Endogenous Opioids at the Intersection of Opioid Addiction, Pain, and Depression: The Search for a Precision Medicine Approach.

Opioid addiction and overdose are at record levels in the United States. This is driven, in part, by their widespread prescription for the treatment of pain, which also increased opportunity for diversion by sensation-seeking users. Despite considerable research on the neurobiology of addiction, treatment options for opioid abuse remain limited. Mood disorders, particularly depression, are often comorbid with both pain disorders and opioid abuse. The endogenous opioid system, a complex neuromodulatory system, sits at the neurobiological convergence point of these three comorbid disease states. We review evidence for dysregulation of the endogenous opioid system as a mechanism for the development of opioid addiction and/or mood disorder. Specifically, individual differences in opioid system function may underlie differences in vulnerability to opioid addiction and mood disorders. We also review novel research, which promises to provide more detailed understanding of individual differences in endogenous opioid neurobiology and its contribution to opioid addiction susceptibility.

Effect of Selective Lesions of Nucleus Accumbens µ-Opioid Receptor-Expressing Cells on Heroin Self-Administration in Male and Female Rats: A Study with Novel Oprm1-Cre Knock-in Rats.

The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based Oprm1-Cre knock-in transgenic rat that provides cell type-specific genetic access to MOR-expressing cells. After performing anatomic and behavioral validation experiments, we used the Oprm1-Cre knock-in rats to study the involvement of NAc MOR-expressing cells in heroin self-administration in male and female rats. Using RNAscope, autoradiography, and FISH chain reaction (HCR-FISH), we found no differences in Oprm1 expression in NAc, dorsal striatum, and dorsal hippocampus, or MOR receptor density (except dorsal striatum) or function between Oprm1-Cre knock-in rats and wildtype littermates. HCR-FISH assay showed that iCre is highly coexpressed with Oprm1 (95%-98%). There were no genotype differences in pain responses, morphine analgesia and tolerance, heroin self-administration, and relapse-related behaviors. We used the Cre-dependent vector AAV1-EF1a-Flex-taCasp3-TEVP to lesion NAc MOR-expressing cells. We found that the lesions decreased acquisition of heroin self-administration in male Oprm1-Cre rats and had a stronger inhibitory effect on the effort to self-administer heroin in female Oprm1-Cre rats. The validation of an Oprm1-Cre knock-in rat enables new strategies for understanding the role of MOR-expressing cells in rat models of opioid addiction, pain-related behaviors, and other opioid-mediated functions. Our initial mechanistic study indicates that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in male and female rats.SIGNIFICANCE STATEMENT The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based Oprm1-Cre knock-in transgenic rat that provides cell type-specific genetic access to brain MOR-expressing cells. After performing anatomical and behavioral validation experiments, we used the Oprm1-Cre knock-in rats to show that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in males and females. The new Oprm1-Cre rats can be used to study the role of brain MOR-expressing cells in animal models of opioid addiction, pain-related behaviors, and other opioid-mediated functions.

Chronic stress in adolescence differentially affects cocaine vulnerability in adulthood in a selectively bred rat model of individual differences: role of accumbal dopamine signaling.

Stress during adolescence has profound effects on the onset and severity of substance use later in life. However, not everyone with adverse experiences during this period will go on to develop a substance use disorder in adulthood, and the factors that alter susceptibility to substance use remain unknown. Here, we investigated individual differences in response to stress and drugs of abuse using our selectively bred high-responder (bHR) and low-responder (bLR) rats. These animals model extremes of temperamental tendencies and differ dramatically in both stress responsiveness and addiction-related traits. The present study investigated how environmental interventions in the form of a chronic variable stress (CVS) regimen in early adolescence interact with the bHR/bLR phenotype to alter behavioral sensitization to cocaine in adulthood. We also determined whether accumbal dopamine signaling is involved in the interaction of stress history and cocaine by assessing the mRNA levels of dopamine D1 (D1R) and D2 (D2R) receptors. Our results showed that CVS history alone had enduring and phenotype-specific effects on accumbal dopamine signaling. Importantly, adolescent stress had opposing effects in the two lines- decreasing the locomotor response to cocaine challenge in bHRs but increasing this measure in bLRs. Moreover, these opposing effects on cocaine sensitivity following adolescent CVS were accompanied by parallel effects in the accumbal dopamine system, with prior stress and cocaine exposure interacting to decrease D2R mRNA in bHRs but increase it in bLRs. Overall, these findings indicate that environmental challenges encountered in adolescence interact with genetic background to alter vulnerability to cocaine later in life.Lay SummaryStress experienced during adolescence affects the onset and severity of drug dependence later in life. However, not everyone with adverse experiences during this period will go on to develop SUD in adulthood. Using a rat model of innate differences in emotional reactivity, this study shows that the interplay between individual temperament and previous experience of adolescent stress/trauma determines whether an individual will be vulnerable or resilient to develop SUDs later in life. In addition, the present study shows that the dopamine D2 receptor in the brain's reward center, nucleus accumbens, may be implicated in this interplay.

