COVID-19 has become a dramatic health problem during this century. In addition to high mortality rate, COVID-19 survivors are at increased risk for cardiovascular diseases 1-year after infection. ...Explanations for these manifestations are still unclear but can involve a constellation of biological alterations. We hypothesized that COVID-19 survivors compared with controls exhibit sympathetic overdrive, vascular dysfunction, cardiac morpho-functional changes, impaired exercise capacity, and increased oxidative stress.
Nineteen severe COVID-19 survivors and 19 well-matched controls completed the study. Muscle sympathetic nerve activity (microneurography), brachial artery flow-mediated dilation and blood flow (Doppler-Ultrasound), carotid-femoral pulse wave velocity (Complior), cardiac morpho-functional parameters (echocardiography), peak oxygen uptake (cardiopulmonary exercise testing), and oxidative stress were measured ~3 months after hospital discharge. Complementary experiments were conducted on human umbilical vein endothelial cells cultured with plasma samples from subjects.
Muscle sympathetic nerve activity and carotid-femoral pulse wave velocity were greater and brachial artery flow-mediated dilation, brachial artery blood flow, E/e' ratio, and peak oxygen uptake were lower in COVID-19 survivors than in controls. COVID-19 survivors had lower circulating antioxidant markers compared with controls, but there were no differences in plasma-treated human umbilical vein endothelial cells nitric oxide production and reactive oxygen species bioactivity. Diminished peak oxygen uptake was associated with sympathetic overdrive, vascular dysfunction, and reduced diastolic function in COVID-19 survivors.
Our study revealed that COVID-19 survivors have sympathetic overactivation, vascular dysfunction, cardiac morpho-functional changes, and reduced exercise capacity. These findings indicate the need for further investigation to determine whether these manifestations are persistent longer-term and their impact on the cardiovascular health of COVID-19 survivors.
Key points
Heart Failure (HF) is accompanied by reduced ventricular function, activation of compensatory neurohormonal mechanisms and marked autonomic dysfunction characterized by exaggerated ...sympathoexcitation and reduced parasympathetic activity.
With 6 weeks of exercise training, HF‐related loss of choline acetyltransferase (ChAT)‐positive vagal preganglionic neurones is avoided, restoring the parasympathetic tonus to the heart, and the immunoreactivity of dopamine β‐hydroxylase‐positive premotor neurones that drive sympathetic outflow to the heart is reduced. Training‐induced correction of autonomic dysfunction occurs even with the persistence of abnormal ventricular function.
Strong positive correlation between improved parasympathetic tonus to the heart and increased ChAT immunoreactivity in vagal preganglionic neurones after training indicates this is a crucial mechanism to restore autonomic function in heart failure.
Exercise training is an efficient tool to attenuate sympathoexcitation, a hallmark of heart failure (HF). Although sympathetic modulation in HF is widely studied, information regarding parasympathetic control is lacking. We examined the combined effects of sympathetic and vagal tonus to the heart in sedentary (Sed) and exercise trained (ET) HF rats and the contribution of respective premotor and preganglionic neurones. Wistar rats submitted to coronary artery ligation or sham surgery were assigned to training or sedentary protocols for 6 weeks. After haemodynamic, autonomic tonus (atropine and atenolol i.v.) and ventricular function determinations, brains were collected for immunoreactivity assays (choline acetyltransferase, ChATir; dopamine β‐hydroxylase, DBHir) and neuronal counting in the dorsal motor nucleus of vagus (DMV), nucleus ambiguus (NA) and rostroventrolateral medulla (RVLM). HF‐Sed vs. SHAM‐Sed exhibited decreased exercise capacity, reduced ejection fraction, increased left ventricle end diastolic pressure, smaller positive and negative dP/dt, decreased intrinsic heart rate (IHR), lower parasympathetic and higher sympathetic tonus, reduced preganglionic vagal neurones and ChATir in the DMV/NA, and increased RVLM DBHir. Training increased treadmill performance, normalized autonomic tonus and IHR, restored the number of DMV and NA neurones and corrected ChATir without affecting ventricular function. There were strong positive correlations between parasympathetic tonus and ChATir in NA and DMV. RVLM DBHir was also normalized by training, but there was no change in neurone number and no correlation with sympathetic tonus. Training‐induced preservation of preganglionic vagal neurones is crucial to normalize parasympathetic activity and restore autonomic balance to the heart even in the persistence of cardiac dysfunction.
