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In clinical practice, there is vast knowledge regarding the evaluation of macrocirculatory parameters, such as systemic blood pressure and cardiac output, for the hemodynamic monitoring of patients. However, assessment of the microcirculation has not yet been incorporated into the bedside armamentarium. Hand-held intravital video microscopy enables the direct, noninvasive, evaluation of the sublingual microcirculation at the bedside, offering insights into the status of the systemic microcirculation. It is easily performed and may be employed in several clinical settings, providing immediate results that may help guide patient management. Therefore, the incorporation of hand-held intravital video microscopy into clinical practice may lead to tremendous improvements in the quality of care of critical, unstable patients or offer new data in the evaluation of patients with chronic diseases, especially those with microcirculatory involvement, such as occurs in diabetes.
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BACKGROUND: Metabolically healthy obesity (MHO), a phenotype of obesity considered to be of lower cardiovascular risk, is still a controversial concept. This study aimed to investigate the presence of subclinical systemic microvascular dysfunction in individuals with MHO. METHODS: This was a cross-sectional study in which 112 volunteers were allocated into three groups: metabolically healthy normal weight (MHNW), MHO, or metabolically unhealthy obesity (MUO). Obesity was defined as a body mass index (BMI) ≥ 30 kg/m2. MHO was defined as the absence of any component of metabolic syndrome, except waist circumference. Microvascular reactivity was evaluated using cutaneous laser speckle contrast imaging. RESULTS: Mean age was 33.2 ± 7.66 years. The median BMI in the MHNW, MHO and MUO groups was 23.6, 32.8, and 35.8 kg/m2, respectively. Baseline microvascular conductance values were lower in the MUO group (0.25 ± 0.08 APU/mmHg) than in MHO (0.30 ± 0.10 APU/mmHg) and MHNW groups (0.33 ± 0.12 APU/mmHg) (P = 0.0008). There were no significant differences regarding endothelial-dependent (acetylcholine stimulation or postocclusive reactive hyperemia) or endothelial-independent (sodium nitroprusside stimulation) microvascular reactivity among the groups. CONCLUSIONS: Individuals with MUO had lower baseline systemic microvascular flow than those with MHNW or MHO, but endothelium-dependent or endothelium-independent microvascular reactivity were not changed in any of the groups. The relatively young age of the study population, the low frequency of class III obesity, or the strict definition of MHO (absence of any metabolic syndrome criteria) might account for the lack of difference of microvascular reactivity among MHNW, MHO or MUO.
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Síndrome Metabólico , Obesidad Metabólica Benigna , Humanos , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/epidemiología , Obesidad Metabólica Benigna/diagnóstico , Obesidad Metabólica Benigna/epidemiología , Estudios Transversales , Obesidad , Índice de Masa Corporal , Fenotipo , Factores de RiesgoRESUMEN
Heart failure (HF) is associated with a reduction of skeletal muscle mass. Whey protein isolate (WPI) has been beneficial in increasing muscle mass and strength, in addition to improving body composition. The goal of this research was to evaluate the effect of WPI on the body composition, muscle mass, and strength of chronic HF patients. For this purpose, twenty-five patients of both genders with predominantly NYHA I functional class and a median age of 65.5 (60.5-71.0) years were used to conduct a randomized, single-blind, placebo-controlled clinical trial and received 30 g per day of WPI for 12 weeks. Anthropometric measurements, body composition analysis, and biochemical exams were performed at the beginning and end of the study. An increase in skeletal muscle mass was observed in the intervention group after 12 weeks. A reduction in waist circumference, body fat percentage, and an increase in skeletal muscle index was observed when compared to the placebo group. No significant effect on muscle strength was observed after 12 weeks of intervention. These data demonstrate that WPI consumption contributed to the increase of skeletal muscle mass, strength, and reduction of body fat in HF patients.
