Hypertension disrupts cerebral blood flow,leading to endothelial dysfunction,breakdown of the blood-brain barrier(BBB),and inflammatory cell infiltration.This cascade triggers glial cell activation,increases oxidative...Hypertension disrupts cerebral blood flow,leading to endothelial dysfunction,breakdown of the blood-brain barrier(BBB),and inflammatory cell infiltration.This cascade triggers glial cell activation,increases oxidative stress,and causes pro-inflammatory cytokine release,creating a neurotoxic environment.In this context,we explore the intricate connection between hypertension,neuroinflammation,and neurodegeneration,as well as how hypertension interacts with other metabolic disorders,such as obesity and diabetes,to further worsen neuroinflammation.Additionally,we discuss the role of the reninangiotensin-aldosterone system,the impact of the microbiome,and the potential contribution of chronic infections in exacerbating neuroinflammation.It is essential to emphasize the potential of nanotechnology to transform therapeutic approaches.Nanoparticle-based drug delivery systems can enhance the bioavailability and selectivity of antihypertensive drugs,antioxidants,and neuroprotective compounds,enabling targeted delivery across the BBB.By combining effective blood pressure management with nanotechnology-enabled therapies that modulate inflammation,oxidative stress,and protein aggregation,we can explore new avenues for preventing and treating hypertension and metabolic disorder-associated neurodegenerative conditions.Ultimately,hypertension significantly contributes to neuroinflammation and neurodegeneration by promoting neuronal cell death,primarily through impaired cerebral blood flow and disruption of the BBB.The interaction of hypertension with metabolic disorders exacerbates these effects.However,advancements in our understanding and new technologies reveal promising nanopharmacological approaches for targeted drug delivery to the brain,thereby improving treatment outcomes,enhancing adherence,and reducing side effects.展开更多
Diabetic foot(DF) is a common complication of diabetes and the first cause of hospital admission in diabetic patients. In recent years several guidelines have been proposed to reinforce the the management of DF with a...Diabetic foot(DF) is a common complication of diabetes and the first cause of hospital admission in diabetic patients. In recent years several guidelines have been proposed to reinforce the the management of DF with a notable increase in diabetes knowledge and an overall reduction of amputations. Significant improvements have been reached in the treatment of diabetic foot ulcers(DFUs) and nowadays clinicians have several advanced medications to apply for the best local therapy. Among these, negative pressure wound therapy(NPWT) is a useful adjunct in the management of chronic and complex wounds to promote healing and wound bed preparation for surgical procedures such as skin grafts and flap surgery. NPWT has shown remarkable results although its mechanisms of action are not completely understood. In this paper, we offer a complete overview of this medication and its implication in the clinical setting. We have examined literature related to NPWT concerning human, animal and in vitro studies, and we have summarized why, when and how we can use NPWT to treat DFUs. Further we have associated our clinical experience to scientific evidence in the field of diabetic foot to identify a defined strategy that could guide clinician in the use of NPWT approaching to DFUs.展开更多
The inflammato ry response plays an important role in neuroprotection and regeneration after ischemic insult.The use of non-ste roidal anti-inflammatory drugs has been a matter of debate as to whether they have benefi...The inflammato ry response plays an important role in neuroprotection and regeneration after ischemic insult.The use of non-ste roidal anti-inflammatory drugs has been a matter of debate as to whether they have beneficial or detrimental effects.In this context,the effects of the anti-inflammatory agent meloxicam have been scarcely documented after stro ke,but its ability to inhibit both cyclooxygenase isoforms(1 and 2) could be a promising strategy to modulate postischemic inflammation.This study analyzed the effect of meloxicam in a transient focal cerebral ischemia model in rats,measuring its neuroprotective effect after 48 hours and 7 days of reperfusion and the effects of the treatment on the glial scar and regenerative events such as the generation of new progenitors in the subventricular zone and axonal sprouting at the edge of the damaged area.We show that meloxicam’s neuroprotective effects remained after 7 days of reperfusion even if its administration was restricted to the two first days after ischemia.Moreover,meloxicam treatment modulated glial scar reactivity,which matched with an increase in axonal sprouting.However,this treatment decreased the formation of neuronal progenitor cells.This study discusses the dual role of anti-inflammatory treatments after stro ke and encourages the careful analysis of both the neuroprotective and the regenerative effects in preclinical studies.展开更多