Key points
Heart Failure (HF) is accompanied by reduced ventricular function, activation of compensatory neurohormonal mechanisms and marked autonomic dysfunction characterized by exaggerated sympathoexcitation and reduced parasympathetic activity.
With 6 weeks of exercise training, HF‐related loss of choline acetyltransferase (ChAT)‐positive vagal preganglionic neurones is avoided, restoring the parasympathetic tonus to the heart, and the immunoreactivity of dopamine β‐hydroxylase‐positive premotor neurones that drive sympathetic outflow to the heart is reduced. Training‐induced correction of autonomic dysfunction occurs even with the persistence of abnormal ventricular function.
Strong positive correlation between improved parasympathetic tonus to the heart and increased ChAT immunoreactivity in vagal preganglionic neurones after training indicates this is a crucial mechanism to restore autonomic function in heart failure.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Refractory angina (RA) is a chronic condition of coronary artery disease (CAD). Endothelial function (EF) measured by flow-mediated dilation (FMD) is an important prognostic marker in CAD. Exercise ...training is a stimulus that improves EF in CAD. However, exercise training effects on EF in RA are unknown. Therefore, we aimed to verify the effects of exercise training on EF in RA. This was a longitudinal, non-randomized clinical study, involving patients with patients limited by angina, aged 45 to 75 years. Patients were prospectively allocated by convenience to either exercise trained (ET) or control group (C). Laboratory analysis, cardiopulmonary exercise test (CPET), and FMD were implemented at inclusion and after 12 weeks of exercise training or clinical treatment period. Exercise training included 60 minutes per session, 3 times a week, including 40 minutes of aerobic exercise on anginal threshold heart rate obtained on the CPET, 15 minutes of resistance training, and 5 minutes of stretching. A total of 38 patients were included (mean age 60 ± 9 years, 22 men); 21 were allocated to the ET and 17 to the C group. Baseline measures showed no differences between groups. After 12 weeks glycated hemoglobin and systolic blood pressure were lower in ET before than ET after (p = 0.004, and p = 0.05, respectively), and exercise time of the CPET was lower in ET before than ET after (p = 0.002). Exercise training did not change FMD. In conclusion, exercise training performed on anginal threshold increases exercise tolerance but causes no changes in EF in patients with RA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Previous studies show that COVID-19 survivors have elevated muscle sympathetic nerve activity (MSNA), endothelial dysfunction, and aortic stiffening. However, the neurovascular responses to mental ...stress and exercise are still unexplored. We hypothesized that COVID-19 survivors, compared with age- and body mass index (BMI)-matched control subjects, exhibit abnormal neurovascular responses to mental stress and physical exercise. Fifteen severe COVID-19 survivors (aged: 49 ± 2 yr, BMI: 30 ± 1 kg/m
) and 15 well-matched control subjects (aged: 46 ± 3 yr, BMI: 29 ± 1 kg/m
) were studied. MSNA (microneurography), forearm blood flow (FBF), and forearm vascular conductance (FVC, venous occlusion plethysmography), mean arterial pressure (MAP, Finometer), and heart rate (HR, ECG) were measured during a 3-min mental stress (Stroop Color-Word Test) and during a 3-min isometric handgrip exercise (30% of maximal voluntary contraction). During mental stress, MSNA (frequency and incidence) responses were higher in COVID-19 survivors than in controls (
< 0.001), and FBF and FVC responses were attenuated (
< 0.05). MAP was similar between the groups (
> 0.05). In contrast, the MSNA (frequency and incidence) and FBF and FVC responses to handgrip exercise were similar between the groups (
> 0.05). MAP was lower in COVID-19 survivors (
< 0.05). COVID-19 survivors exhibit an exaggerated MSNA and blunted vasodilatory response to mental challenge compared with healthy adults. However, the neurovascular response to handgrip exercise is preserved in COVID-19 survivors. Overall, the abnormal neurovascular control in response to mental stress suggests that COVID-19 survivors may have an increased risk to cardiovascular events during mental challenge.