International recommendations for electrocardiographic interpretation in athletes.

Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural, or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly over the last decade; pushed by a growing body of scientific data that both tests proposed criteria sets and establishes new evidence to guide refinements. On 26-27 February 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington, to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD.

Inhibiting social support from massage-like stroking increases morphine dependence.

Our previous studies showed that altering solely the drug experience of the cage mates with which rodents are housed affects the development of morphine dependence. In this study, we used designer receptors exclusively activated by designer drugs to artificially increase or decrease the activity of peripheral dorsal root ganglia sensory neurons expressing the G-protein-coupled receptor MRGPRB4. This is because sensory MRGPRB4-expressing neurons were shown to specifically detect the sensation of massage-like stroking resulting from social grooming, which is an important affiliative social behavior in the rodent. Blocking the sensation of social grooming in morphine-treated mice housed with drug-naive mice (i.e. morphine cage mates) significantly increased the display of jumping behavior in morphine-withdrawn animals. Activating the sensation of social grooming in morphine-treated animals housed solely with other morphine-treated animals (i.e. morphine only) did not significantly alter the display of jumping behavior in morphine-withdrawn animals. Repetitive jumping behaviors have been shown to correlate with morphine dependence. Thus, this study showed a role of social grooming in the protective effect of being housed with drug-naive mice on the development of morphine dependence. It further confirms a role of social support in the development of substance use problems.

Burn injury decreases the antinociceptive effects of opioids.

Burn victim patients are frequently prescribed opioids at doses that are significantly higher than standard analgesic dosing guidelines, and, even despite an escalation in opioid dosing, many continue to experience pain. Thus, the aim of this study was to determine the effect of burn injury on opioid antinociception. Mice were examined for their baseline pain sensitivity thresholds using the von Frey filaments test. Then, they were subjected to burn or sham injury to the dorsal surface of the hindpaw and treated orally with morphine, oxycodone, hydrocodone (20 or 40 mg/kg), or saline twice daily throughout the study. They were retested on days 4, 7, 11, 14, 21, and 28 following the burn injury. The antinociceptive effects of the various drugs were analyzed by computing the daily difference between pain sensitivity threshold scores (in g) before and after treatment. This study showed that burn injury decreases opioid antinociception potency. A marked reduction was observed in the antinociceptive effectiveness of all opioids, and for both doses, in the burn-injured versus the sham animals. These results suggest that burn trauma limits the ability of opioids to be effective in reducing pain.

Hydrocodone is More Effective than Morphine or Oxycodone in Suppressing the Development of Burn-Induced Mechanical Allodynia.

BACKGROUND: Pain is the most frequent complaint of burn-injured patients. Opioids are commonly used in the course of treatment. However, there is a lack of rodent studies that examine the differential effects of various opioids on burn pain. OBJECTIVE: This study compared the ability of morphine, oxycodone, and hydrocodone to suppress the development of burn-induced mechanical allodynia and reduce pain sensitivity. METHODS: Mice were examined for their baseline pain sensitivity thresholds using the von Frey Filaments test. Then, they were subjected to burn or sham injury and treated orally with morphine, oxycodone, hydrocodone (20 or 40 mg/kg), or saline twice daily throughout the study. They were retested on days 4, 7, 11, 14, 21, and 28 postburn. RESULTS: In the sham animals, morphine produced significant opioid-induced hyperalgesia (OIH). Development of OIH was minimal for hydrocodone and was not observed for oxycodone. Secondary mechanical allodynia was observed beginning four days after the burn injury and intensified with time. All opioids produced comparable antinociceptive effects. Hydrocodone was effective in suppressing the development of burn-induced mechanical allodynia and fully treated the burn-induced increase in pain sensitivity. In contrast, morphine and oxycodone had only minimal effects on the development of burn-induced mechanical allodynia and only partially treated the burn-induced increase in pain sensitivity. CONCLUSIONS: This study demonstrated that hydrocodone is effective in suppressing the development of burn-induced mechanical allodynia, while both morphine and oxycodone had minimal effects. These findings underscore the need for additional studies on the differences among various opioids using clinically relevant pain models.

