise PH is between that of controls and patients with pulmonary arterial hypertension.
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http://dx.doi.org/10.1177/2045894019882623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822198PMC
October 2019

Unexplained exertional intolerance associated with impaired systemic oxygen extraction.

Eur J Appl Physiol 2019 Oct 6;119(10):2375-2389. Epub 2019 Sep 6.

Division of Pulmonary and Critical Care Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.

Purpose: The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE).

Methods: We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO)/[Hb] ≤ 0.8 and VO < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO)/[Hb] > 0.8, VO ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO < [1.5 × HCO + 6].

Results: Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs. 7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001).

Conclusions: We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.
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http://dx.doi.org/10.1007/s00421-019-04222-6DOI Listing
October 2019

Fatigue, Sleep, and Autoimmune and Related Disorders.

Front Immunol 2019 6;10:1827. Epub 2019 Aug 6.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

Profound and debilitating fatigue is the most common complaint reported among individuals with autoimmune disease, such as systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, celiac disease, chronic fatigue syndrome, and rheumatoid arthritis. Fatigue is multi-faceted and broadly defined, which makes understanding the cause of its manifestations especially difficult in conditions with diverse pathology including autoimmune diseases. In general, fatigue is defined by debilitating periods of exhaustion that interfere with normal activities. The severity and duration of fatigue episodes vary, but fatigue can cause difficulty for even simple tasks like climbing stairs or crossing the room. The exact mechanisms of fatigue are not well-understood, perhaps due to its broad definition. Nevertheless, physiological processes known to play a role in fatigue include oxygen/nutrient supply, metabolism, mood, motivation, and sleepiness-all which are affected by inflammation. Additionally, an important contributing element to fatigue is the central nervous system-a region impacted either directly or indirectly in numerous autoimmune and related disorders. This review describes how inflammation and the central nervous system contribute to fatigue and suggests potential mechanisms involved in fatigue that are likely exhibited in autoimmune and related diseases.
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http://dx.doi.org/10.3389/fimmu.2019.01827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691096PMC
October 2020

Dynamic right ventricular-pulmonary arterial uncoupling during maximum incremental exercise in exercise pulmonary hypertension and pulmonary arterial hypertension.

Pulm Circ 2019 Jul-Sep;9(3):2045894019862435

2 Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Despite recent advances, the prognosis of pulmonary hypertension (PH) remains poor. While the initial insult in PH implicates the pulmonary vasculature, the functional state, exercise capacity, and survival of such patients are closely linked to right ventricular (RV) function. In the current study, we sought to investigate the effects of maximum incremental exercise on the matching of RV contractility and afterload (i.e. right ventricular-pulmonary arterial [RV-PA] coupling) in patients with exercise PH (ePH) and pulmonary arterial hypertension (PAH). End-systolic elastance (Ees), pulmonary arterial elastance (Ea), and RV-PA coupling (Ees/Ea) were determined using single-beat pressure-volume loop analysis in 40 patients that underwent maximum invasive cardiopulmonary exercise testing. Eleven patients had ePH, nine had PAH, and 20 were age-matched controls. During exercise, the impaired exertional contractile reserve in PAH was associated with blunted stroke volume index (SVI) augmentation and reduced peak oxygen consumption (peak VO %predicted). Compared to PAH, ePH demonstrated increased RV contractility in response to increasing RV afterload during exercise; however, this was insufficient and resulted in reduced peak RV-PA coupling. The dynamic RV-PA uncoupling in ePH was associated with similarly blunted SVI augmentation and peak VO as PAH. In conclusion, dynamic rest-to-peak exercise RV-PA uncoupling during maximum exercise blunts SV increase and reduces exercise capacity in exercise PH and PAH. In ePH, the insufficient increase in RV contractility to compensate for increasing RV afterload during maximum exercise leads to deterioration of RV-PA coupling. These data provide evidence that even in the early stages of PH, RV function is compromised.
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http://dx.doi.org/10.1177/2045894019862435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643191PMC
June 2019

Pulmonary Vascular Distensibility and Early Pulmonary Vascular Remodeling in Pulmonary Hypertension.

Chest 2019 10 20;156(4):724-732. Epub 2019 May 20.

Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. Electronic address:

Background: Exercise stress testing of the pulmonary circulation may uncover decreased pulmonary vascular (PV) distensibility as a cause of impaired aerobic exercise capacity and right ventricular (RV)-pulmonary arterial (PA) uncoupling. As such, it may help in the differential diagnosis of unexplained dyspnea, including pulmonary hypertension (PH) and/or heart failure with preserved ejection fraction (HFpEF). We investigated rest and exercise invasive pulmonary hemodynamics, ventilation, and gas exchange in patients with unexplained dyspnea, including 44 patients with HFpEF (of whom 20 had a normal pulmonary vascular resistance [PVR] during exercise [ie, passive HFpEF] and 24 had a higher than normal exercise PVR), 22 patients with exercise PH, 19 patients with pulmonary arterial hypertension (PAH), and 24 age- and sex-matched normal control subjects.

Methods: A PV distensibility coefficient α (%/mm Hg) was determined from multipoint PV pressure-flow plots. RV-PA coupling was quantified from the analysis of RV pressure curves to determine ratios of end-systolic to arterial elastances (Ees/Ea). Aerobic exercise capacity was estimated by peak oxygen consumption.

Results: The α coefficient decreased from 1.35 ± 0.58%/mm Hg in control subjects and 1.1 ± 0.48%/mm Hg in patients with passive HFpEF to 0.62 ± 0.32%/mm Hg in exercise PH, 0.54 ± 0.27%/mm Hg in HFpEF with high exercise PVR, and 0.18 ± 0.16%/mm Hg in PAH. On multivariate analysis, PV distensibility was associated with decreased Ees/Ea and maximal volume of oxygen consumed.

Conclusions: PV distensibility is an early and sensitive hemodynamic marker of PV disease that is associated with RV-PA uncoupling and decreased aerobic exercise capacity.
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http://dx.doi.org/10.1016/j.chest.2019.04.111DOI Listing
October 2019

Right Ventricular-Arterial Uncoupling During Exercise in Heart Failure With Preserved Ejection Fraction: Role of Pulmonary Vascular Dysfunction.

Chest 2019 11 16;156(5):933-943. Epub 2019 May 16.

Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. Electronic address:

Background: Right ventricular (RV) dysfunction is associated with shortened life expectancy in heart failure with preserved ejection fraction (HFpEF). The contribution of pulmonary vascular dysfunction to RV dysfunction in HFpEF is not well understood.

Methods: We investigated rest and exercise invasive pulmonary hemodynamics, ventilation, and gas exchange in 67 patients with HFpEF (of whom 28 had an abnormal pulmonary vascular response during exercise referred to as HFpEF+PVR group and 39 had a normal pulmonary vascular response during exercise referred to as HFpEF group) and in 21 matched control subjects.

Results: Both groups of patients with HFpEF had a markedly decreased peak oxygen consumption (Vo), decreased oxygen delivery, and impaired chronotropic response. Single beat analysis of RV pressure waveforms was used to compute the end-systolic elastance (Ees) and pulmonary arterial elastance (Ea). Right ventricular-pulmonary artery (RV-PA) coupling was measured as the ratio of Ees/Ea. Exercise was associated with a preserved Ees response but a decreased Ees/Ea in patients with HFpEF with a normal PVR response, indicating partially preserved RV contractile reserve. In HFpEF+PVR, exercise-induced increase in Ees was markedly reduced, resulting in decreased Ees/Ea and RV-PA uncoupling. Patients with HFpEF+PVR with an exercise-induced decrease in Ees/Ea had lower pulmonary artery compliance, lower peak Vo, and lower stroke volume than patients with HFpEF.

Conclusions: We conclude that RV-PA uncoupling is common in HFpEF and is caused by both intrinsic RV contractile impairment and afterload mismatch. Resting and dynamic RV-PA uncoupling in HFpEF is driven by an increase in RV pulsatile rather than resistive afterload. However, with the additive effects of increased RV resistive afterload, RV-PA uncoupling worsens dynamically during exercise.
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http://dx.doi.org/10.1016/j.chest.2019.04.109DOI Listing
November 2019

Right ventriculo-arterial uncoupling and impaired contractile reserve in obese patients with unexplained exercise intolerance.

Eur J Appl Physiol 2018 Jul 30;118(7):1415-1426. Epub 2018 Apr 30.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

Background: Right ventricular (RV) dysfunction and heart failure with preserved ejection fraction may contribute to exercise intolerance in obesity. To further define RV exercise responses, we investigated RV-arterial coupling in obesity with and without development of exercise pulmonary venous hypertension (ePVH).