Patients with heart failure with reduced ejection fraction related to anthracycline-based chemotherapy have increased sympathetic nerve activity and decreased exercise capacity. These alterations in ...autonomic control and physical capacity are similar to those observed in patients with heart failure due to other etiologies. These findings highlight the importance of special care of oncological patients treated with chemotherapy.
Cardiotoxicity is the most worrying cardiovascular alteration in patients treated with chemotherapy. To improve the understanding regarding the cardiotoxicity, we studied whether 1) patients with cardiac dysfunction related to anthracycline-based chemotherapy have augmented sympathetic nerve activity and decreased exercise capacity and 2) these responses are similar to those observed in patients with heart failure caused by other etiologies. Sixteen patients with heart failure with reduced ejection fraction related to anthracycline-based chemotherapy with or without chest radiation (HFrEFCA), 10 patients with heart failure with reduced ejection not related to cancer therapy (HFrEF), and 16 age- and body mass index (BMI)-matched healthy control subjects were studied. Left ventricular ejection fraction (LVEF, echocardiography), peak oxygen consumption (peak V̇o
2
, cardiopulmonary exercise test), muscle sympathetic nerve activity (MSNA, microneurography), and forearm blood flow (FBF, venous occlusion plethysmography) were measured. We found that peak oxygen consumption peak V̇o
2
and LVEF were significantly reduced in patients with HFrEFCA compared with that of control subjects ( P < 0.0001) but similar to those found in patients with HFrEFCA. The sympathetic nerve activity burst frequency and incidence were significantly higher in patients with HFrEFCA than that in control subjects ( P < 0.0001). No differences were found between patients with HFrEF and HFrEFCA. Peak V̇o
2
was inversely associated with MSNA burst frequency ( r = −0.53, P = 0.002) and burst incidence ( r = −0.38, P = 0.01) and directly associated with LVEF ( r = 0.71, P < 0.0001). Taken together, we conclude that patients who develop heart failure due to anthracycline-based chemotherapy have sympathetic neural overdrive and reduced exercise capacity. In addition, these physiological changes are similar to those observed in patients with HFrEF.
NEW & NOTEWORTHY Patients with heart failure with reduced ejection fraction related to anthracycline-based chemotherapy have increased sympathetic nerve activity and decreased exercise capacity. These alterations in autonomic control and physical capacity are similar to those observed in patients with heart failure due to other etiologies. These findings highlight the importance of special care of oncological patients treated with chemotherapy.
