About
We investigate how cardiac metabolism is altered in heart failure, and use these discoveries to seek new therapeutic interventions.
Research topics
- Medicine
- Internal medicine
- Biology
- Chemistry
- Biochemistry
- Endocrinology
- Cell biology
- Artificial Intelligence
- Machine Learning
- Computer Science
- Bioinformatics
- Computational biology
- Biophysics
Selected publications
Society of Critical Care Medicine Guidelines on Caring for Older Adults in the ICU
Critical Care Medicine · 2026-03-20
articleRATIONALE: Older adults (those 65 years old or greater) compose a substantial proportion of the ICU population. As older adults with critical illness possess unique factors and considerations relevant to their care and outcomes, there is a need for evidence-based recommendations to guide critical care clinicians in the care of older ICU patients. OBJECTIVE: The objective of this guideline is to develop evidence-based recommendations addressing the care of older adults during and after critical illness. DESIGN: The American College of Critical Care Medicine Board convened a 22-member interprofessional panel, comprising physicians, advanced practice providers, nurses, a pharmacist, physical therapist, occupational therapist, and a patient representative. The panel included two expert methodologists specialized in developing evidence-based recommendations in alignment with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Conflict-of-interest policies were strictly followed during all phases of guideline development including task force selection and voting. METHODS: The panel members prioritized five Population, Intervention, Comparator, and Outcomes questions. A systematic review was conducted for each question to identify the best available evidence, synthesize the evidence and assess the certainty of evidence using GRADE. The evidence-to-decision framework was used to formulate recommendations. RESULTS: The panel generated two conditional recommendations and three "no recommendation" statements. The conditional recommendations are: 1) We suggest a geriatric model of care for all older adults admitted to the ICU and 2) We suggest not using antipsychotic medications for the prevention of delirium in older adults with critical illness. The three "no recommendation" statements are: 1) We make no recommendation regarding specialized post-ICU follow-up for older survivors of critical illness, 2) For older adults (age 65 and over) admitted to the ICU with vasodilatory shock, we make no recommendation with regard to targeting a mean arterial pressure (MAP) of 60-65 mm Hg as compared with usual care (MAP target > 65 mm Hg), and 3) We make no recommendation regarding the use of antipsychotic medication in the treatment of delirium in older adults with critical illness. CONCLUSIONS: The guideline panel developed recommendations on caring for older adults during and after critical illness. Areas for future research were also identified during the guideline process.
bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-16
articleOpen accessSenior authorCorrespondingABSTRACT Metabolic-associated steatohepatitis (MASH) involves hepatocyte damage that cannot be explained solely by lipid accumulation. Here, to discover injury-specific pathways, we focused on a gene of uncertain function, EF-Hand Domain Family Member D1 (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We show that EFHD1, a Ca 2+ -dependent actin crosslinker, stabilizes endoplasmic reticulum–mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar proximity and ER Ca 2+ release. During MASH, EFHD1 upregulation drives pathological mitochondrial fragmentation via excessive contact persistence. This structural failure promotes mitochondrial double-stranded RNA escape and activation of a maladaptive antiviral PKR-dependent stress response, a causal relationship also supported by Mendelian randomization in humans. Consequently, inhibiting EFHD1 in human and mouse models blunts hepatocyte damage. These findings identify EFHD1 as a Ca 2+ -dependent ERMCS stabilizer, reveal a hepatocyte-intrinsic injury pathway, and suggest EFHD1 inhibition as a therapeutic strategy.
