Search

Noninvasive left ventricular (LV) pressure estimation in obese patients has not been well described. Simultaneous B-type natriuretic peptide (BNP) and echocardiographic Doppler examinations were performed in patients with dyspnea undergoing cardiac catheterization. Patients were divided into body mass index (BMI) >35 (markedly obese), 31 to 35 (obese), and < or =30 kg/m2 (nonobese). BNP levels and mitral early diastolic/tissue Doppler annular velocity (E/Ea) were compared with invasively measured LV end-diastolic and pre-atrial (pre-A) pressures. Seventy-two patients were studied. Except for BMI, LV mass index, and LV diastolic dimension, there were no significant differences in baseline, echocardiographic Doppler, or hemodynamic characteristics among the groups. However, BNP was significantly lower in markedly obese compared with obese and nonobese patients (116 +/- 187 vs 241 +/- 674 and 277 +/- 352 pg/ml, respectively; p = 0.03). BNP did not correlate with LV pre-A pressure in markedly obese patients (R = 0.13, p = 0.47), whereas BNP significantly correlated with this variable in the obese (R = 0.64) and nonobese (R = 0.58) groups. Mitral E/Ea significantly correlated with LV pre-A and LV end-diastolic pressures in all BMI groups. In markedly obese patients with dyspnea, BNP did not correlate with invasively measured LV filling pressure, whereas this correlated in obese and nonobese patients. However, mitral E/Ea significantly correlated with LV filling pressures in all BMI groups. In conclusion, BNP is not recommended for LV filling pressure estimation in ambulatory patients with dyspnea with BMI >35 kg/m2. [ABSTRACT FROM AUTHOR]

Background: There are no randomized data to inform the extent to which transvenous cardiac leads cause tricuspid regurgitation (TR)., Objectives: This study sought to determine the effect of a transvenous implantable cardioverter-defibrillator (TV-ICD) on TR severity, and secondarily, on right ventricular (RV) size and function., Methods: We evaluated TR severity before and 6 months after implantable cardioverter-defibrillator insertion in a post hoc analysis of adults randomized to receive a transvenous (n = 252) or subcutaneous implantable cardioverter-defibrillator (S-ICD) (n = 251) device. TR and RV size and systolic function were assessed by echocardiographic images analyzed in a core laboratory., Results: At baseline, at least mild TR was present in 30% of individuals. At 6 months, the proportion of participants with any TR in the TV-ICD group was 42% vs 19% in the S-ICD group (P < 0.001). The proportion with moderate or severe TR was 7% in the TV-ICD group vs 2% in the S-ICD group (P = 0.021). At 6 months, the OR of at least 1 grade worsening of TR in the TV-ICD group as compared with the S-ICD group was 7.2 (95% CI: 3.3-15.8; P < 0.001). There were no differences between groups with respect to RV size or systolic function., Conclusions: Six months following TV-ICD insertion, there was a 7-fold increase in the risk of at least 1 grade worsening of TR, with 7% of individuals having TR that was moderate or severe. There was no detectable difference in RV size or function; however, longer follow-up is needed., Competing Interests: Funding Support and Author Disclosures This study was funded by Boston Scientific through an unrestricted research grant. Boston Scientific did not have any input into the preparation of this manuscript. Dr Leong has received consultancy fees from Boston Scientific. Dr Mondésert has received consultancy and speaking fees from Bostin Scientific, Abbott, Medtronic, and Biotronik. Dr Joza has received research support from Medtronic Inc; consulting fees from Boston Scientific; and honoraria from Biosense Webster Canada. Dr Healey has received research support and speaking fees from BMS/Pfizer, Boston Scientific, and Medtronic; speaking fees from Servier; and consultancy fees from Bayer and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Most epidemiological studies of heart failure (HF) have been conducted in high-income countries with limited comparable data from middle- or low-income countries., Objective: To examine differences in HF etiology, treatment, and outcomes between groups of countries at different levels of economic development., Design, Setting, and Participants: Multinational HF registry of 23 341 participants in 40 high-income, upper-middle-income, lower-middle-income, and low-income countries, followed up for a median period of 2.0 years., Main Outcomes and Measures: HF cause, HF medication use, hospitalization, and death., Results: Mean (SD) age of participants was 63.1 (14.9) years, and 9119 (39.1%) were female. The most common cause of HF was ischemic heart disease (38.1%) followed by hypertension (20.2%). The proportion of participants with HF with reduced ejection fraction taking the combination of a β-blocker, renin-angiotensin system inhibitor, and mineralocorticoid receptor antagonist was highest in upper-middle-income (61.9%) and high-income countries (51.1%), and it was lowest in low-income (45.7%) and lower-middle-income countries (39.5%) (P < .001). The age- and sex- standardized mortality rate per 100 person-years was lowest in high-income countries (7.8 [95% CI, 7.5-8.2]), 9.3 (95% CI, 8.8-9.9) in upper-middle-income countries, 15.7 (95% CI, 15.0-16.4) in lower-middle-income countries, and it was highest in low-income countries (19.1 [95% CI, 17.6-20.7]). Hospitalization rates were more frequent than death rates in high-income countries (ratio = 3.8) and in upper-middle-income countries (ratio = 2.4), similar in lower-middle-income countries (ratio = 1.1), and less frequent in low-income countries (ratio = 0.6). The 30-day case-fatality rate after first hospital admission was lowest in high-income countries (6.7%), followed by upper-middle-income countries (9.7%), then lower-middle-income countries (21.1%), and highest in low-income countries (31.6%). The proportional risk of death within 30 days of a first hospital admission was 3- to 5-fold higher in lower-middle-income countries and low-income countries compared with high-income countries after adjusting for patient characteristics and use of long-term HF therapies., Conclusions and Relevance: This study of HF patients from 40 different countries and derived from 4 different economic levels demonstrated differences in HF etiologies, management, and outcomes. These data may be useful in planning approaches to improve HF prevention and treatment globally.

Background: Influenza increases the risk of cardiovascular events and deaths. We aimed to see whether influenza vaccination reduces death and vascular events in patients with heart failure., Methods: We did a pragmatic, randomised, double-blind, placebo-controlled trial in 30 centres (mostly hospitals affliated with universities or a research institute) in ten countries in Asia, the Middle East, and Africa (7 in India, 4 in Philippines, 4 in Nigeria, 6 in China, 1 in Zambia, 2 in Mozambique, 3 in Saudi Arabia, 1 in Kenya, 1 in Uganda, and 1 in Zambia). Participants (aged ≥18 years; 52·1% female; not disaggregated by race or ethnicity) with heart failure (New York Heart Association class II, III, or IV) were randomly assigned (1:1) by a centralised web-based system with block randomisation stratified by site, to receive 0·5 ml intramuscularly once a year for up to 3 years of either inactivated standard dose influenza vaccine or placebo (saline). We excluded people who had received influenza vaccine in 2 of the previous 3 years, and those likely to require valve repair or replacement. Those who administered assigned treatments were not masked and had no further role in the study. Investigators, study coordinators, outcome adjudicators, and participants were masked to group assignment. The first of two co-primary outcomes was a first-event composite for cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, and the second was a recurrent-events composite for cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalisation for heart failure. Outcomes were assessed every 6 months in the intention-to-treat population. Secondary outcomes were all-cause death, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, all-cause hospitalisation, hospitalisation for heart failure, and pneumonia, both overall and during periods of peak influenza exposure. This study is registered with ClinicalTrials.gov, NCT02762851., Findings: Between June 2, 2015, and Nov 21, 2021, we enrolled 5129 participants and randomly assigned (1:1) 2560 (50·0%) to influenza vaccine and 2569 (50·0%) to placebo. The first co-primary outcome occurred in 380 (14·8%) of 2560 participants in the vaccine group and 410 (16·0%) of 2569 participants in the placebo group (hazard ratio [HR] 0·93 [95% CI 0·81-1·07]; p=0·30). The second co-primary outcome occurred in 754 (29·5%) of 2560 participants in the vaccine group and 819 (31·9%) of 2569 participants in the placebo group; HR 0·92 [95% CI 0·84-1·02]; p=0·12). The secondary outcomes of all-cause hospitalisations (HR 0·84 [95% CI 0·74-0·97]; p=0·013) and pneumonia (HR 0·58 [0·42-0·80]; p=0·0006) were significantly