Background Patients treated for breast cancer have a high incidence of cardiovascular complications. In this study, we evaluated the impact of breast cancer on cardiac function and cardiomyocyte ...Ca2+-handling protein expression. We also investigated whether exercise training (ET) would prevent these potential alterations. Methods and Results Transgenic mice with spontaneous breast cancer (mouse mammary tumor virus-polyomavirus middle T antigen MMTV-PyMT+, n=15) and littermate mice with no cancer (MMTV-PyMT-, n=14) were studied. For the ET analysis, MMTV-PyMT+ were divided into sedentary (n=10) and exercise-trained (n=12) groups. Cardiac function was evaluated by echocardiography with speckle-tracking imaging. Exercise tolerance test was conducted on a treadmill. Both studies were performed when the tumor became palpable and when it reached 1 cm3. After euthanasia, Ca2+-handling protein expression (Western blot) was evaluated. Exercise capacity was reduced in MMTV-PyMT+ compared with MMTV-PyMT- (Pinteraction=0.031). Longitudinal strain (Pgroup <0.001) and strain rate (Pgroup=0.030) were impaired. Cardiomyocyte phospholamban was increased (P=0.011), whereas phospho-phospholamban and sodium/calcium exchanger were decreased (P=0.038 and P=0.017, respectively) in MMTV-PyMT+. No significant difference in sarcoplasmic or endoplasmic reticulum calcium 2 ATPase (SERCA2a) was found. SERCA2a/phospholamban ratio was reduced (P=0.007). ET was not associated with increased exercise capacity. ET decreased left ventricular end-systolic diameter (Pgroup=0.038) and end-diastolic volume (Pgroup=0.026). Other morphological and functional cardiac parameters were not improved by ET in MMTV-PyMT+. ET did not improve cardiomyocyte Ca2+-handling protein expression. Conclusions Breast cancer is associated with decreased exercise capacity and subclinical left ventricular dysfunction in MMTV-PyMT+, which is at least partly associated with dysregulation of cardiomyocyte Ca2+ handling. ET did not prevent or reverse these changes.Background Patients treated for breast cancer have a high incidence of cardiovascular complications. In this study, we evaluated the impact of breast cancer on cardiac function and cardiomyocyte Ca2+-handling protein expression. We also investigated whether exercise training (ET) would prevent these potential alterations. Methods and Results Transgenic mice with spontaneous breast cancer (mouse mammary tumor virus-polyomavirus middle T antigen MMTV-PyMT+, n=15) and littermate mice with no cancer (MMTV-PyMT-, n=14) were studied. For the ET analysis, MMTV-PyMT+ were divided into sedentary (n=10) and exercise-trained (n=12) groups. Cardiac function was evaluated by echocardiography with speckle-tracking imaging. Exercise tolerance test was conducted on a treadmill. Both studies were performed when the tumor became palpable and when it reached 1 cm3. After euthanasia, Ca2+-handling protein expression (Western blot) was evaluated. Exercise capacity was reduced in MMTV-PyMT+ compared with MMTV-PyMT- (Pinteraction=0.031). Longitudinal strain (Pgroup <0.001) and strain rate (Pgroup=0.030) were impaired. Cardiomyocyte phospholamban was increased (P=0.011), whereas phospho-phospholamban and sodium/calcium exchanger were decreased (P=0.038 and P=0.017, respectively) in MMTV-PyMT+. No significant difference in sarcoplasmic or endoplasmic reticulum calcium 2 ATPase (SERCA2a) was found. SERCA2a/phospholamban ratio was reduced (P=0.007). ET was not associated with increased exercise capacity. ET decreased left ventricular end-systolic diameter (Pgroup=0.038) and end-diastolic volume (Pgroup=0.026). Other morphological and functional cardiac parameters were not improved by ET in MMTV-PyMT+. ET did not improve cardiomyocyte Ca2+-handling protein expression. Conclusions Breast cancer is associated with decreased exercise capacity and subclinical left ventricular dysfunction in MMTV-PyMT+, which is at least partly associated with dysregulation of cardiomyocyte Ca2+ handling. ET did not prevent or reverse these changes.
•OUES analysis is useful for assessing functional capacity in refractory angina.•O2 pulse curve is correlated with contractile alterations in exercise echocardiogram.•Cardiopulmonary exercise test is ...useful toll in patients with refractory angina.
Refractory angina (RA) is a chronic condition clinically characterized by low effort tolerance; therefore, physical stress testing is not usually requested for these patients. Cardiopulmonary exercise testing (CPET) is considered a gold standard examination for functional capacity evaluation, even in submaximal tests, and it has gained great prominence in detecting ischemia. The authors aimed to determine cardiorespiratory capacity by using the oxygen consumption efficiency slope (OUES) in patients with refractory angina. The authors also studied the O2 pulse response by CPET and the association of ischemic changes with contractile modifications by exercise stress echocardiography (ESE).