BACKGROUND Non-invasive differential diagnosis between hepatocellular carcinoma(HCC)and other liver cancer(i.e.cholangiocarcinoma or metastasis)is highly challenging and definitive diagnosis still relies on histologic...BACKGROUND Non-invasive differential diagnosis between hepatocellular carcinoma(HCC)and other liver cancer(i.e.cholangiocarcinoma or metastasis)is highly challenging and definitive diagnosis still relies on histological exam.The patterns of enhancement and wash-out of liver nodules can be used to stratify the risk of malignancy only in cirrhotic patients and HCC frequently shows atypical features.Dynamic contrast-enhanced ultrasound(DCEUS)with standardized software could help to overcome these obstacles,providing functional and quantitative parameters and potentially improving accuracy in the evaluation of tumor perfusion.AIM To explore clinical evidence regarding the application of DCEUS in the differential diagnosis of liver nodules.METHODS A comprehensive literature search of clinical studies was performed to identify the parameters of DCEUS that could relate to histological diagnosis.In accordance with the study protocol,a qualitative and quantitative analysis of the evidence was planned.RESULTS Rise time was significantly higher in HCC patients with a standardized mean difference(SMD)of 0.83(95%CI:0.48-1.18).Similarly,other statistically significant parameters were mean transit time local with a SMD of 0.73(95%CI:0.20-1.27),peak enhancement with a SMD of 0.37(95%CI:0.03-0.70),area wash-in area under the curve with a SMD of 0.47(95%CI:0.13-0.81),wash-out area under the curve with a SMD of 0.55(95%CI:0.21-0.89)and wash-in and wash-out area under the curve with SMD of 0.51(95%CI:0.17-0.85).SMD resulted not significant in fall time and wash-in rate,but the latter presented a trend towards greater values in HCC compared to intrahepatic cholangiocarcinoma.CONCLUSION DCEUS could improve non-invasive diagnosis of HCC,leading to less liver biopsy and early treatment.This quantitative analysis needs to be applied on larger cohorts to confirm these preliminary results.展开更多
We determined whether the inclusion of 100 g/kg dry matter of grape pomace silage (GPS) and grape pomace bran (GPB) as substitutes for other traditional fiber sources in the diet of steers (Charolais x Nellore) would ...We determined whether the inclusion of 100 g/kg dry matter of grape pomace silage (GPS) and grape pomace bran (GPB) as substitutes for other traditional fiber sources in the diet of steers (Charolais x Nellore) would improve carcass characteristics, meat quality and composition, and shelf life. Twenty-four animals (248 ± 19.32 kg of initial body weight) were fed a high concentrate diet for 121 days. Carcass characteristics were measured, and the longissimus dorsi muscle was analyzed for fatty acid (FA) profile and composition. The meat was sliced and stored in air-permeable packages for 10 days. On each sampling day (d 1, 3, 7, and 10), oxidative stability, bacterial load, lipid and protein oxidation, and staining were analyzed. The experimental diets influenced the pH of cold carcasses only. The GPS group had a higher pH than the control. The GPS and GPB groups showed improved oxidant status (i.e., lower lipid peroxidation and concentrations of reactive oxygen species were in the meat of both groups than in control). On the first day of storage, the antioxidant enzyme glutathione S-transferase activity was more significant in the meat of the GPS and GPB groups than in the control. The bacterial loads in the meat were attenuated by GPS inclusion;there were lower total coliform counts and a trend toward lower counts for enterobacteria in the control group. The diets altered the FA profile of the meat;i.e., the GPB diet allowed for a more significant amount of the n-6 omegas in the meat, while the GPS diet showed a tendency for a more significant amount of n-6 and 9 omegas. Both diets (GPS and GPB) increased the amounts of long-chain FAs. The GPS diet decreased saturated FA levels. We conclude that the dietary treatments GPS and GPB are a promising alternative to maintain meat quality standards throughout in real-world retail conditions. These treatments gave rise to an improvement in the nutritional value of the meat due to the more significant amounts of FAs that improve human health.展开更多
BACKGROUND Metastatic pancreatic ductal adenocarcinoma(PDAC)is a lethal malignancy with dispiriting survival data.Immunotherapy is a promising approach to many cancer types,but achieves poor outcomes in advanced PDAC ...BACKGROUND Metastatic pancreatic ductal adenocarcinoma(PDAC)is a lethal malignancy with dispiriting survival data.Immunotherapy is a promising approach to many cancer types,but achieves poor outcomes in advanced PDAC due to its immunosuppressive tumor microenvironment.We describe a case of metastatic PDAC effectively treated with pembrolizumab.CASE SUMMARY We report the case of a 67-year-old woman with unresectable locally advanced PDAC,treated with gemcitabine plus nab-paclitaxel followed by radiotherapy plus capecitabine.At nine months,pancreatic tumor progression was observed at the level of the hepatic hilum with the appearance of a new pulmonary nodule suggestive of a second primary,confirmed by left lung