Critical Care Medicine · 2026-01-02
article1st authorCorrespondingOBJECTIVE: The Pa o2 /F io2 (PF) ratio is widely used as an assessment of respiratory failure in guiding ventilation strategies and prognostication in critically ill patients. However, given that it mandates invasive arterial access, the Sp o2 /F io2 (SF) ratio has been suggested as a noninvasive and readily accessible alternative. What are the best ways to convert SF and PF ratios in critically ill patients, in terms of their diagnostic/prognostic accuracy and clinical utility? DATA SOURCES: We comprehensively searched databases (MEDLINE, Embase, Web of Science, Cochrane library) to identify relevant studies. STUDY SELECTION: Any observational studies that compared the SF to PF ratio in critically ill patients. We assessed individual study risk of bias (ROB) using the revised QUADAS II tool. DATA EXTRACTION: We included 45 observational studies, ranging from 61 to 141,000 measurements. DATA SYNTHESIS: SF to PF imputation was less accurate when the Sp o2 was equal to or greater than 97%. Otherwise, all studies were able to establish strong correlational relationships between SF and PF ratios, but there was no clear best equation. Based on ease of use, size, generalizability and methodology, we were able to prioritize four equations (one linear, one logarithmic linear, and two nonlinear). All four equations showed strong correlation between SF and PF ratios, with the linear equation being easiest to apply. The SF ratio also correlated well with clinical outcomes when compared with the PF ratio, both as an individual value and as part of a comprehensive score, with more discriminating performance in some cases. CONCLUSIONS: SF and PF ratios demonstrate good correlation, and may have similar prognostic value. Although there is no clear optimal method to convert SF to PF ratios, linear equations show acceptable correlation and are most easily applied at the bedside.
Critical Care Medicine · 2026-03-20
articleFor the past 25 years, older adults, defined as those 65 years old or older, have composed more than half of all ICU days in the United States (1). With the number of older Americans projected to increase from 58 million in 2022 to 82 million by 2050, the proportion of ICU patients who are older is expected to rise (2–4). Caring for older patients in critical care settings requires knowledge of their unique factors and considerations, such as geriatric syndromes and outcomes that matter most to this growing demographic (5). The Board of the American College of Critical Care Medicine convened a multidisciplinary panel to develop focused, evidence-based recommendations on caring for older adults in the ICU. The panel conducted a systematic review of the published scientific literature, focusing on patient-oriented, clinically relevant outcomes to answer Patient, Intervention, Comparator, and Outcomes (PICO) questions regarding the care of older adults in the ICU. The clinical practice recommendations were developed according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) process (3). This clinical practice guidelines reflect the state of knowledge at the time of publication. The full guidelines may be accessed via (6). RECOMMENDATIONS The panel made two conditional recommendations as presented below. A “Conditional” recommendation reflects a low degree of certainty in the appropriateness of the patient care strategy for all patients. It requires that the clinician use clinical knowledge and expertise and strongly considers the individual patient’s values and preferences to determine the best course of action. The ultimate judgment regarding any specific care must be made by the treating clinician and the patient, taking into consideration the individual circumstances of the patient, available treatment options, and resources. The remaining three PICO questions addressed in these guidelines resulted in no recommendation being made due to inconsistent or insufficient evidence. Future research is needed on several topic areas covered by this guideline. A summary of research priorities for each topic is presented in Table 3 of the full guidelines (6). We suggest a geriatric model of care for all older adults admitted to the ICU (conditional recommendation, very low certainty of evidence). Remarks: The parameters in geriatric models of care may vary depending on hospital, resources, and expertise available. The included studies intentionally incorporated geriatric principles into the care of older adults (e.g., removal of unnecessary tethering devices, addressing hearing impairment, improving functional and cognitive outcomes through occupational therapy). A systematic literature search was completed, and three studies investigating a geriatric-specific model of care or formal geriatrics consultation were included in discussion with the panel (7–9). The GRADE evidence synthesis showed very low certainty across all evaluated outcomes due to risk of bias, imprecision, and indirectness. In one randomized controlled trial (RCT), mortality and hospital length of stay showed an uncertain effect (7). In another RCT, activities of daily living outcomes showed an uncertain effect (8). Pooled analysis from these two RCTs showed an uncertain effect on in-hospital delirium and discharge to a nursing home. The final included study, a