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Insuficiencia Cardíaca , Entrenamiento de Fuerza , Humanos , Masculino , Femenino , Anciano , Proteína de Suero de Leche , Método Simple Ciego , Suplementos Dietéticos , Fuerza Muscular , Músculo Esquelético , Composición Corporal , Método Doble CiegoRESUMEN
Systemic microvascular dysfunction has been shown to be present in COVID-19, and serum cytokines are known to be involved in the regulation of vascular function. We sought to evaluate systemic microvascular endothelial function, with laser doppler perfusion monitoring (LDPM), and plasma levels of cytokines after acute COVID-19. Individuals admitted to a Cardiology hospital with acute COVID-19 and followed for 12-15 months after recovery underwent noninvasive evaluation of systemic endothelium-dependent microvascular reactivity by cutaneous LDPM with local thermal hyperemia (LTH). A multiplex biometric immunoassay panel was used to assess 48 serum cytokines and chemokines. Twenty patients and 14 control volunteers were enrolled. The areas under the curves of vasodilation induced by LTH were significantly increased after recovery (P=0.009) and were not different from values obtained in healthy volunteers (P = 0.85). The peak microvascular flow during LTH did also significantly increase (P = 0.02), and was not different form values obtained in healthy volunteers (P = 0.55). Several cytokines displayed significantly reduced serum concentrations after recovery from COVID-19. In conclusion, endothelium-dependent systemic microvascular reactivity improved after recovery from COVID-19 in patients with cardiovascular diseases, in parallel with a reduction in the levels of several serum cytokines and chemokines involved in the regulation of vascular function and inflammation.
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COVID-19 , Hiperemia , Humanos , Citocinas , Microcirculación/fisiología , Vasodilatación/fisiología , Piel/irrigación sanguíneaRESUMEN
Abstract Systemic microvascular dysfunction has been shown to be present in COVID-19, and serum cytokines are known to be involved in the regulation of vascular function. We sought to evaluate systemic microvascular endothelial function, with laser doppler perfusion monitoring (LDPM), and plasma levels of cytokines after acute COVID-19. Individuals admitted to a Cardiology hospital with acute COVID-19 and followed for 12-15 months after recovery underwent noninvasive evaluation of systemic endothelium-dependent microvascular reactivity by cutaneous LDPM with local thermal hyperemia (LTH). A multiplex biometric immunoassay panel was used to assess 48 serum cytokines and chemokines. Twenty patients and 14 control volunteers were enrolled. The areas under the curves of vasodilation induced by LTH were significantly increased after recovery (P=0.009) and were not different from values obtained in healthy volunteers (P= 0.85). The peak microvascular flow during LTH did also significantly increase (P= 0.02), and was not different form values obtained in healthy volunteers (P= 0.55). Several cytokines displayed significantly reduced serum concentrations after recovery from COVID-19. In conclusion, endothelium-dependent systemic microvascular reactivity improved after recovery from COVID-19 in patients with cardiovascular diseases, in parallel with a reduction in the levels of several serum cytokines and chemokines involved in the regulation of vascular function and inflammation.
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BACKGROUND: Metabolic syndrome (MS) is defined as a low-grade proinflammatory state in which abnormal metabolic and cardiovascular factors increase the risk of developing cardiovascular disease and neuroinflammation. Events, such as the accumulation of visceral adipose tissue, increased plasma concentrations of free fatty acids, tissue hypoxia, and sympathetic hyperactivity in MS may contribute to the direct or indirect activation of Toll-like receptors (TLRs), specifically TLR4, which is thought to be a major component of this syndrome. Activation of the innate immune response via TLR4 may contribute to this state of chronic inflammation and may be related to the neuroinflammation and neurodegeneration observed in MS. In this study, we investigated the role of TLR4 in the brain microcirculation and in the cognitive performance of high-fat diet (HFD)-induced MS mice. METHODS: Wild-type (C3H/He) and TLR4 mutant (C3H/HeJ) mice were maintained under a normal diet (ND) or a HFD for 24 weeks. Intravital video-microscopy was used to investigate the functional capillary density, endothelial function, and endothelial-leukocyte interactions in the brain microcirculation. Plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), adipokines and metabolic hormones were measured with a multiplex immunoassay. Brain postsynaptic density protein-95 and synaptophysin were evaluated by western blotting; astrocytic coverage of the vessels, microglial activation and structural capillary density were evaluated by immunohistochemistry. RESULTS: The HFD-induced MS model leads to metabolic, hemodynamic, and microcirculatory alterations, as evidenced by capillary rarefaction, increased rolling and leukocyte adhesion in postcapillary venules, endothelial dysfunction, and less coverage of astrocytes in the vessels, which are directly related to cognitive decline and neuroinflammation. The same model of MS reproduced in mice deficient for TLR4 because of a genetic mutation does not generate such changes. Furthermore, the comparison of wild-type mice fed a HFD and a normolipid diet revealed differences in inflammation in the cerebral microcirculation, possibly related to lower TLR4 activation. CONCLUSIONS: Our results demonstrate that TLR4 is involved in the microvascular dysfunction and neuroinflammation associated with HFD-induced MS and possibly has a causal role in the development of cognitive decline.