biopsy.Systemic immunotherapy was then initiated with pembrolizumab,an immune checkpoint inhibitor targeting programmed cell death protein-1 that covers the two tumor types.The patient showed a complete metabolic response that was maintained throughout the treatment.The patient continues to be disease-free at 5.6 years since the start of immunotherapy.CONCLUSION These results suggest that the administration of pembrolizumab after chemoradiotherapy has a beneficial effect in patients with metastatic PDAC.To our knowledge,this is the first reported case of a patient with metastatic PDAC and metastatic lung cancer showing such a long-lasting complete response after pembrolizumab treatment without curative surgery.Further studies are required to determine biomarkers that identify PDAC patients most likely to benefit from this immunotherapy.展开更多
Mesenchymal stromal cells are an excellent source of stem cells because they are isolated from adult tissues or perinatal derivatives, avoiding the ethical concerns that encumber embryonic stem cells. In preclinical m...Mesenchymal stromal cells are an excellent source of stem cells because they are isolated from adult tissues or perinatal derivatives, avoiding the ethical concerns that encumber embryonic stem cells. In preclinical models, it has been shown that mesenchymal stromal cells have neuroprotective and immunomodulatory properties, both of which are ideal for central nervous system treatment and repair. Here we will review the current literature on mesenchymal stromal cells, focusing on bone marrow mesenchymal stromal cells, adipose-derived mesenchymal stromal cells and mesenchymal stromal cells from the umbilical cord stroma, i.e.,Wharton’s jelly mesenchymal stromal cells. Finally, we will discuss the use of these cells to alleviate retinal ganglion cell degeneration following axonal trauma.展开更多
Our aim was to evaluate the reproducibility of the Functional Independence Measure (FIM) scale when assessed by physical therapists in the routine setting of a Rehabilitation Hospital. We included a consecutive series...Our aim was to evaluate the reproducibility of the Functional Independence Measure (FIM) scale when assessed by physical therapists in the routine setting of a Rehabilitation Hospital. We included a consecutive series of patients with spinal cord or cerebral lesions. Each of the 50 selected patients was evaluated by two of the 5 experienced physical therapists participating in the study. The degree of inter-rater and intrarater agreement was measured by a weighted k statistic, k for perfect agreement, and k for the agreement with tolerance. The weighted k index for inter-rater agreement on the FIM score was in the almost perfect range (k 0.87;95% CI = 0.79 - 0.95), but a 20-point tolerance was necessary to reach a k value of 0.81 (95% CI = 0.66 - 0.95). Agreement was substantial or almost perfect for most subscales, but the k index with 1-point tolerance reached the almost perfect rating for comprehension only. For intra-rater agreement, weighted k index was in the almost perfect range for the FIM score and for all subscales;kappa index reached the almost perfect range with a 4-point tolerance for FIM score and with 1-point of tolerance for all subscales except interpersonal relations. FIM is useful to monitor patient improvement during rehabilitation treatment, mostly when assessed by the same physical therapist.展开更多
Aims: The G protein-coupled receptor kinase-2(GRK2 or β-ARK1) regulates β-adrenergic receptors(β-ARs) in the heart, and its cardiac expression is elevated in human heart failure(HF). We sought to determine whether ...Aims: The G protein-coupled receptor kinase-2(GRK2 or β-ARK1) regulates β-adrenergic receptors(β-ARs) in the heart, and its cardiac expression is elevated in human heart failure(HF). We sought to determine whether myocardial levels and activity of GRK2 could be monitored using white blood cells, which have been used to study cardiac β-ARs. Moreover, we were interested in determining whether GRK2 levels in myocardium and lymphocytes may be associated with β-AR dysfunction and HF severity. Methods and results: In myocardial biopsies from explanted failing human hearts, GRK activity was inversely correlated with β-AR-mediated cAMP production(R2=0.215, P< 0.05, n=24). Multiple regression analysis confirmed that GRK activity participates with β-AR density to regulate catecholamine-sensitive cAMP responses. Importantly, there was a direct correlation between myocardial and lymphocytes GRK2 activity(R2=0.5686, P< 0.05, n=10). Lymphocyte GRK activity was assessed in HF patients with various ejection fractions(EFs)(n=33), and kinase activity was significantly higher in patients with lower EFs and was higher with increasing NYHA class(P< 0.001). Conclusion: Myocardial GRK2 expression and activity are mirrored by lymphocyte levels of this kinase, and its elevation in HF is associated with the loss of β-AR responsiveness and appears to increase with disease severity. Therefore, lymphocytes may provide a surrogate for monitoring cardiac GRK2 in human HF.展开更多
基金Supported by Agencia Nacional de Promoción de la Investigación,el Desarrollo Tecnológico y la Innovación,No.PICT 2020 Serie A 4000.