Thirty-one patients of both sexes, aged 45 to 75 years, with symptomatic (Canadian Cardiovascular Society class II to IV) angina who underwent CPET on a treadmill and exercise stress echocardiography on a lower limb cycle ergometer were studied. ClinicalTrials.gov: NCT03218891.
The patients had low cardiorespiratory capacity (OUES of 1.74 ± 0.4 L/min; 63.9±14.7% of predicted), and 77% of patients had a flattening or drop in O2 pulse response. There was a direct association between Heart Rate (HR) at the onset of myocardial ischemia detected by ESE and HR at the onset of flattening or drop in oxygen pulse response detected by CPET (R = 0.48; p = 0.019).
Patients with refractory angina demonstrate low cardiorespiratory capacity. CPET shows good sensitivity for detecting abnormal cardiovascular response in these patients with a significant relationship between flattening O2 pulse response during CEPT and contractile alterations detected by exercise stress echocardiography.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Doxorubicin causes cardiotoxicity and exercise intolerance. Pre-conditioning exercise training seems to prevent doxorubicin-induced cardiac damage. However, the effectiveness of the cardioprotective ...effects of exercise training concomitantly with doxorubicin treatment remains largely unknown. To determine whether low-to-moderate intensity aerobic exercise training during doxorubicin treatment would prevent cardiotoxicity and exercise intolerance, we performed exercise training concomitantly with chronic doxorubicin treatment in mice. Ventricular structure and function were accessed by echocardiography, exercise tolerance by maximal exercise test, and cardiac biology by histological and molecular techniques. Doxorubicin-induced cardiotoxicity, evidenced by impaired ventricular function, cardiac atrophy, and fibrosis. Exercise training did not preserve left ventricular ejection fraction or reduced fibrosis. However, exercise training preserved myocardial circumferential strain alleviated cardiac atrophy and restored cardiomyocyte cross-sectional area. On the other hand, exercise training exacerbated doxorubicin-induced body wasting without affecting survival. Finally, exercise training blunted doxorubicin-induced exercise intolerance. Exercise training performed during doxorubicin-based chemotherapy can be a valuable approach to attenuate cardiotoxicity.
Purpose
Central and peripheral chemoreceptors are hypersensitized in patients with heart failure with reduced ejection fraction. Whether this autonomic alteration occurs in patients with heart ...failure with preserved ejection fraction (HFpEF) remains little known. We test the hypothesis that the central and peripheral chemoreflex control of muscle sympathetic nerve activity (MSNA) is altered in HFpEF.
Methods
Patients aged 55–80 years with symptoms of heart failure, body mass index ≤ 35 kg/m
2
, left ventricular ejection fraction > 50%, left atrial volume index > 34 mL/m
2
, left ventricular early diastolic filling velocity and early diastolic tissue velocity of mitral annulus ratio (E/e′ index) ≥ 13, and BNP levels > 35 pg/mL were included in the study (HFpEF,
n
= 9). Patients without heart failure with preserved ejection fraction (non-HFpEF,
n
= 9), aged-paired, were also included in the study. Peripheral chemoreceptors stimulation (10% O
2
and 90% N
2
, with CO
2
titrated) and central chemoreceptors stimulation (7% CO
2
and 93% O
2
) were conducted for 3 min. MSNA was evaluated by microneurography technique, and forearm blood flow (FBF) by venous occlusion plethysmography.
Results
During hypoxia, MSNA responses were greater (
p
< 0.001) and FBF responses were lower in patients with HFpEF (
p
= 0.006). Likewise, MSNA responses during hypercapnia were higher (
p
< 0.001) and forearm vascular conductance (FVC) levels were lower (
p
= 0.030) in patients with HFpEF.
Conclusions
Peripheral and central chemoreflex controls of MSNA are hypersensitized in patients with HFpEF, which seems to contribute to the increase in MSNA in these patients. In addition, peripheral and central chemoreceptors stimulation in patients with HFpEF causes muscle vasoconstriction.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