reduced in the vaccine group compared with in the placebo group but there was no significant difference between groups for all-cause death, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalisation for heart failure. In a prespecified analysis, in which events were limited to periods of peak influenza circulation, the first co-primary outcome, and the secondary outcomes of all-cause death, cardiovasular death, and pneumonia were significantly lower in the vaccinated group than in the placebo group, whereas the second co-primary outcome and the secondary outcomes of non-fatal myocardial infarction, non-fatal stroke, all-cause hospitalisation, and hospitalisation for heart failure were not significantly lower., Interpretation: Although the prespecified co-primary outcomes during the entire period of observation were not statistically significant, the reduction during the peak influenza circulating period suggests that there is likely to be a clinical benefit of giving influenza vaccine, given the clear reduction in pneumonia, a moderate reduction in hospitalisations, and a reduction in cardiovascular events and deaths during periods of peak circulation of influenza. Taken in conjunction with previous trials and the observational studies, the collective data suggest benefit., Funding: UK Joint Global Health Trials Scheme and Canadian Institutes for Health Research Foundation., Competing Interests: Declaration of interests ML reports grants from the Joint Global Health Trials Scheme of the UK Dept for International Development, UK Medical Research Council (MRC), UK National Institute for Health Research, and the Wellcome Trust) and the Canadian Institutes of Health Research (CIHR); in-kind support from Sanofi Pasteur during the conduct of the study; paid participation on advisory boards for Sanofi Pasteur, Medicago, GlaxoSmithKline, Pfizer, Merck, and Seqirus and on the data safety monitoring board for CanSino Biologics. LMP-V reports grant support from the Wellcome Trust. JZ and YL report grant payments from the Population Health Research Institute to their institution, payment from Bayer, Boehringer Ingelheim, and Novartis for presentations, and travel support from Bayer to attend the European Society of Cardiology 2019 Congress. TM reports grants from CIHR and the Joint Global Health Scheme paid to McMaster University and Hamilton Health Sciences for the conduct of the study. AR, HD, AnD, KK, FG, AlD, KFA, GY, CM, WA, AAM, VT, PR-M, AG, SIB, and SY declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: A wide knowledge gap exists on the clinical profiles and outcomes of heart failure (HF) in sub-Saharan Africa., Objectives: To determine the clinical profiles and outcomes of HF patients from five African countries., Methods: The INTERnational Congestive Heart Failure Study (INTER-CHF) is a prospective, multicenter cohort study. A total of 1,294 HF patients were consecutively recruited from Nigeria (383 patients), South Africa (169 patients), Sudan (501 patients), Uganda (151patients), and Mozambique (90 patients). HF was defined according to the Boston criteria for diagnosis. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) score., Results: Of the 1294 patients, 51.4% were recruited as out-patients, 53.7% had HF with reduced ejection fraction (EF), 30.1% had HF with mid-range EF and 16.2% had HF with preserved EF (16.2%). The commonest etiologies of HF were hypertensive heart disease (35%) and ischemic heart disease (20%). The mean MoCA score was highest in Uganda (24.3 ± 1.1) and lowest in Sudan (13.6 ± 0.3). Prescriptions for guideline-recommended HF therapies were poor; only 1.2% of South African patients received an Implantable Cardioverter Defibrillator, and none of the patients received Cardiac Resynchronised Therapy. The composite outcome of death or HF hospitalization at one year among the patients was highest in Sudan (59.7%) and lowest in Mozambique (21.1%). Six variables were associated with higher mortality risk, while digoxin use (adjusted hazard ratio [aHR]: 0.69; 95% confidence interval [CI]: 0.49-0.97; p = 0.034) and 10mmHg unit increase in systolic blood pressure (aHR 0.86; 95%CI 0.81-0.93; p < 0.001) were associated with lower risk for mortality., Conclusions: This is the largest HF study in Africa that included in- and out-patients from the West, East, North, Central and South African sub-regions. Clinically relevant differences, including cognitive functional impairment, were found between the involved countries., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2021 The Author(s).)