Methods: RV-arterial coupling defined as RV end-systolic elastance/pulmonary artery elastance (Ees/Ea) was calculated from invasive cardiopulmonary exercise test data in 6 controls, 8 obese patients without ePVH (Obese-ePVH) and 8 obese patients with ePVH (Obese+ePVH) within a larger series. ePVH was defined as a resting pulmonary arterial wedge pressure < 15 mmHg but ≥ 20 mmHg on exercise. Exercise haemodynamics were further evaluated in 18 controls, 20 Obese-ePVH and 17 Obese+ePVH patients.

Results: Both Obese-ePVH and Obese+ePVH groups developed exercise RV-arterial uncoupling (peak Ees/Ea = 1.45 ± 0.26 vs 0.67 ± 0.18 vs 0.56 ± 0.11, p < 0.001, controls vs Obese-ePVH vs Obese+ePVH respectively) with higher peak afterload (peak Ea = 0.31 ± 0.07 vs 0.75 ± 0.32 vs 0.88 ± 0.62 mL/mmHg, p = 0.043) and similar peak contractility (peak Ees = 0.50 ± 0.16 vs 0.45 ± 0.22 vs 0.48 ± 0.17 mL/mmHg, p = 0.89). RV contractile reserve was highest in controls (ΔEes = 224 ± 80 vs 154 ± 39 vs 141 ± 34% of baseline respectively, p < 0.001). Peak Ees/Ea correlated with peak pulmonary vascular compliance (PVC, r = 0.53, p = 0.02) but not peak pulmonary vascular resistance (PVR, r = - 0.20, p = 0.46). In the larger cohort, Obese+ePVH patients on exercise demonstrated higher right atrial pressure, lower cardiac output and steeper pressure-flow responses. BMI correlated with peak PVC (r = - 0.35, p = 0.04) but not with peak PVR (r = 0.24, p = 0.25).

Conclusions: Exercise RV-arterial uncoupling and reduced RV contractile reserve further characterise obesity-related exercise intolerance. RV dysfunction in obesity may develop independent of exercise LV filling pressures.
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http://dx.doi.org/10.1007/s00421-018-3873-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028899PMC
July 2018

Pulmonary haemodynamics and mortality in chronic hypersensitivity pneumonitis.

Eur Respir J 2018 06 21;51(6). Epub 2018 Jun 21.

Division of Respiratory Diseases, Dept of Medicine, Federal University of São Paulo (Unifesp), São Paulo, Brazil.

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http://dx.doi.org/10.1183/13993003.00430-2018DOI Listing
June 2018

Network Analysis to Risk Stratify Patients With Exercise Intolerance.

Circ Res 2018 03 5;122(6):864-876. Epub 2018 Feb 5.

From the Department of Medicine (W.M.O., R.K.F.O., R.-S.W., D.M.R., B.M.W., C.A.M., J.L., A.B.W., D.M.S., J.A.L.), Division of Pulmonary and Critical Care Medicine (W.M.O., B.M.W., A.B.W., D.M.S.), Division of Cardiovascular Medicine (A.R.O., C.A.M., J.L., J.A.L., B.A.M.), and Department of Radiology (J.H.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Division of Respiratory Diseases, Department of Medicine, Federal University of São Paulo (UNIFESP), Brazil (R.K.F.O.); Department of Cardiology, Boston Children's Hospital and Harvard Medical School, MA (A.R.O.); Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston (G.A.A.); Division of Cardiology, Department of Medicine, Providence Veterans Affairs Medical Center and Alpert Medical School of Brown University, Providence, RI (G.C.); Department of Pulmonology, Medical University of Graz, Austria (A.T., H.O., G.K.); Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (A.T., H.O., G.K.); and Department of Cardiology, Boston VA Healthcare System, MA (B.A.M.).

Rationale: Current methods assessing clinical risk because of exercise intolerance in patients with cardiopulmonary disease rely on a small subset of traditional variables. Alternative strategies incorporating the spectrum of factors underlying prognosis in at-risk patients may be useful clinically, but are lacking.

Objective: Use unbiased analyses to identify variables that correspond to clinical risk in patients with exercise intolerance.