Interassociation consensus statement on cardiovascular care of college student-athletes.

Cardiovascular evaluation and care of college student-athletes is gaining increasing attention from both the public and medical communities. Emerging strategies include screening of the general athlete population, recommendations of permissible levels of participation by athletes with identified cardiovascular conditions and preparation for responding to unanticipated cardiac events in athletic venues. The primary focus has been sudden cardiac death and the usefulness of screening with or without advanced cardiac screening. The National Collegiate Athletic Association convened a multidisciplinary task force to address cardiovascular concerns in collegiate student-athletes, and to develop consensus for an interassociation statement. This document summarises the task force deliberations and follow-up discussions, and includes available evidence on cardiovascular risk, preparticipation evaluation and the recognition of and response to cardiac arrest. Future recommendations for cardiac research initiatives, education and collaboration are also provided.

International criteria for electrocardiographic interpretation in athletes: Consensus statement.

Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly, advanced by a growing body of scientific data and investigations that both examine proposed criteria sets and establish new evidence to guide refinements. On 26-27 February 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington (USA), to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD.

Ventilation and the Response to Hypercapnia after Morphine in Opioid-naive and Opioid-tolerant Rats.

BACKGROUND: Opioid-related deaths are a leading cause of accidental death, with most occurring in patients receiving chronic pain therapy. Respiratory arrest is the usual cause of death, but mechanisms increasing that risk with increased length of treatment remain unclear. Repeated administration produces tolerance to opioid analgesia, prompting increased dosing, but depression of ventilation may not gain tolerance to the same degree. This study addresses differences in the degree to which chronic morphine (1) produces tolerance to ventilatory depression versus analgesia and (2) alters the magnitude and time course of ventilatory depression. METHODS: Juvenile rats received subcutaneous morphine for 3 days (n = 116) or vehicle control (n = 119) and were then tested on day 4 following one of a range of morphine doses for (a) analgesia by paw withdraw from heat or (b) respiratory parameters by plethysmography-respirometry. RESULTS: Rats receiving chronic morphine showed significant tolerance to morphine sedation and analgesia (five times increased ED50). When sedation was achieved for all animals in a dose group (lowest effective doses: opioid-tolerant, 15 mg/kg; opioid-naive, 3 mg/kg), the opioid-tolerant showed similar magnitudes of depressed ventilation (-41.4 ± 7.0%, mean ± SD) and hypercapnic response (-80.9 ± 15.7%) as found for morphine-naive (-35.5 ± 16.9% and -67.7 ± 15.1%, respectively). Ventilation recovered due to tidal volume without recovery of respiratory rate or hypercapnic sensitivity and more slowly in morphine-tolerant. CONCLUSIONS: In rats, gaining tolerance to morphine analgesia does not reduce ventilatory depression effects when sedated and may inhibit recovery of ventilation.

Differential Effects of Oxycodone, Hydrocodone, and Morphine on Activation Levels of Signaling Molecules.

BACKGROUND: Opioids alter the responses of D2-like dopamine receptors (D2DRs), known to be involved in the pathology of addiction and other mental illnesses. Importantly, our recent results demonstrated that various opioids differentially modulate the behavioral responses of D2DRs. OBJECTIVE: To examine the effect of various opioids on striatal activation levels of Akt and ERK1/2, as well as the signaling responses of D2DRs following opioid exposure. METHODS: Mice were pre-treated with 20 mg/kg morphine, hydrocodone, oxycodone, or saline for 6 days. Twenty-four hours later, mice were injected with vehicle or a D2/D3 receptor agonist, quinpirole. Thirty minutes later, dorsal striatum was collected and analyzed using Western blot. RESULTS: In morphine-pretreated animals, baseline Akt activation level was unchanged, but was reduced in response to quinpirole. In contrast, baseline Akt activation levels were reduced in mice pretreated with hydrocodone and oxycodone, but were unchanged in response to quinpirole. In mice pretreated with all opioids, baseline ERK2 activation levels were unchanged and increased in response to quinpirole. However, quinpirole-induced ERK2 activation was significantly higher than drug naïve animals only in the morphine-pretreated mice. CONCLUSIONS: Various opioids differentially modulate the baseline activation levels of signaling molecules, which in turn results in ligand-selective effects on the responses to a D2/D3 dopamine receptor agonist. This demonstrates a complex interplay between opioid receptors and D2DRs, and supports the notion that various opioids carry differential risks to the dopamine reward system. This information should be considered when prescribing opioid pain medication, to balance effectiveness with minimal risk.