文摘Hypertension disrupts cerebral blood flow,leading to endothelial dysfunction,breakdown of the blood-brain barrier(BBB),and inflammatory cell infiltration.This cascade triggers glial cell activation,increases oxidative stress,and causes pro-inflammatory cytokine release,creating a neurotoxic environment.In this context,we explore the intricate connection between hypertension,neuroinflammation,and neurodegeneration,as well as how hypertension interacts with other metabolic disorders,such as obesity and diabetes,to further worsen neuroinflammation.Additionally,we discuss the role of the reninangiotensin-aldosterone system,the impact of the microbiome,and the potential contribution of chronic infections in exacerbating neuroinflammation.It is essential to emphasize the potential of nanotechnology to transform therapeutic approaches.Nanoparticle-based drug delivery systems can enhance the bioavailability and selectivity of antihypertensive drugs,antioxidants,and neuroprotective compounds,enabling targeted delivery across the BBB.By combining effective blood pressure management with nanotechnology-enabled therapies that modulate inflammation,oxidative stress,and protein aggregation,we can explore new avenues for preventing and treating hypertension and metabolic disorder-associated neurodegenerative conditions.Ultimately,hypertension significantly contributes to neuroinflammation and neurodegeneration by promoting neuronal cell death,primarily through impaired cerebral blood flow and disruption of the BBB.The interaction of hypertension with metabolic disorders exacerbates these effects.However,advancements in our understanding and new technologies reveal promising nanopharmacological approaches for targeted drug delivery to the brain,thereby improving treatment outcomes,enhancing adherence,and reducing side effects.
文摘Diabetic foot(DF) is a common complication of diabetes and the first cause of hospital admission in diabetic patients. In recent years several guidelines have been proposed to reinforce the the management of DF with a notable increase in diabetes knowledge and an overall reduction of amputations. Significant improvements have been reached in the treatment of diabetic foot ulcers(DFUs) and nowadays clinicians have several advanced medications to apply for the best local therapy. Among these, negative pressure wound therapy(NPWT) is a useful adjunct in the management of chronic and complex wounds to promote healing and wound bed preparation for surgical procedures such as skin grafts and flap surgery. NPWT has shown remarkable results although its mechanisms of action are not completely understood. In this paper, we offer a complete overview of this medication and its implication in the clinical setting. We have examined literature related to NPWT concerning human, animal and in vitro studies, and we have summarized why, when and how we can use NPWT to treat DFUs. Further we have associated our clinical experience to scientific evidence in the field of diabetic foot to identify a defined strategy that could guide clinician in the use of NPWT approaching to DFUs.
基金supported by MINECO and FEDER funds:ref CPP2021-008855 and RTC-2015-4094-1,Junta de Castilla y León ref.LE025P1 7Neural Therapies SLref.NTDev-01 (all to AFL and JMGO)。
文摘The inflammato ry response plays an important role in neuroprotection and regeneration after ischemic insult.The use of non-ste roidal anti-inflammatory drugs has been a matter of debate as to whether they have beneficial or detrimental effects.In this context,the effects of the anti-inflammatory agent meloxicam have been scarcely documented after stro ke,but its ability to inhibit both cyclooxygenase isoforms(1 and 2) could be a promising strategy to modulate postischemic inflammation.This study analyzed the effect of meloxicam in a transient focal cerebral ischemia model in rats,measuring its neuroprotective effect after 48 hours and 7 days of reperfusion and the effects of the treatment on the glial scar and regenerative events such as the generation of new progenitors in the subventricular zone and axonal sprouting at the edge of the damaged area.We show that meloxicam’s neuroprotective effects remained after 7 days of reperfusion even if its administration was restricted to the two first days after ischemia.Moreover,meloxicam treatment modulated glial scar reactivity,which matched with an increase in axonal sprouting.However,this treatment decreased the formation of neuronal progenitor cells.This study discusses the dual role of anti-inflammatory treatments after stro ke and encourages the careful analysis of both the neuroprotective and the regenerative effects in preclinical studies.