Methods And Results: Data from 738 consecutive patients referred for invasive cardiopulmonary exercise testing at a single center (2011-2015) were analyzed retrospectively (derivation cohort). A correlation network of invasive cardiopulmonary exercise testing parameters was assembled using |r|>0.5. From an exercise network of 39 variables (ie, nodes) and 98 correlations (ie, edges) corresponding to <9.5e for each correlation, we focused on a subnetwork containing peak volume of oxygen consumption (pVo) and 9 linked nodes. K-mean clustering based on these 10 variables identified 4 novel patient clusters characterized by significant differences in 44 of 45 exercise measurements (<0.01). Compared with a probabilistic model, including 23 independent predictors of pVo and pVo itself, the network model was less redundant and identified clusters that were more distinct. Cluster assignment from the network model was predictive of subsequent clinical events. For example, a 4.3-fold (<0.0001; 95% CI, 2.2-8.1) and 2.8-fold (=0.0018; 95% CI, 1.5-5.2) increase in hazard for age- and pVo-adjusted all-cause 3-year hospitalization, respectively, were observed between the highest versus lowest risk clusters. Using these data, we developed the first risk-stratification calculator for patients with exercise intolerance. When applying the risk calculator to patients in 2 independent invasive cardiopulmonary exercise testing cohorts (Boston and Graz, Austria), we observed a clinical risk profile that paralleled the derivation cohort.

Conclusions: Network analyses were used to identify novel exercise groups and develop a point-of-care risk calculator. These data expand the range of useful clinical variables beyond pVo that predict hospitalization in patients with exercise intolerance.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.312482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924425PMC
March 2018

Impaired systemic oxygen extraction in treated exercise pulmonary hypertension: a new engine in an old car?

Pulm Circ 2018 Jan-Mar;8(1):2045893218755325. Epub 2018 Jan 8.

1 Division of Pulmonary and Critical Care Medicine, 1861 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Ambrisentan in 22 patients with pulmonary hypertension diagnosed during exercise (ePH) improved pulmonary hemodynamics; however, there was only a trend toward increased maximum oxygen uptake (VOmax) secondary to decreased maximum exercise systemic oxygen extraction (Ca-vO). We speculate that improved pulmonary hemodynamics at maximum exercise "unmasked" a pre-existing skeletal muscle abnormality.
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http://dx.doi.org/10.1177/2045893218755325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788103PMC
January 2018

Pulmonary Vascular Resistance During Exercise Predicts Long-Term Outcomes in Heart Failure With Preserved Ejection Fraction.

J Card Fail 2018 Mar 24;24(3):169-176. Epub 2017 Nov 24.

Pulmonary and Critical Care Medicine, Center for Pulmonary Heart Disease, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address:

Background: In heart failure with preserved ejection fraction (HFpEF), the prognostic value of pulmonary vascular dysfunction (PV-dysfunction), identified by elevated pulmonary vascular resistance (PVR) at peak exercise, is not completely understood. We evaluated the long-term prognostic implications of PV-dysfunction in HFpEF during exercise in consecutive patients undergoing invasive cardiopulmonary exercise testing for unexplained dyspnea.

Methods: Patients with HFpEF were classified into 2 main groups: resting HFpEF (n = 104, 62% female, age 61 years) with a pulmonary arterial wedge pressure (PAWP) >15 mmHg at rest; and exercise HFpEF (eHFpEF; n = 81) with a PAWP <15 mmHg at rest, but >20 mmHg during exercise. The eHFpEF group was further subdivided into eHFpEF + PV-dysfunction (peak PVR ≥80 dynes/s/cm; n = 55, 60% female, age 64) group and eHFpEF - PV-dysfunction (peak PVR <80 dynes/s/cm; n = 26, 42% female, age 54 years) group. Outcomes were analyzed for the first 9 years of follow-up and included any cause mortality and heart failure (HF)-related hospitalizations. The mean follow-up time was 6.7 ± 2.6 years (0.5-9.0).

Results: Mortality rate did not differ among the groups. However, survival free of HF-related hospitalization was lower for the eHFpEF + PV-dysfunction group compared with eHFpEF - PV-dysfunction (P = .01). These findings were similar between eHFpEF + PV-dysfunction and the resting HFpEF group (P = .774). By Cox analysis, peak PVR ≥80 dynes/s/cm was a predictor of HF-related hospitalization for eHFpEF (hazard ratio 5.73, 95% confidence interval 1.05-31.22, P = .01). In conclusion, the present study provides insight into the impact of PV-dysfunction on outcomes of patients with exercise-induced HFpEF. An elevated peak PVR is associated with a high risk of HF-related hospitalization.
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http://dx.doi.org/10.1016/j.cardfail.2017.11.003DOI Listing
March 2018

PVDOMICS: A Multi-Center Study to Improve Understanding of Pulmonary Vascular Disease Through Phenomics.