Cardiopulmonary Exercise Testing Interpretation in Athletes: What the Cardiologist Should Know.

The noninvasive assessment of oxygen consumption, carbon dioxide production, and ventilation during a cardiopulmonary exercise test (CPET) provides insight into the cardiovascular, pulmonary, and metabolic system's ability to respond to exercise. Exercise physiology has been shown to be distinct for competitive athletes and highly active persons (CAHAPs), thus creating more nuanced interpretations of CPET parameters. CPET in CAHAP is an important test that can be used for both diagnosis (provoking symptoms during a truly maximal test) and performance.

Ethnic Differences in Survival among Brazilian Modern-era Olympic Medalists from 1920 to 1992: A Cohort Study. / Diferenças Étnicas na Sobrevida entre Medalhistas Olímpicos Brasileiros da Era Moderna de 1920 a 1992: Um Estudo de Coorte.

BACKGROUND: Disparities in health outcomes among racial groups warrant investigation, even among elite athletes. Therefore, understanding the impact of race upon post-medal survival in Brazilian Olympians becomes essential. OBJECTIVE: To compare post-medal survival between white and non-white Brazilian Olympic medalists from 1920 to 1992. METHODS: This study used publicly available data for a retrospective cohort study on all Brazilian Olympic medalists from 1920 to 1992 (males only). Athletes were classified into white and non-white groups using structured ethnicity determination. Kaplan-Meier analyses computed the restricted mean survival time (RMST) for each ethnic group. A Cox proportional hazards analysis assessed ethnicity-based survival differences, adjusting for medal-winning age and birth year (p<0.05). RESULTS: Among 123 athletes (73.9% white), the mean age of medal achievement was 25.03±4.8 years. During the study, 18.7% of white and 37.5% of non-white athletes died (p=0.031). White athletes had a mean age at death of 75.10±18.01 years, while non-white athletes had an age of 67.13±14.90 years (p=0.109). The RMST for white athletes was 51.59 (95% CI 49.79-53.39) years, while for non-white athletes, it was 45.026 (95% CI 41.31-48.74) years, resulting in a ΔRMST of 6.56 (95% CI 2.43-10.70; p=0.0018). Multivariate analysis showed that non-white athletes had a higher mortality risk than did white athletes (HR 5.58; 95% CI, 2.18-14.31). CONCLUSION: Following their first medal, white Brazilian Olympians typically enjoy a six-year longer lifespan than their non-white counterparts, illustrating a marked mortality gap and health disparities among healthy individuals in Brazil.

FUNDAMENTO: As disparidades nos resultados de saúde entre grupos raciais merecem investigação, mesmo em atletas de elite. Portanto, compreender o impacto da raça na sobrevida pós-medalha em atletas olímpicos brasileiros torna-se essencial. OBJETIVO: Comparar a sobrevida pós-medalha entre medalhistas olímpicos brasileiros brancos e não brancos de 1920 a 1992. MÉTODOS: Utilizamos dados disponíveis publicamente para um estudo de coorte retrospectivo de todos os medalhistas olímpicos brasileiros de 1920 a 1992 (somente homens). Os atletas foram classificados nos grupos brancos e não brancos usando determinação estruturada de etnia. As análises de Kaplan-Meier calcularam o tempo médio de sobrevida restrito (TMSR) para cada grupo étnico. Uma análise de riscos proporcionais de Cox avaliou as diferenças de sobrevida baseadas na etnia, ajustando para a idade da conquista da medalha e ano de nascimento (p<0,05). RESULTADOS: Entre 123 atletas (73,9% brancos), a idade média da conquista de medalhas foi de 25,03 ± 4,8 anos. Durante o estudo, 18,7% dos atletas brancos e 37,5% dos atletas não brancos morreram (p=0,031). Os atletas brancos tiveram média de idade ao óbito de 75,10 ± 18,01 anos, enquanto os atletas não brancos tiveram idade média de 67,13 ± 14,90 anos (p=0,109). O TMSR para atletas brancos foi de 51,59 (IC 95%, 49,79 - 53,39) anos, e para atletas não brancos foi de 45,026 (IC 95%, 41,31 - 48,74) anos, resultando em um ΔTMSR de 6,56 (IC 95%, 2,43 - 10,70; p=0,0018). A análise multivariada mostrou que atletas não brancos apresentavam maior risco de mortalidade do que atletas brancos (RC 5,58; IC 95%, 2,18 - 14,31). CONCLUSÃO: Após a primeira medalha, os atletas olímpicos brasileiros brancos normalmente desfrutam de uma expectativa de vida seis anos mais longa do que seus colegas não brancos, ilustrando uma acentuada diferença de mortalidade e disparidades de saúde entre indivíduos saudáveis no Brasil.