Background: Poor health-related quality of life (HRQL) is common in heart failure (HF), but there are few data on HRQL in HF and the association between HRQL and mortality outside Western countries., Methods: We used the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) to record HRQL in 23 291 patients with HF from 40 countries in 8 different world regions in the G-CHF study (Global Congestive Heart Failure). We compared standardized KCCQ-12 summary scores (adjusted for age, sex, and markers of HF severity) among regions (scores range from 0 to 100, with higher score indicating better HRQL). We used multivariable Cox regression with adjustment for 15 variables to assess the association between KCCQ-12 summary scores and the composite of all-cause death, HF hospitalization, and each component over a median follow-up of 1.6 years., Results: The mean age of participants was 65 years; 61% were men; 40% had New York Heart Association class III or IV symptoms; and 46% had left ventricular ejection fraction ≥40%. Average HRQL differed between regions (lowest in Africa [mean± SE, 39.5±0.3], highest in Western Europe [62.5±0.4]). There were 4460 (19%) deaths, 3885 (17%) HF hospitalizations, and 6949 (30%) instances of either event. Lower KCCQ-12 summary score was associated with higher risk of all outcomes; the adjusted hazard ratio (HR) for each 10-unit KCCQ-12 summary score decrement was 1.18 (95% CI, 1.17-1.20) for death. Although this association was observed in all regions, it was less marked in South Asia, South America, and Africa (weakest association in South Asia: HR, 1.08 [95% CI, 1.03-1.14]; strongest association in Eastern Europe: HR, 1.31 [95% CI, 1.21-1.42]; interaction P <0.0001). Lower HRQL predicted death in patients with New York Heart Association class I or II and III or IV symptoms (HR, 1.17 [95% CI, 1.14-1.19] and HR, 1.14 [95% CI, 1.12-1.17]; interaction P =0.13) and was a stronger predictor for the composite outcome in New York Heart Association class I or II versus class III or IV (HR 1.15 [95% CI, 1.13-1.17] versus 1.09 [95% CI, [1.07-1.11]; interaction P <0.0001). HR for death was greater in ejection fraction ≥40 versus <40% (HR, 1.23 [95% CI, 1.20-1.26] and HR, 1.15 [95% CI, 1.13-1.17]; interaction P <0.0001)., Conclusion: HRQL is a strong and independent predictor of all-cause death and HF hospitalization across all geographic regions, in mildly and severe symptomatic HF, and among patients with preserved and reduced ejection fraction. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03078166.

Lessons Learned: Despite strong preclinical rationale, combined cobimetinib-mediated MEK inhibition and GDC-0994-mediated ERK inhibition was not tolerable on two 28-day dosing schedules in which GDC-0994 was given for 21 days continuously and cobimetinib administered over 21 days either continuously or intermittently. Adverse events were as expected for mitogen-activated protein kinase pathway inhibition, but overlapping and cumulative toxicities could not be managed on either dosing schedule. Pharmacokinetic parameters of cobimetinib and GDC-0994 given in combination were similar to those previously observed in monotherapy studies, so that there was no evidence of drug-drug interaction. Cycle 1 metabolic responses were observed by 18F-fluorodeoxyglucose-positron emission tomography but were not predictive of outcome measured by RECIST 1.1., Background: Simultaneous targeting of multiple nodes in the mitogen-activated protein kinase (MAPK) pathway offers the prospect of enhanced activity in RAS-RAF-mutant tumors. This phase Ib trial evaluated the combination of cobimetinib (MEK inhibitor) and GDC-0994 (ERK inhibitor) in patients with locally advanced or metastatic solid tumors., Methods: Cobimetinib and GDC-0994 were administered orally on two separate dosing schedules. Arm A consisted of concurrent cobimetinib and GDC-0994 once daily for 21 days of a 28-day cycle; Arm B consisted of intermittent dosing of cobimetinib on a 28-day cycle concurrent with GDC-0994 daily for 21 days of a 28-day cycle., Results: In total, 24 patients were enrolled. For Arm