pre-/post-intervention pilot trial, suggested that a three-component ICU intervention reduced incident delirium (9). Despite uncertain effects in the evidence, the panel determined the desirable effects of a geriatric model of care are small to moderate, especially in considering that many of the point estimates fall on the side of benefit and align with outcomes that matter most to older adults. Undesirable effects were determined trivial by the panel, highlighting the perceived lack of harms in a geriatric model of care. There was no evidence to address cost effectiveness of the interventions. With regard to equity, the panel acknowledged that geriatricians may not be widely available in critical care settings. However, the panel noted that geriatric models of care can be implemented without a geriatrician and that implementation of age-friendly principles would improve equitable care for older adults with critical illness. We suggest not using antipsychotic medications for the prevention of delirium in critically ill older adult patients (conditional recommendation, very low certainty evidence). Remarks: The antipsychotic drugs used in the included studies were haloperidol and quetiapine. A systematic literature search was completed, and three RCTs investigating the prevention of delirium in adults with critical illness (but not exclusively over the age of 65) were included (10–12). The GRADE evidence synthesis showed very low certainty across all evaluated outcomes due to indirectness, risk of bias, inconsistency, and imprecision. Pooled analysis of the three RCTs showed an uncertain effect on the incidence and duration of delirium. Likewise, pooled effects of mortality, duration of invasive mechanical ventilation, ICU length of stay, hospital length of stay, and adverse events showed uncertain effects. The panel was limited in its ability to make conclusions for older adults based on this evidence, particularly in light of the trials not being conducted exclusively in this population. The panel expressed concern about the potential harms of routine antipsychotic use in older patients with critical illness, acknowledging that antipsychotics are included in high-risk medication lists for older adults and have been clearly associated with adverse events in other studies of older adults (13–15). There was no evidence to address cost effectiveness of the interventions, and the panel expressed concern about the role of social determinants of health, race, ethnicity, and language in detecting delirium in older adults. RESEARCH AGENDA We developed a research agenda for the care of older adults in the ICU, presented in Table 3 of the main guidelines document (6). In addition to the research agenda outlined in each area, the panel acknowledged the dearth of critical care trials that exclusively enroll older persons. The panel also noted that many critical care trials enrolling the general ICU population often have age cutoffs for upper limit that are not justified scientifically. With the aging of the population, it is imperative that the critical care research community designs clinical trials that exclusively enroll older adults and prioritizes improved inclusion of older adults in critical care clinical trials in the general ICU population.
Circulation Research · 2025-08-01
articleSenior authorMitochondria use the proton motive force created by the activity of the electron transport chain to produce ATP. Thus, ionic movement across the inner membrane is restricted and strictly controlled to avoid dissipating the mitochondrial membrane potential. Unlike electroneutral mitochondrial transporters, electrogenic transporters are scarce and few such transporters or ion channels have been identified. Here, we report the presence of a new mitochondrial current. While recording inner-membrane currents in mitoplasts (mitochondria devoid of the outer membrane) in MCU knockout ( Mcu -/- ) hearts, we observed an outward rectifying cationic current activated with voltage-ramps under symmetric divalent-free pipette and bath solutions. We saw this current in mitochondria from various organs including liver, brain, spleen, and the heart, and in cultured cell lines (HEK293T and Hap1). This ubiquitous current, named here LUNA (Large, Ubiquitous, Non-selective, Amiloride-sensitive channel), is a non-selective cation current (K + > Na + > Ca 2+ ≈ Mg 2+ ≈ NMDG + ) active at depolarized membrane potentials (≥0 mV), a condition that normally leads to the activation of proapoptotic mechanisms. We observed that the basal activity of LUNA currents in wild type mice hearts augmented upon chelation of external Ca 2+ and Mg 2+ . Moreover, the activity of LUNA was enhanced approximately three-fold in both the cardiac-specific knockout of the nuclear-encoded mitochondrial transcription factor Tfam (Tfam cKO) , a model for mitochondrial cardiomyopathies, and in mice with cardiac pressure overload due to transverse aortic constriction compared to the respective controls. Importantly, we were able to observe LUNA current in human end-stage heart failure patients (HFrEF), with near nanoampere amplitudes, making LUNA the largest-ever current directly recorded from mitochondria. Taken together, our results indicate that LUNA is expressed in mammals, and that LUNA amplitude increases during a variety of forms of human or murine cardiac injury.