文摘BACKGROUND Non-invasive differential diagnosis between hepatocellular carcinoma(HCC)and other liver cancer(i.e.cholangiocarcinoma or metastasis)is highly challenging and definitive diagnosis still relies on histological exam.The patterns of enhancement and wash-out of liver nodules can be used to stratify the risk of malignancy only in cirrhotic patients and HCC frequently shows atypical features.Dynamic contrast-enhanced ultrasound(DCEUS)with standardized software could help to overcome these obstacles,providing functional and quantitative parameters and potentially improving accuracy in the evaluation of tumor perfusion.AIM To explore clinical evidence regarding the application of DCEUS in the differential diagnosis of liver nodules.METHODS A comprehensive literature search of clinical studies was performed to identify the parameters of DCEUS that could relate to histological diagnosis.In accordance with the study protocol,a qualitative and quantitative analysis of the evidence was planned.RESULTS Rise time was significantly higher in HCC patients with a standardized mean difference(SMD)of 0.83(95%CI:0.48-1.18).Similarly,other statistically significant parameters were mean transit time local with a SMD of 0.73(95%CI:0.20-1.27),peak enhancement with a SMD of 0.37(95%CI:0.03-0.70),area wash-in area under the curve with a SMD of 0.47(95%CI:0.13-0.81),wash-out area under the curve with a SMD of 0.55(95%CI:0.21-0.89)and wash-in and wash-out area under the curve with SMD of 0.51(95%CI:0.17-0.85).SMD resulted not significant in fall time and wash-in rate,but the latter presented a trend towards greater values in HCC compared to intrahepatic cholangiocarcinoma.CONCLUSION DCEUS could improve non-invasive diagnosis of HCC,leading to less liver biopsy and early treatment.This quantitative analysis needs to be applied on larger cohorts to confirm these preliminary results.
文摘We determined whether the inclusion of 100 g/kg dry matter of grape pomace silage (GPS) and grape pomace bran (GPB) as substitutes for other traditional fiber sources in the diet of steers (Charolais x Nellore) would improve carcass characteristics, meat quality and composition, and shelf life. Twenty-four animals (248 ± 19.32 kg of initial body weight) were fed a high concentrate diet for 121 days. Carcass characteristics were measured, and the longissimus dorsi muscle was analyzed for fatty acid (FA) profile and composition. The meat was sliced and stored in air-permeable packages for 10 days. On each sampling day (d 1, 3, 7, and 10), oxidative stability, bacterial load, lipid and protein oxidation, and staining were analyzed. The experimental diets influenced the pH of cold carcasses only. The GPS group had a higher pH than the control. The GPS and GPB groups showed improved oxidant status (i.e., lower lipid peroxidation and concentrations of reactive oxygen species were in the meat of both groups than in control). On the first day of storage, the antioxidant enzyme glutathione S-transferase activity was more significant in the meat of the GPS and GPB groups than in the control. The bacterial loads in the meat were attenuated by GPS inclusion;there were lower total coliform counts and a trend toward lower counts for enterobacteria in the control group. The diets altered the FA profile of the meat;i.e., the GPB diet allowed for a more significant amount of the n-6 omegas in the meat, while the GPS diet showed a tendency for a more significant amount of n-6 and 9 omegas. Both diets (GPS and GPB) increased the amounts of long-chain FAs. The GPS diet decreased saturated FA levels. We conclude that the dietary treatments GPS and GPB are a promising alternative to maintain meat quality standards throughout in real-world retail conditions. These treatments gave rise to an improvement in the nutritional value of the meat due to the more significant amounts of FAs that improve human health.