Real-world experience with mavacamten in obstructive hypertrophic cardiomyopathy: Observations from a tertiary care center.

BACKGROUND: In symptomatic obstructive hypertrophic cardiomyopathy (oHCM) patients, mavacamten is commercially approved to help improve left ventricular (LV) outflow tract (LVOT) gradients, symptoms, and reduce eligibility for septal reduction therapy (SRT) under the risk evaluation and mitigation strategy (REMS) program. We sought to prospectively report the initial real-world clinical experience with the use of commercially available mavacamten in a multi-hospital tertiary healthcare system. METHODS: We studied the first 150 consecutive oHCM patients (mean age 65 years, 53% women, 83% on betablockers and 61% in New York Heart Association [NYHA] class III) who were initiated on 5 mg of mavacamten with dose titrations using symptom assessment and echocardiographic measurements of LVOT gradient and LV ejection fraction (LVEF) measurements. We measured changes in NYHA class, LVEF, LVOT gradients (resting and Valsalva) at baseline, 4, 8 and 12 weeks. RESULTS: At 261 ± 143 days (range of 31-571 days), 69 (46%) patients had ≥1 NYHA class, and 27 (18%) additional patients had ≥2 NYHA class improvement. The mean Valsalva LVOT gradient decreased from 72 ± 43 mmHg at baseline to 29 ± 31 mmHg at 4 weeks, 29 ± 28 mmHg at 8 weeks and 30 ± 29 mmHg at 12 weeks (p < 0.001). At baseline, 100% patients had Valsalva LVOT gradients ≥30 mmHg, which reduced to 29% at 4 weeks, 28% at 8 weeks and 30% at 12 weeks. In 40 patients who reported no symptomatic improvement, the mean Valsalva LVOT gradient decreased from 73 ± 39 mmHg at baseline to 34 ± 27 mmHg at 4 weeks, 35 ± 28 mmHg at 8 weeks and 30 ± 24 mmHg at 12 weeks (P < 0.001). The mean LVEF at baseline was 66 ± 6% and changed to 64 ± 5% at 4 weeks, 63 ± 5% at 8 weeks and 62 ± 7% at 12 weeks (p < 0.0001). No patient underwent SRT, developed LVEF ≤30% or developed heart failure requiring admission. Three (2%) patients needed temporary interruption of mavacamten due to LVEF<50%. CONCLUSIONS: In a real-world study in symptomatic oHCM patients at a multi-hospital tertiary care referral center, we demonstrate the efficacy and safety, along with the logistic feasibility of prescribing mavacamten under the REMS program.

Cardiopulmonary Exercise Testing Interpretation in Athletes: What the Cardiologist Should Know.

The noninvasive assessment of oxygen consumption, carbon dioxide production, and ventilation during a cardiopulmonary exercise test (CPET) provides insight into the cardiovascular, pulmonary, and metabolic system's ability to respond to exercise. Exercise physiology has been shown to be distinct for competitive athletes and highly active persons (CAHAPs), thus creating more nuanced interpretations of CPET parameters. CPET in CAHAP is an important test that can be used for both diagnosis (provoking symptoms during a truly maximal test) and performance.

Exercise recommendations for patients with hypertrophic cardiomyopathy.

Individuals with hypertrophic cardiomyopathy (HCM) have historically been advised to limit exercise and sports participation to mild-intensity activities due to concerns for sudden cardiac arrest (SCA). However, more contemporary data have shown SCA is rare in patients with HCM and emerging data is shifting towards support for the safety of exercise in this patient population. Recent guidelines endorse exercise in patients with HCM after a comprehensive evaluation and shared-decision making with an expert provider.