Mechanism of MCUB‐Dependent Inhibition of Mitochondrial Calcium Uptake
Journal of Cellular Physiology · 2025-04-01 · 1 citations
articleOpen accessSenior authorCorrespondingABSTRACT Mitochondrial Ca 2+ levels are regulated to balance stimulating respiration against the harm of Ca 2+ overload. Contributing to this balance, the main channel transporting Ca 2+ into the matrix, the mitochondrial Ca 2+ uniporter, can incorporate a dominant‐negative subunit (MCUB). MCUB is homologous to the pore‐forming subunit MCU, but when present in the pore‐lining tetramer, inhibits Ca 2+ transport. Here, using cell lines deleted of both MCU and MCUB, we identify three factors that contribute to MCUB‐dependent inhibition. First, MCUB protein requires MCU to express. The effect is mediated via the N‐terminal domain (NTD) of MCUB. Replacement of the MCUB NTD with the MCU NTD recovers autonomous expression but fails to rescue Ca 2+ uptake. Surprisingly, mutations to MCUB that affect interactions with accessory subunits or the conduction pore all failed to rescue Ca 2+ uptake, suggesting the mechanism of inhibition may involve more global domain rearrangements. Second, using concatemeric tetramers with varying MCU:MCUB ratios, we find that MCUB incorporation does not abolish conduction, but rather inhibits Ca 2+ influx proportional to the amount of MCUB present in the channel. Reducing rather than abolishing Ca 2+ transport is consistent with MCUB retaining the highly‐conserved selectivity filter DIME sequence. Finally, we apply live‐cell Förster resonance energy transfer to establish that the endogenous stoichiometry is 2:2 MCU:MCUB. Taken together, our results suggest MCUB preferentially incorporates into nascent uniporters, and the amount of MCUB protein present linearly correlates with the degree of inhibition of Ca 2+ transport, creating a precise, tunable mechanism for cells to regulate mitochondrial Ca 2+ uptake.
Transient Receptor Potential channels (TRP) in GtoPdb v.2025.1
IUPHAR/BPS Guide to Pharmacology CITE · 2025-04-01 · 2 citations
articleOpen accessThe TRP superfamily of channels (nomenclature as agreed by NC-IUPHAR [177, 1080]), whose founder member is the Drosophila Trp channel, exists in mammals as six families; TRPC, TRPM, TRPV, TRPA, TRPP and TRPML based on amino acid homologies. TRP subunits contain six putative TM domains and assemble as homo- or hetero-tetramers to form cation selective channels with diverse modes of activation and varied permeation properties (reviewed by [734]). Established, or potential, physiological functions of the individual members of the TRP families are discussed in detail in the recommended reviews and in a number of books [404, 690, 1163, 258]. The established, or potential, involvement of TRP channels in disease [1134] is reviewed in [452, 689], [692] and [468], together with a special edition of Biochemica et Biophysica Acta on the subject [689]. Additional disease related reviews, for pain [637], stroke [1143], sensation and inflammation [994], itch [130], and airway disease [313, 1058], are available. The pharmacology of most TRP channels has been advanced in recent years. Broad spectrum agents are listed in the tables along with more selective, or recently recognised, ligands that are flagged by the inclusion of a primary reference. See Rubaiy (2019) for a review of pharmacological tools for TRPC1/C4/C5 channels [810]. Most TRP channels are regulated by phosphoinostides such as PtIns(4,5)P2 although the effects reported are often complex, occasionally contradictory, and likely to be dependent upon experimental conditions, such as intracellular ATP levels (reviewed by [1015, 693, 806]). Such regulation is generally not included in the tables.When thermosensitivity is mentioned, it refers specifically to a high Q10 of gating, often in the range of 10-30, but does not necessarily imply that the channel's function is to act as a 'hot' or 'cold' sensor. In general, the search for TRP activators has led to many claims for temperature sensing, mechanosensation, and lipid sensing. All proteins are of course sensitive to energies of binding, mechanical force, and temperature, but the issue is whether the proposed input is within a physiologically relevant range resulting in a response. TRPA (ankyrin) familyTRPA1 is the sole mammalian member of this