Circ Res 2017 10;121(10):1136-1139

From the Vanderbilt University, Nashville, TN (A.R.H., J.H.N.); Cleveland Clinic, OH (G.J.B., M.A.A., J.B., S.A.A.C., S.C.E., B.H., J.K.L., M.A.O., W.H.W.T.); Wayne State University/John D. Dingell VAMC, Detroil, MI (A.A.); Columbia University, New York, NY (E.B.R., W.K.C.); Mayo Clinic, Rochester, MN (B.A.B., R.P.F.); Pulmonary Hypertension Association, Silver Spring, MD (M.P.G.); New York University Medical Center (G.G.); Johns Hopkins Hospital, Baltimore, MD (P.M.H., S.C.M.); Tufts Medical Center, Boston, MA (N.S.H.); Weill Cornell Medicine, New York, NY (E.M.H.); Brigham and Women's Hospital, Boston, MA (B.A.M., D.M.S., A.B.W., J.A.L.); The University of Arizona, Tucson (F.P.R., J.X.-J.Y.); and National Heart, Lung and Blood Institute, Bethesda, MD (L.X.).

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http://dx.doi.org/10.1161/CIRCRESAHA.117.311737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685561PMC
October 2017

Functional impact of exercise pulmonary hypertension in patients with borderline resting pulmonary arterial pressure.

Pulm Circ 2017 Jul-Sep;7(3):654-665. Epub 2017 Jun 8.

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Borderline resting mean pulmonary arterial pressure (mPAP) is associated with adverse outcomes and affects the exercise pulmonary vascular response. However, the pathophysiological mechanisms underlying exertional intolerance in borderline mPAP remain incompletely characterized. In the current study, we sought to evaluate the prevalence and functional impact of exercise pulmonary hypertension (ePH) across a spectrum of resting mPAP's in consecutive patients with contemporary resting right heart catheterization (RHC) and invasive cardiopulmonary exercise testing. Patients with resting mPAP <25 mmHg and pulmonary arterial wedge pressure ≤15 mmHg (n = 312) were stratified by mPAP < 13, 13-16, 17-20, and 21-24 mmHg. Those with ePH (n = 35) were compared with resting precapillary pulmonary hypertension (rPH; n = 16) and to those with normal hemodynamics (non-PH; n = 224). ePH prevalence was 6%, 8%, and 27% for resting mPAP 13-16, 17-20, and 21-24 mmHg, respectively. Within each of these resting mPAP epochs, ePH negatively impacted exercise capacity compared with non-PH (peak oxygen uptake 70 ± 16% versus 92 ± 19% predicted, P < 0.01; 72 ± 13% versus 86 ± 17% predicted, P < 0.05; and 64 ± 15% versus 82 ± 19% predicted, P < 0.001, respectively). Overall, ePH and rPH had similar functional limitation (peak oxygen uptake 67 ± 15% versus 68 ± 17% predicted, P > 0.05) and similar underlying mechanisms of exercise intolerance compared with non-PH (peak oxygen delivery 1868 ± 599 mL/min versus 1756 ± 720 mL/min versus 2482 ± 875 mL/min, respectively; P < 0.05), associated with chronotropic incompetence, increased right ventricular afterload and signs of right ventricular/pulmonary vascular uncoupling. In conclusion, ePH is most frequently found in borderline mPAP, reducing exercise capacity in a manner similar to rPH. When borderline mPAP is identified at RHC, evaluation of the pulmonary circulation under the stress of exercise is warranted.
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http://dx.doi.org/10.1177/2045893217709025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841910PMC
June 2017

Hemodynamic and metabolic characteristics associated with development of a right ventricular outflow tract pressure gradient during upright exercise.

PLoS One 2017 21;12(6):e0179053. Epub 2017 Jun 21.

Department of Cardiology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts, United States of America.

Background: We recently reported a novel observation that many patients with equal resting supine right ventricular(RV) and pulmonary artery(PA) systolic pressures develop an RV outflow tract(RVOT) pressure gradient during upright exercise. The current work details the characteristics of patients who develop such an RVOT gradient.