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Disfunción Cognitiva , Síndrome Metabólico , Animales , Disfunción Cognitiva/complicaciones , Dieta Alta en Grasa/efectos adversos , Inflamación/metabolismo , Síndrome Metabólico/etiología , Ratones , Ratones Endogámicos C3H , Microcirculación , Mutación , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
The coronavirus disease 2019 (COVID-19) pandemic has put into evidence another pandemic - obesity. Currently, several studies have documented the association between obesity and COVID-19 severity. The mechanisms underlying the increased risk of complications and mortality in obese patients with COVID-19 are of diverse nature. Inflammation plays a central role in obesity. Metabolic alterations seen in obese patients are related to an inflammatory response, and several studies report elevated levels of circulating inflammatory cytokines in obese patients. Also, deregulated expression of adipokines, such as leptin and resistin, increase the expression of vascular adhesion molecule 1 and intercellular adhesion molecule 1 that contribute to increased vascular leukocyte adhesiveness and additional oxidative stress. Additionally, it is now recognized that the chronic impairment of systemic vascular endothelial function in patients with cardiovascular and metabolic disorders, including obesity, when intensified by the detrimental effects of SARS-CoV-2 over the endothelium, may explain their worse outcomes in COVID-19. In fact, vascular endothelial dysfunction may contribute to a unfavorable response of the endothelium to the infection by SARS-CoV-2, whereas alterations in cardiac structure and function and the prothrombotic environment in obesity may also provide a link to the increased cardiovascular events in these patients.
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OBJECTIVE: This study compares microvascular reactivity (MR) in chronic Chagas disease (CD) patients with healthy individuals, matched for sex and age. In addition, we evaluated the association between MR and left ventricular ejection fraction (LVEF) in patients. METHODS: Acetylcholine iontophoresis was performed on the forearm skin, using laser speckle contrast imaging, to evaluate endothelium-dependent vasodilation. Clinical data were obtained from medical records. RESULTS: Thirty-six patients were compared to 25 healthy individuals (controls). Vasodilation was higher in controls, when compared to patients (p < .0001). There was a significant association between LVEF, stratified into quartiles, and MR (p-value for linear trend = .002). In addition, there was no difference in MR between patients with normal LVEF and the control group. In patients, MR was independent of the presence of arterial hypertension or diabetes. CONCLUSIONS: We have shown for the first time that the reduction of MR is associated with a decrease of LVEF in a cohort of chronic CD patients. The results were not affected by comorbidities, such as hypertension or diabetes. The evaluation of systemic endothelial function may be useful to tailor therapeutic and preventive approaches, targeted at systolic left ventricular failure associated with chronic CD cardiomyopathy.
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Enfermedad de Chagas , Hipertensión , Disfunción Ventricular Izquierda , Endotelio Vascular , Humanos , Volumen Sistólico , Vasodilatadores , Función Ventricular IzquierdaRESUMEN
This randomized crossover and placebo-controlled trial evaluated the effects of daily use of sildenafil citrate (SIL, 1-month 50 mg twice daily) on penile and systemic endothelial microvascular function in hypertensive patients presenting with erectile dysfunction. The effects of SIL on arterial pressure were evaluated using ambulatory blood pressure monitoring (ABPM). Fifty patients diagnosed with primary arterial hypertension and erectile dysfunction (aged 57.4 ± 5.6 years), recruited in a tertiary public hospital, were treated with SIL (50 mg twice daily) or placebo (PLA) for two 30-day periods with a 30-day washout between them. Laser speckle contrast imaging coupled with acetylcholine skin iontophoresis was used to evaluate penile and systemic (forearm) cutaneous microvascular reactivity. SIL treatment increased penile basal microvascular flow (P = 0.002) and maximal endothelial-dependent peak response to skin iontophoresis of acetylcholine (ACh, P = 0.006). The area under the curve of microvascular vasodilation induced by ACh was also significantly increased (P = 0.02). Lastly, SIL treatment did not modify systemic microvascular reactivity. Twenty-four-hour ABPM (P = 0.0002) and daytime (P = 0.002) and nighttime (P = 0.001) mean diastolic blood pressure values were significantly reduced after SIL treatment. The scores of the Simplified International Index of Erectile Function (P < 0.0001) and the number of patients with positive responses to Sexual Encounter Profile question 3 (P < 0.0001) also increased after SIL treatment. Penile endothelium-dependent microvascular reactivity improved after continuous use of sildenafil in hypertensive patients with erectile dysfunction; the treatment also reduced blood pressure, suggesting that, in addition to improving erectile function, daily use of sildenafil could improve blood pressure control.