group (reviewed by [295]). TRPA1 activation of sensory neurons contribute to nociception [417, 895, 606]. Pungent chemicals such as mustard oil (AITC), allicin, and cinnamaldehyde activate TRPA1 by modification of free thiol groups of cysteine side chains, especially those located in its amino terminus [579, 60, 368, 581]. Alkenals with α, β-unsaturated bonds, such as propenal (acrolein), butenal (crotylaldehyde), and 2-pentenal can react with free thiols via Michael addition and can activate TRPA1. However, potency appears to weaken as carbon chain length increases [26, 60]. Covalent modification leads to sustained activation of TRPA1. Chemicals including carvacrol, menthol, and local anesthetics reversibly activate TRPA1 by non-covalent binding [428, 515, 1089, 1088]. TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures [429, 213]. The electron cryo-EM structure of TRPA1 [745] indicates that it is a 6-TM homotetramer. Each subunit of the channel contains two short ‘pore helices’ pointing into the ion selectivity filter, which is big enough to allow permeation of partially hydrated Ca2+ ions. TRPC (canonical) familyMembers of the TRPC subfamily (reviewed by [286, 783, 18, 4, 94, 450, 744, 70]) fall into the subgroups outlined below. TRPC2 is a pseudogene in humans. It is generally accepted that all TRPC channels are activated downstream of Gq/11-coupled receptors, or receptor tyrosine kinases (reviewed by [770, 959, 1080]). A comprehensive listing of G-protein coupled receptors that activate TRPC channels is given in [4]. Hetero-oligomeric complexes of TRPC channels and their association with proteins to form signalling complexes are detailed in [18] and [451]. TRPC channels have frequently been proposed to act as store-operated channels (SOCs) (or compenents of mulimeric complexes that form SOCs), activated by depletion of intracellular calcium stores (reviewed by [746, 18, 775, 825, 1129, 157, 730, 64, 158]). However, the weight of the evidence is that they are not directly gated by conventional store-operated mechanisms, as established for Stim-gated Orai channels. TRPC channels are not mechanically gated in physiologically relevant ranges of force. All members of the TRPC family are blocked by 2-APB and SKF96365 [350, 349]. Activation of TRPC channels by lipids is discussed by [70]. Important progress has been recently made in TRPC pharmacology [810, 623, 440, 102, 856, 192, 293]. TRPC channels regulate a variety of physiological functions and are implicated in many human diseases [298, 71, 890, 1038, 1032, 154, 103, 565, 918, 412]. TRPC1/C4/C5 subgroup TRPC1 alone may not form a functional ion channel [230]. The structures of the apo and antagonist-bound states of TRPC1/TRPC4 heteromeric channels have been resolved by cryo-EM [1070]. TRPC4/C5 may be distinguished from other TRP channels by their potentiation by micromolar concentrations of La3+. TRPC2 is a pseudogene in humans, but in other mammals appears to be an ion channel localized to microvilli of the vomeronasal organ. It is required for normal sexual behavior in response to pheromones in mice. It may also function in the main olfactory epithelia in mice [1122, 727, 728, 1123, 543, 1176, 1117].TRPC3/C6/C7 subgroup All members are activated by diacylglycerol independent of protein kinase C stimulation [350].TRPM (melastatin) familyMembers of the TRPM subfamily (reviewed by [277, 349, 746, 1159]) fall into the five subgroups outlined below. TRPM1/M3 subgroupIn darkness, glutamate released by the photoreceptors and ON-bipolar cells binds to the metabotropic glutamate receptor 6 , leading to activation of Go . This results in the closure of TRPM1. When the photoreceptors are stimulated by light, glutamate release is reduced, and TRPM1 channels are more active, resulting in cell membrane depolarization. Human TRPM1 mutations are associated with congenital stationary night blindness (CSNB), whose patients lack rod function. TRPM1 is also found melanocytes. Isoforms of TRPM1 may present in melanocytes, melanoma, brain, and retina. In melanoma cells, TRPM1 is prevalent in highly dynamic intracellular vesicular structures [401, 712]. TRPM3 (reviewed by [718]) exists as multiple splice variants which differ significantly in their biophysical properties. TRPM3 is expressed in somatosensory neurons and may be important in development of heat hyperalgesia during inflammation (see review [947]). TRPM3 is frequently coexpressed with TRPA1 and TRPV1 in these neurons. TRPM3 is expressed in pancreatic beta cells as well as brain, pituitary gland, eye, kidney, and adipose tissue [717, 946]. TRPM3 may contribute to the detection of noxious heat [1024]. TRPM2TRPM2 is activated under conditions of oxidative stress (respiratory burst of phagocytic cells). The direct activators are calcium, adenosine diphosphate ribose (ADPR) [976] and cyclic ADPR (cADPR) [1126]. As for many ion channels, PI(4,5)P2 must also be present [1117]. Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [240]. Recent studies have reported structures of human (hs) TRPM2, which demonstrate two ADPR binding sites in hsTRPM2, one in the N-terminal MHR1/2 domain and the other in the C-terminal NUDT9-H domain. In addition, one Ca2+ binding site in the intracellular S2-S3 loop is revealed and proposed to mediate Ca2+ binding that induces conformational changes leading the ADPR-bound closed channel to open [390, 1034]. Meanwhile, a quadruple-residue motif (979FGQI982) was identified as the ion selectivity filter and a gate to control ion permeation in hsTRPM2 [1128]. TRPM2 is involved in warmth sensation [853], and contributes to several diseases [76]. TRPM2 interacts with extra synaptic NMDA receptors (NMDAR) and enhances NMDAR activity in ischemic stroke [1172]. Activation of TRPM2 in macrophages promotes atherosclerosis [1173, 1155]. Moreover, silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction [1035]. Recent studies have designed various compounds for their potential to selectively inhibit the TRPM2 channel, including ACA derivatives A23, and 2,3-dihydroquinazolin-4(1H)-one derivatives [1145, 1147]. TRPM4/5 subgroupTRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to Ca2+ [1080]. A splice variant of TRPM4 (i.e.TRPM4b) and TRPM5 are molecular candidates for endogenous calcium-activated cation (CAN) channels [330]. TRPM4 is active in the late phase of repolarization of the cardiac ventricular action potential. TRPM4 deletion or knockout enhances beta adrenergic-mediated inotropy [597]. Mutations are associated with conduction defects [407, 597, 884]. TRPM4 has been shown to be an important regulator of Ca2+ entry in to mast cells [999] and dendritic cell migration [52]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [541] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [517]. Both TRPM4 and TRPM5 are required transduction of taste stimuli [247]. TRPM6/7 subgroupTRPM6 and 7 combine channel and enzymatic activities (‘chanzymes’) [173]. These channels have the unusual property of permeation by divalent (Ca2+, Mg2+, Zn2+) and monovalent cations, high single channel conductances, but overall extremely small inward conductance when expressed to the plasma membrane. They are inhibited by internal Mg2+ at ~0.6 mM, around the free level of Mg2+ in cells. Whether they contribute to Mg2+ homeostasis is a contentious is
Matrix Polyamines Facilitate Influx and Prevent Efflux of Calcium Through MCU
SSRN Electronic Journal · 2025-01-01
preprintOpen accessCell Reports Medicine · 2025-05-07 · 5 citations
articleOpen accessFibroblast growth factor (FGF) 21 is a hormone produced mainly by the liver but also other organs, including the heart. Although FGF21 analogs are used for treating obesity and metabolic syndrome in humans, preclinical and clinical studies have elicited mixed results about whether prolonged FGF21 signaling is protective or detrimental for cardiac function. Based on our findings, showing elevated serum and cardiac FGF21 levels in humans with increased left ventricular afterload, we explore the involvement of FGF21 in cardiac hypertrophy. Our mouse studies reveal interorgan liver-heart crosstalk, which is controlled by an initial hepatic FGF21 release followed by the induction of cardiomyocyte (CM) FGF21 expression. Tissue-specific genetic ablation or anti-sense oligonucleotide-based inhibition of FGF21 shows that, in response to pressure overload, CM FGF21 upregulation is a critical event that is stimulated by liver-derived FGF21 and drives cardiac hypertrophy likely by interfering with cardioprotective oxytocin signaling. Conclusively, the hepato-cardiac FGF21-based signaling axis governs cardiac hypertrophy.