Methods: We studied 294 patients (59.7±15.5 years-old, 49% male) referred for clinical invasive cardiopulmonary exercise testing, who did not have a resting RVOT pressure gradient defined by the simultaneously measured peak-to-peak difference between RV and PA systolic pressures.

Results: The magnitude of RVOT gradient did not correspond to clinical or hemodynamic findings suggestive of right heart failure; rather, higher gradients were associated with favorable exercise findings. The presence of a high peak RVOT gradient (90th percentile, ≥33mmHg) was associated with male sex (70 vs. 46%, p = 0.01), younger age (43.6±17.7 vs. 61.8±13.9 years, p<0.001), lower peak right atrial pressure (5 [3-7] vs. 8 [4-12]mmHg, p<0.001), higher peak heart rate (159±19 vs. 124±26 beats per minute, p<0.001), and higher peak cardiac index (8.3±2.3 vs. 5.7±1.9 L/min/m2, p<0.001). These associations persisted when treating peak RVOT as a continuous variable and after age and sex adjustment. At peak exercise, patients with a high exercise RVOT gradient had both higher RV systolic pressure (78±11 vs. 66±17 mmHg, p<0.001) and lower PA systolic pressure (34±8 vs. 50±19 mmHg, p<0.001).

Conclusions: Development of a systolic RV-PA pressure gradient during upright exercise is not associated with an adverse hemodynamic exercise response and may represent a normal physiologic finding in aerobically fit young people.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179053PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479527PMC
October 2017

Invasive cardiopulmonary exercise testing in the evaluation of unexplained dyspnea: Insights from a multidisciplinary dyspnea center.

Eur J Prev Cardiol 2017 07 16;24(11):1190-1199. Epub 2017 May 16.

2 Pulmonary and Critical Care Medicine, Pulmonary Vascular Disease Program, Brigham and Women's Hospital, Boston, USA.

Background Unexplained dyspnea is a common diagnosis that often results in repeated diagnostic testing and even delayed treatments while a determination of the cause is being investigated. Through a retrospective study, we evaluated the diagnostic efficacy of a multidisciplinary dyspnea evaluation center (MDEC) using invasive cardiopulmonary exercise test to diagnose potential causes of unexplained dyspnea. Methods We reviewed the medical records of all patients referred with unexplained dyspnea to the MDEC between March 2011 and October 2014. We assessed the diagnostic efficacy before and after presentation to the MDEC. Results During the study period a total of 864 patients were referred to the MDEC and, of those, 530 patients underwent further investigation with invasive cardiopulmonary exercise test and constituted the study sample. The median age was 57 (44-68) years, 67.2% were women, and median body mass index was 26.22 (22.78-31.01). A diagnosis was made in 530 patients including: exercise pulmonary arterial hypertension of 88 (16.6%), heart failure with preserved ejection fraction of 94 (17.7%), dysautonomia 112 (21.1%), oxidative myopathy of 130 (24.5%), primary hyperventilation of 43 (8.1%), and other 58 (10.9%). The time from initial presentation to referral was significantly longer than time to diagnosis after referral for non-standardized conventional methods versus diagnosis through MDEC using invasive cardiopulmonary exercise test (511 days (292-1095 days) vs. 27 days (13-53 days), p < 0.0001). In a subgroup analysis, we reviewed that patients referred from cardiovascular clinics were more likely to have a greater number of diagnostic tests performed and, conversely, patients referred from pulmonary clinics were more likely to have a greater number of treatments prescribed before referral to MDEC. Conclusions As a result of this retrospective study, we have evaluated that a multidisciplinary approach that includes invasive cardiopulmonary exercise test dramatically reduces the time to diagnosis compared with traditional treatment and testing methods.
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http://dx.doi.org/10.1177/2047487317709605DOI Listing
July 2017

Accuracy of Echocardiography to Estimate Pulmonary Artery Pressures With Exercise: A Simultaneous Invasive-Noninvasive Comparison.

Circ Cardiovasc Imaging 2017 Apr;10(4)

From the Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands (A.C.M.J.v.R., B.J.M.M., B.J.B.); Netherlands Heart Institute, Utrecht (A.C.M.J.v.R., B.J.M.M.); Department of Cardiology, Boston Children's Hospital, and Harvard Medical School, MA (A.R.O., M.J.L.); Cardiovascular Medicine, Department of Medicine (A.R.O., J.M.R., A.D., M.J.L., A.M.S.) and Pulmonary and Critical Care Medicine, Department of Medicine, (A.B.W., D.M.S.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; and Department of Physiology and Cardiothoracic Surgery, Cardiovascular R&D Unit, Faculty of Medicine, University of Porto, Portugal (M.S.).