A, owing to cumulative grade 1-2 toxicity, the dose of cobimetinib was decreased. For Arm B, dose increases of GDC-0994 and cobimetinib were intolerable with grade 3 dose-limiting toxicities of myocardial infarction and rash. Pharmacokinetic data did not show evidence of a drug-drug interaction. Overall, seven patients had a best overall response of stable disease (SD) and one patient with pancreatic adenocarcinoma had an unconfirmed partial response., Conclusion: The safety profile of MEK and ERK inhibition demonstrated classic MAPK inhibitor-related adverse events (AEs). However, overlapping AEs and cumulative toxicity could not be adequately managed on either dosing schedule, restricting the ability to further develop this combination., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

The goal of the global congestive heart failure (G-CHF) registry is to collect comparative international data on heart failure characteristics, management, and outcomes and to better understand the determinants that impact the clinical course of heart failure. METHODS: G-CHF is a multicenter, prospective cohort study of adult patients with a new or prior clinical diagnosis of heart failure. We have enrolled 23,047 participants from 257 centers in 40 countries from 8 major geographic regions of the world, with recruitment ongoing. Approximately 4,000 participants will also participate in substudies to assess frailty, comorbidity, diet, barriers to care, biomarkers, and planned detailed echocardiographic analyses. Follow-up is planned for a period of 5 years. The primary outcome is cause-specific mortality. Key secondary outcomes include hospitalizations, quality of life, and major cardiovascular and noncardiovascular outcomes. A total of 31.9% of participants were enrolled as inpatients. Thus far, mean age of the cohort at baseline is 63.1 years, and 60.8% are male. Participants most commonly have heart failure with reduced ejection fraction (53.6%) followed by preserved ejection fraction (24.2%) and midrange ejection fraction (20.6%). The most common causes of heart failure are ischemic (37.8%) followed by hypertensive (20.0%), idiopathic (15.1%), and valvular disease (8.8%). CONCLUSION: G-CHF will provide a greater understanding of the characteristics of the global heart failure population, variations in its management, clinical outcomes, and what continues to impact morbidity and mortality in this high-risk population., Competing Interests: Declaration of competing interest All authors report receiving grants from Bayer AG to support this study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: ERK1/2 signaling can be dysregulated in cancer. GDC-0994 is an oral inhibitor of ERK1/2. A first-in-human, phase I dose escalation study of GDC-0994 was conducted in patients with locally advanced or metastatic solid tumors., Patients and Methods: GDC-0994 was administered once daily on a 21-day on/7-day off schedule to evaluate safety, pharmacokinetics, and preliminary signs of efficacy. Patients with pancreatic adenocarcinoma and BRAF-mutant colorectal cancer were enrolled in the expansion stage., Results: Forty-seven patients were enrolled in six successive cohorts (50-800 mg). A single DLT of grade 3 rash occurred at 600 mg. The most common drug-related adverse events (AE) were diarrhea, rash, nausea, fatigue, and vomiting. Pharmacokinetic data showed dose-proportional increases in exposure, with a mean half-life of 23 hours, supportive of once daily dosing. In evaluable paired biopsies, MAPK pathway inhibition ranged from 19% to 51%. Partial metabolic responses by FDG-PET were observed in 11 of 20 patients across dose levels in multiple tumor types. Overall, 15 of 45 (33%) patients had a best overall response of stable disease and 2 patients with BRAF-mutant colorectal cancer had a confirmed partial response., Conclusions: GDC-0994 had an acceptable safety profile and pharmacodynamic effects were observed by FDG-PET and in serial tumor biopsies. Single-agent activity was observed in 2 patients with BRAF-mutant colorectal cancer., (©2019 American Association for Cancer Research.)