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Disfunción Eréctil , Hipertensión , Monitoreo Ambulatorio de la Presión Arterial , Estudios Cruzados , Método Doble Ciego , Disfunción Eréctil/tratamiento farmacológico , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Masculino , Hidrolasas Diéster FosfóricasRESUMEN
BACKGROUND: Microvascular dysfunction, serum cytokines and chemokines may play important roles in pathophysiology of coronavirus disease 2019 (COVID-19), especially in severe cases. METHODS: Patients with COVID-19 underwent non-invasive evaluation of systemic endothelium-dependent microvascular reactivity - using laser Doppler perfusion monitoring in the skin of the forearm - coupled to local thermal hyperemia. Maximal microvascular vasodilatation (44 °C thermal plateau phase) was used as endpoint. A multiplex biometric immunoassay was used to assess a panel of 48 serum cytokines and chemokines. Severe COVID-19 (S-COVID) was defined according to WHO criteria, while all other cases of COVID-19 were considered mild to moderate (M-COVID). A group of healthy individuals who tested negative for SARS-CoV-2 served as a control group and was also evaluated with LDPM. RESULTS: Thirty-two patients with COVID-19 (25% S-COVID) and 14 controls were included. Basal microvascular flow was similar between M-COVID and controls (P = 0.69) but was higher in S-COVID than in controls (P = 0.005) and M-COVID patients (P = 0.01). The peak microvascular vasodilator response was markedly decreased in both patient groups (M-COVID, P = 0.001; S-COVID, P < 0.0001) compared to the healthy group. The percent increases in microvascular flow were markedly reduced in both patient groups (M-COVID, P < 0.0001; S-COVID, P < 0.0001) compared to controls. Patients with S-COVID had markedly higher concentrations of dissimilar proinflammatory cytokines and chemokines, compared to patients with M-COVID. CONCLUSIONS: In patients with COVID-19, especially with S-COVID, endothelium-dependent microvascular vasodilator responses are reduced, while serum cytokines and chemokines involved in the regulation of vascular function and inflammation are increased.
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COVID-19/fisiopatología , Quimiocinas/metabolismo , Citocinas/metabolismo , Endotelio Vascular/fisiopatología , Microcirculación , Adulto , Anciano , Quimiocinas/sangre , Citocinas/sangre , Femenino , Voluntarios Sanos , Hemodinámica , Humanos , Inmunoensayo , Flujometría por Láser-Doppler , Masculino , Persona de Mediana Edad , Perfusión , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Chagas heart disease (CHD) impairs the systemic microvascular function. We investigated the effects of exercise training on cutaneous microvascular function among patients with CHD. METHODS: Patients from the PEACH study were randomly assigned to a supervised exercise training 3 times/week for 6 months (Trained; n = 10) or a control group (Untrained; n = 8). Both groups underwent evaluation of microvascular function before, and at 3- and 6-months of follow-up. Cutaneous vascular conductance (CVC) was assessed in the skin of the forearm using laser speckle contrast imaging coupled with iontophoresis of acetylcholine (ACh), sodium nitroprusside (SNP) and during post-occlusive reactive hyperemia (PORH). RESULTS: At 3-months of follow-up, no difference was detected between groups in CVC responses to ACh (p = 0.50), SNP (p = 0.26) and HRPO (p = 0.65). However, at 6-months of follow-up, trained vs. untrained patients improved CVC induced by SNP-iontophoresis (0.19 ± 0.10 vs. 0.14 ± 0.15 APU.mmHg-1; p = 0.05) and PORH (0.63 ± 0.15 vs. 0.48 ± 0.18 APU.mmHg-1; p = 0.05). CVC response to ACh-iontophoresis was similar between groups (0.19 ± 0.11 vs. 0.22 ± 0.17 APU.mmHg-1; p = 0.38). CONCLUSION: Exercise training performed during 6 months improved the cutaneous microvascular function of CHD patients. Further studies evaluating the mechanism involved in this response are warranted.