Background: Exercise echocardiography is often applied as a noninvasive strategy to screen for abnormal pulmonary hemodynamic response, but it is technically challenging, and limited data exist regarding its accuracy to estimate pulmonary arterial pressure during exercise.

Methods And Results: Among 65 patients with exertional intolerance undergoing upright invasive exercise testing, tricuspid regurgitation (TR) Doppler estimates and invasive measurement of pulmonary arterial pressure at rest and peak exercise were simultaneously obtained. TR Doppler envelopes were assessed for quality. Correlation, Bland-Altman, and receiver-operating characteristic curve analyses were performed to evaluate agreement and diagnostic accuracy. Mean age was 62±13 years, and 31% were male. High-quality (grade A) TR Doppler was present in 68% at rest and 34% at peak exercise. For grade A TR signals, echocardiographic measures of systolic pulmonary arterial pressure correlated reasonably well with invasive measurement at rest (=0.72, <0.001; bias, -2.9±8.0 mm Hg) and peak exercise (=0.75, <0.001; bias, -1.9±15.6 mm Hg). Lower quality TR signals (grade B and C) correlated poorly with invasive measurements overall. In patients with grade A TR signals, mean pulmonary arterial pressure-to-workload ratio at a threshold of 1.4 mm Hg/10 W was able to identify abnormal pulmonary hemodynamic response during exercise (>3.0 mm Hg/L per minute increase), with 91% sensitivity and 82% specificity (area under the curve, 0.90; 95% confidence interval, 0.77-1.0; =0.001).

Conclusions: Agreement between echocardiographic and invasive measures of pulmonary pressures during upright exercise is good among the subset of patients with high-quality TR Doppler signal. While the limits of agreement are broad, our results suggest that in those patients, sensitivity is adequate to screen for abnormal pulmonary hemodynamic response during exercise.
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http://dx.doi.org/10.1161/CIRCIMAGING.116.005711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408510PMC
April 2017

Left ventricular deformation at rest predicts exercise-induced elevation in pulmonary artery wedge pressure in patients with unexplained dyspnoea.

Eur J Heart Fail 2017 01 22;19(1):101-110. Epub 2016 Nov 22.

Division of Cardiovascular Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.

Aims: Impaired left ventricular (LV) deformation despite preserved LV ejection fraction (LVEF) is common and predicts outcomes in heart failure with preserved LVEF. We hypothesized that impaired LV deformation at rest is a marker of impaired cardiac systolic and diastolic reserve, and aimed to determine whether resting longitudinal (LS) and circumferential strain (CS) are associated with invasively measured haemodynamic response to exercise in patients with dyspnoea and a normal LVEF.

Methods And Results: We studied 85 patients with LVEF ≥50% and free of significant valvular disease who were referred for evaluation of dyspnoea. All patients underwent rest echocardiography followed by right heart catheterization and cardiopulmonary exercise testing with concomitant invasive haemodynamic monitoring. The LS, CS and CS/LS ratio were measured by two-dimensional speckle-tracking echocardiography at rest. Lower absolute LS at rest was associated with greater increase in pulmonary arterial wedge pressure (PAWP) from rest to peak exercise (r = 0.23, P = 0.034). In contrast, higher absolute CS at rest predicted a greater increase in PAWP (r = - 0.27, P = 0.032) and greater stroke volume augmentation with exercise (r = - 0.26, P = 0.021). Higher CS/LS ratio was most predictive of elevation in PAWP with exercise (r = 0.30, P = 0.015). Of the measures of LV systolic and diastolic function assessed, the CS/LS ratio resulted in the highest area under the curve and specificity for the presence of rest- or exercise-induced pulmonary venous hypertension.

Conclusion: Left ventricular deformation at rest predicts exercise-induced rise in PAWP among patients with dyspnoea and a preserved LVEF. A pattern of rest deformation characterized by worse LS and exaggerated CS is most strongly associated with exercise-induced rise in PAWP.
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http://dx.doi.org/10.1002/ejhf.659DOI Listing
January 2017
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