COVID-19 and elite sport: Cardiovascular implications and return-to-play.

Curtailing elite sports during the coronavirus disease 2019 (COVID-19) pandemic was necessary to prevent widespread viral transmission. Now that elite sport and international competitions have been largely restored, there is still a need to devise appropriate screening and management pathways for athletes with a history of, or current, COVID-19 infection. These approaches should support the decision-making process of coaches, sports medicine practitioners and the athlete about the suitability to return to training and competition activities. In the absence of longitudinal data sets from athlete populations, the incidence of developing prolonged and debilitating symptoms (i.e., Long COVID) that affects a return to training and competition remains a challenge to sports and exercise scientists, sports medicine practitioners and clinical groups. As the world attempts to adjust toward 'living with COVID-19' the very nature of elite and international sporting competition poses a risk to athlete welfare that must be screened for and managed with bespoke protocols that consider the cardiovascular implications for performance.

Abnormal exercise adaptation after varying severities of COVID-19: A controlled cross-sectional analysis of 392 survivors.

The multisystem impairment promoted by COVID-19 may be associated with a reduction in exercise capacity. Cardiopulmonary abnormalities can change across the acute disease severity spectrum. We aimed to verify exercise physiology differences between COVID-19 survivors and SARS-CoV-2-naïve controls and how illness severity influences exercise limitation. A single-centre cross-sectional analysis of prospectively collected data from COVID-19 survivors who underwent cardiopulmonary exercise testing (CPET) in their recovery phase (x = 50[36;72] days). Patients with COVID-19 were stratified according to severity as mild [M-Cov (outpatient)] vs severe/critical [SC-Cov(inpatients)] and were compared with SARS-CoV-2-naïve controls (N-Cov). Collected information included demographics, anthropometrics, previous physical exercise, comorbidities, lung function test and CPET parameters. A multivariate logistic regression analysis was performed to identify low aerobic capacity (LAC) predictors post COVID-19. Of the 702 included patients, 310 (44.2%), 305 (43.4%) and 87 (12.4%) were N-Cov, M-Cov and SC-Cov, respectively. LAC was identified in 115 (37.1%), 102 (33.4%), and 66 (75.9%) of N-CoV, M-CoV and SC-CoV, respectively (p < 0.001). SC-Cov were older, heavier with higher body fat, more sedentary lifestyle, more hypertension and diabetes, lower forced vital capacity, higher prevalence of early anaerobiosis, ventilatory inefficiency and exercise-induced hypoxia than N-Cov. M-Cov had lower weight, fat mass, and coronary disease prevalence and did not demonstrate more CEPT abnormalities than N-Cov. After adjustment for covariates, SC-Cov was an independent predictor of LAC (OR = 2.7; 95% CI, 1.3-5.6). Almost two months after disease onset, SC-CoV presented several exercise abnormalities of oxygen uptake, ventilatory adaptation and gas exchange, including a high prevalence of LAC.Highlights Weeks after the acute disease phase, one-third of mild and three-quarters of severe and critical patients with COVID-19 presented a reduced aerobic capacity. Previous studies including SARS-CoV-1 survivors observed much lower values.A severe or critical COVID-19 case was an independent predictor for low aerobic capacity.In our sample, pre-COVID-19 exercise significantly reduced the odds of post-COVID-19 low aerobic capacity. Even severe or critical patients who exercised regularly had a prevalence of low aerobic capacity 2.5 times lower than those who did not have this routine before sickening.

Exercise and cardiovascular health: A state-of-the-art review.

Cardiovascular (CV) disease (CVD) is the leading cause of global morbidity and mortality, and low levels of physical activity (PA) is a leading independent predictor of poor CV health and associated with an increased prevalence of risk factors that predispose to CVD development. In this review, we evaluate the benefits of exercise on CV health. We discuss the CV adaptations to exercise, focusing on the physiological changes in the heart and vasculature. We review the impact and benefits of exercise on specific CV prevention, including type II diabetes, hypertension, hyperlipidemia, coronary artery disease, and heart failure, in addition to CVD-related and all-cause mortality. Lastly, we evaluate the current PA guidelines and various modes of exercise, assessing the current literature for the effective regimens of PA that improve CVD outcomes.