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Rehabilitación Cardiaca , Cardiomiopatía Chagásica/rehabilitación , Terapia por Ejercicio , Microcirculación , Piel/irrigación sanguínea , Anciano , Brasil , Cardiomiopatía Chagásica/diagnóstico por imagen , Cardiomiopatía Chagásica/parasitología , Cardiomiopatía Chagásica/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recuperación de la Función , Flujo Sanguíneo Regional , Factores de Tiempo , Resultado del TratamientoRESUMEN
Antioxidant effects of statins have been implicated in the reduction in microvascular permeability and edema formation in experimental and clinical studies. Bradykinin (Bk)-induced increases in microvascular permeability are potentiated by IL-1ß; however, no studies have examined the protection afforded by statins against microvascular hyperpermeability. We investigated the effects of simvastatin pretreatment on albumin-fluorescein isothiocyanate conjugate (FITC-albumin) permeability in post-capillary venules in rat cremaster muscle. Inhibition of nitric oxide synthase with L-NAME (10µM) increased basal permeability to FITC-albumin, which was abrogated by superoxide dismutase and catalase. Histamine-induced (1 µM) permeability was blocked by L-NAME but unaffected by scavenging reactive oxygen species with superoxide dismutase (SOD) and catalase. In contrast, bradykinin-induced (1-100 nM) permeability increases were unaffected by L-NAME but abrogated by SOD and catalase. Acute superfusion of the cremaster muscle with IL-1ß (30 pM, 10 min) resulted in a leftward shift of the bradykinin concentration-response curve. Potentiation by IL-1ß of bradykinin-induced microvascular permeability was prevented by the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) inhibitor apocynin (1 µM). Pretreatment of rats with simvastatin (5 mg·kg-1, i.p.) 24 h before permeability measurements prevented the potentiation of bradykinin permeability responses by IL-1ß, which was not reversed by inhibition of heme oxygenase-1 with tin protoporphyrin IX (SnPP). This study highlights a novel mechanism by which simvastatin prevents the potentiation of bradykinin-induced permeability by IL-1ß, possibly by targeting the assembly of NADPH oxidase subunits. Our findings highlight the therapeutic potential of statins in the prevention and treatment of patients predisposed to inflammatory diseases.
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COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), while having lung injury as its most prominent feature, has been increasingly shown to affect endothelial cell function and the microvasculature. In this report, a woman with COVID-19, cardiac valve disease and spherocytosis was assessed with laser Doppler perfusion monitoring. Systemic microvascular reactivity was impaired during a worsening phase of COVID-19, but improved after clinical recovery; microcirculatory dysfunction paralleled systemic inflammation and pulmonary involvement. The assessment of systemic microcirculatory function may therefore provide insights on COVID-19 pathophysiology.
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The recently described severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people, with thousands of fatalities. It has prompted global efforts in research, with focus on the pathophysiology of coronavirus disease-19 (COVID-19), and a rapid surge of publications. COVID-19 has been associated with a myriad of clinical manifestations, including the lungs, heart, kidneys, central nervous system, gastrointestinal system, skin, and blood coagulation abnormalities. The endothelium plays a key role in organ dysfunction associated with severe infection, and current data suggest that it is also involved in SARS-CoV-2-induced sepsis. This critical review aimed to address a possible unifying mechanism underlying the diverse complications of COVID-19: microvascular dysfunction, with emphasis on the renin-angiotensin system. In addition, research perspectives are suggested in order to expand understanding of the pathophysiology of the infection.
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Infecciones por Coronavirus , Microvasos , Pandemias , Neumonía Viral , Sistema Renina-Angiotensina/fisiología , Betacoronavirus/fisiología , COVID-19 , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/fisiopatología , Humanos , Microvasos/metabolismo , Microvasos/fisiopatología , Microvasos/virología , Neumonía Viral/metabolismo , Neumonía Viral/fisiopatología , SARS-CoV-2RESUMEN
Obesity is a major risk factor for noncommunicable diseases that is responsible for more than 70% of early deaths in the world. In the 1980's decade, some studies started to describe a "benign" obesity phenotype, named "metabolically healthy obesity" (MHO), which represents obesity without comorbidities such as hypertension, cardiovascular diseases, insulin resistance, diabetes, dyslipidemia or metabolic syndrome. However, it is still unclear if this "benign" obesity phenotype is really favorable or just a transition status to unhealthy obesity and if these subjects presented subclinical levels of cardiovascular risk that are not commonly detected. To further elucidate these issues, the investigation of pathophysiological mechanisms that can increase cardiovascular risk in MHO individuals, such as hormones and cytokines, may offer some responses. In parallel, the evaluation of subclinical cardiovascular derangement, using the systemic microcirculation as a proxy, may be an alternative to anticipate overt cardiovascular disease. Overall, further studies are needed to better understand the pathophysiology of MHO as well as to identify high-risk individuals who deserve more intensive management.