SPIROMICS HF: Rationale, Design, and Reproducibility of Measures
Circulation Heart Failure · 2025-11-05
articleOpen accessBACKGROUND: Although chronic obstructive pulmonary disease (COPD) and heart failure with preserved ejection fraction often coexist with overlapping clinical features, they are usually studied separately. The SPIROMICS HF (Subpopulations and Intermediate Outcome Measures in COPD and Heart Failure Study) is testing hypotheses that new computed tomography emphysema subtypes are associated with specific cardiovascular phenotypes (eg, cor pulmonale , cor pulmonale parvus ), common airway branch variants are associated with right heart dysfunction, and symptomatic tobacco-exposed persons with preserved spirometry have signs of increased left ventricular afterload. METHODS: SPIROMICS is a multicenter observational study of COPD with extensive pulmonary phenotyping of participants with ≥20 pack-years smoking and nonsmoking controls. COPD and COPD severity were defined by standard spirometric criteria and symptomatic tobacco-exposed persons with preserved spirometry by ≥20 pack-years, normal spirometry, and COPD Assessment Test score >10. SPIROMICS HF selected all participants in SPIROMICS visit 5 at major sites. Its comprehensive speckle-tracking echocardiography, which included physiological perturbations of leg raise and low-intensity exercise, was harmonized prospectively with the Multi-Ethnic Study of Atherosclerosis Early Heart Failure and HeartSHARE (Combining Omics, Deep Phenotyping, and Electronic Health Records for Heart Failure Subtypes and Treatment Targets) studies. The cardiopulmonary magnetic resonance imaging protocol with gadolinium administration included myocardial fibrosis sequences, pulmonary angiography, time-resolved 3-dimensional cine magnetic resonance imaging (4-dimensional flow) of venous return, and metronome-paced tachypnea to induce dynamic hyperinflation. Coronary artery calcium was assessed on computed tomography scans. The Kansas City Cardiomyopathy Questionnaire was administered. RESULTS: Of the final sample of 753 participants, 57% had COPD (15% mild, 27% moderate, and 15% severe), 18% had symptomatic tobacco-exposed persons with preserved spirometry, 16% were smoking controls, and 8% were nonsmoking controls. Reproducibility of the main measures from speckle-tracking echocardiography (intraclass correlation coefficient, 0.83–0.99), exercise echocardiography (intraclass correlation coefficient, 0.71–0.99) and magnetic resonance imaging (intraclass correlation coefficient, 0.57–0.99) were good-to-excellent, including in severe COPD. CONCLUSIONS: SPIROMICS HF aims to characterize and understand cardiopulmonary interactions in COPD and COPD-related phenotypes to inform targeted treatments for combined cardiopulmonary failure.
Recent grants
NIH · $137k · 2013
Regulation of the mitochondrial calcium uniporter
NIH · $2.0M · 2022–2027
NIH · $4.3M · 2018–2027
Structural basis for mitochondrial calcium uniporter function
NIH · $292k · 2014–2016
Structural basis for mitochondrial calcium uniporter function
NIH · $747k · 2014–2019
Frequent coauthors
- 89 shared
David E. Clapham
Howard Hughes Medical Institute
- 81 shared
Eilish McConville
Ottawa Hospital Research Institute
- 81 shared
Annelies Boonen
Maastricht University
- 81 shared
Peter Tugwell
Ottawa Hospital
- 81 shared
Peter F. Cronholm
University of Pennsylvania
- 81 shared
Joanna Robson
University Hospitals Bristol and Weston NHS Foundation Trust
- 81 shared
Susan P. Ashdown
- 81 shared
Peter A. Merkel
Labs
- Resume-aware match score
- Save to shortlist
- AI-drafted outreach
See your match with Dipayan Chaudhuri
PhdFit ranks faculty by your research interests, methods, and publications — grounded in their actual work, not templates.
- Free to start
- No credit card
- 30-second signup