Background: Influenza is associated with an increase in the risk of cardiac and other vascular events. Observational data and small randomized trials suggest that influenza vaccination may reduce such adverse vascular events., Research Design and Methods: In a randomized controlled trial patients with heart failure are randomized to receive either inactivated influenza vaccine or placebo annually for 3 years. Patients aged ≥18 years with a clinical diagnosis of heart failure and NYHA functional class II, III and IV are eligible. Five thousand patients from 10 countries where influenza vaccination is not common (Asia, the Middle East, and Africa) have been enrolled. The primary outcome is a composite of the following: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalizations for heart failure using standardized criteria. Analyses will be based on comparing event rates between influenza vaccine and control groups and will include time to event, rate comparisons using Poisson methods, and logistic regression. The analysis will be conducted by intention to treat i.e. patients will be analyzed in the group in which they were assigned. Multivariable secondary analyses to assess whether variables such as age, sex, seasonality modify the benefits of vaccination are also planned for the primary outcome., Conclusion: This is the largest randomized trial to test if influenza vaccine compared to control reduces adverse vascular events in high risk individuals., Trial Registration Number: Clinicaltrials.govNCT02762851., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Tricuspid regurgitation (TR) has been associated with cardiac rhythm device (CRD) implantation with intracardiac lead insertion. However, data on the incidence of postdevice TR are limited and largely from retrospective studies. We hypothesized that permanent lead implantation would be associated with an increase in TR., Methods: We prospectively included consecutive patients with a clinical indication for CRD. Patients underwent transthoracic echocardiography 1 month before and 1 year after CRD implantation., Results: A total of 328 patients were prospectively enrolled (69 ± 15 years, 38% female). Echocardiograms before and 1 year after CRD were available in 290 patients (15 died, 23 lost to follow-up). Compared with baseline, there was a significant change in TR grade 1 year after CRD insertion (no/trivial TR: 66% vs 29%; mild TR: 29% vs 61%; moderate TR: 3% vs 8%; severe TR 2% vs 2%; P < 0.001 for an increase in TR by at least 1 grade). Compared with baseline, there was a higher prevalence of moderate or severe TR in the 247 patients with CRD without cardiac resynchronization therapy (4% vs 10%, P = 0.004), but no progression in the 43 patients who received cardiac resynchronization therapy (14% vs 11%, P = 1). Multivariable analysis in the patients with less than moderate TR at baseline (n = 274) showed that only a history of atrial fibrillation was independently associated with progression to moderate or severe TR after correction for baseline TR grade (P = 0.013)., Conclusions: One year after endocardial lead insertion, there was a 5% increase in the prevalence of moderate or severe TR, which may be clinically relevant., (Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: There is a paucity of data on the utility of right atrial pressure (RAP) for estimating pulmonary capillary wedge pressure (PCWP) in patients with normal ejection fraction (EF), including patients with heart failure with preserved EF., Methods: Mean RAP was compared with PCWP in 129 patients (mean age, 61 ± 11 years; 45% men) with exertional dyspnea enrolled in a multicenter study. Measurements included left ventricular volumes, EF, and mitral inflow velocities., Results: Mean PCWP was 14 ± 7 mm Hg, and mean RAP was 8 ± 5 mm Hg. A significant relation was present between mean RAP and mean PCWP (r 2  = 0.5, P < .001). RAP > 8 mm Hg had 76% sensitivity and 86% specificity in detecting mean PCWP > 12 mm Hg. In 101 patients with inconclusive mitral filling pattern (defined according to American Society of Echocardiography/European Association of Cardiovascular Imaging 2016 diastolic function recommendations), RAP by catheterization had sensitivity of 73% and specificity of 91%. In a subset of 59 patients with echocardiographic assessment of mean RAP, RAP by echocardiography had sensitivity of 76% and specificity of 89%., Conclusions: Mean RAP provides useful information about mean PCWP in many patients with normal left ventricular EF. There is good sensitivity and excellent specificity when combining invasive or noninvasive RAP and mitral velocities to determine if PCWP is elevated., (Copyright © 2018 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

A pathway of vibrational energy flow in myoglobin was studied by time-resolved anti-Stokes ultraviolet resonance Raman spectroscopy combined with site-directed mutagenesis. Our previous study suggested that atomic contacts in proteins provide the dominant pathway for energy transfer while covalent bonds do not. In the present study, we directly examined the contributions of covalent bonds and atomic contacts to the pathway of vibrational energy flow by comparing the anti-Stokes resonance Raman spectra of two myoglobin mutants: one lacked a covalent bond between heme and the polypeptide chain, and the other retained the intact bond. The two mutants showed no significant difference in temporal changes in the anti-Stokes Raman intensities of the tryptophan bands, implying that the dominant channel of vibrational energy transfer is not through the covalent bond but rather through van der Waals atomic contacts between heme and the protein moiety. The obtained insights contribute to our general understanding of energy transfer in the condensed phase.