文摘BACKGROUND Metastatic pancreatic ductal adenocarcinoma(PDAC)is a lethal malignancy with dispiriting survival data.Immunotherapy is a promising approach to many cancer types,but achieves poor outcomes in advanced PDAC due to its immunosuppressive tumor microenvironment.We describe a case of metastatic PDAC effectively treated with pembrolizumab.CASE SUMMARY We report the case of a 67-year-old woman with unresectable locally advanced PDAC,treated with gemcitabine plus nab-paclitaxel followed by radiotherapy plus capecitabine.At nine months,pancreatic tumor progression was observed at the level of the hepatic hilum with the appearance of a new pulmonary nodule suggestive of a second primary,confirmed by left lung biopsy.Systemic immunotherapy was then initiated with pembrolizumab,an immune checkpoint inhibitor targeting programmed cell death protein-1 that covers the two tumor types.The patient showed a complete metabolic response that was maintained throughout the treatment.The patient continues to be disease-free at 5.6 years since the start of immunotherapy.CONCLUSION These results suggest that the administration of pembrolizumab after chemoradiotherapy has a beneficial effect in patients with metastatic PDAC.To our knowledge,this is the first reported case of a patient with metastatic PDAC and metastatic lung cancer showing such a long-lasting complete response after pembrolizumab treatment without curative surgery.Further studies are required to determine biomarkers that identify PDAC patients most likely to benefit from this immunotherapy.
基金supported by the Spanish Ministry of Economy and Competitiveness,Instituto de Salud Carlos Ⅲ(ISCⅢ)Fondo Europeo de Desarrollo Regional “Una Manera de Hacer Europa”(SAF2015-67643-P to MVS and PI16/00031 to MAB)Fundación Séneca,Agencia de Ciencia y Tecnología Región de Murcia(19881/GERM/15 to MVS)
文摘Mesenchymal stromal cells are an excellent source of stem cells because they are isolated from adult tissues or perinatal derivatives, avoiding the ethical concerns that encumber embryonic stem cells. In preclinical models, it has been shown that mesenchymal stromal cells have neuroprotective and immunomodulatory properties, both of which are ideal for central nervous system treatment and repair. Here we will review the current literature on mesenchymal stromal cells, focusing on bone marrow mesenchymal stromal cells, adipose-derived mesenchymal stromal cells and mesenchymal stromal cells from the umbilical cord stroma, i.e.,Wharton’s jelly mesenchymal stromal cells. Finally, we will discuss the use of these cells to alleviate retinal ganglion cell degeneration following axonal trauma.
文摘Our aim was to evaluate the reproducibility of the Functional Independence Measure (FIM) scale when assessed by physical therapists in the routine setting of a Rehabilitation Hospital. We included a consecutive series of patients with spinal cord or cerebral lesions. Each of the 50 selected patients was evaluated by two of the 5 experienced physical therapists participating in the study. The degree of inter-rater and intrarater agreement was measured by a weighted k statistic, k for perfect agreement, and k for the agreement with tolerance. The weighted k index for inter-rater agreement on the FIM score was in the almost perfect range (k 0.87;95% CI = 0.79 - 0.95), but a 20-point tolerance was necessary to reach a k value of 0.81 (95% CI = 0.66 - 0.95). Agreement was substantial or almost perfect for most subscales, but the k index with 1-point tolerance reached the almost perfect rating for comprehension only. For intra-rater agreement, weighted k index was in the almost perfect range for the FIM score and for all subscales;kappa index reached the almost perfect range with a 4-point tolerance for FIM score and with 1-point of tolerance for all subscales except interpersonal relations. FIM is useful to monitor patient improvement during rehabilitation treatment, mostly when assessed by the same physical therapist.
文摘Aims: The G protein-coupled receptor kinase-2(GRK2 or β-ARK1) regulates β-adrenergic receptors(β-ARs) in the heart, and its cardiac expression is elevated in human heart failure(HF). We sought to determine whether myocardial levels and activity of GRK2 could be monitored using white blood cells, which have been used to study cardiac β-ARs. Moreover, we were interested in determining whether GRK2 levels in myocardium and lymphocytes may be associated with β-AR dysfunction and HF severity. Methods and results: In myocardial biopsies from explanted failing human hearts, GRK activity was inversely correlated with β-AR-mediated cAMP production(R2=0.215, P< 0.05, n=24). Multiple regression analysis confirmed that GRK activity participates with β-AR density to regulate catecholamine-sensitive cAMP responses. Importantly, there was a direct correlation between myocardial and lymphocytes GRK2 activity(R2=0.5686, P< 0.05, n=10). Lymphocyte GRK activity was assessed in HF patients with various ejection fractions(EFs)(n=33), and kinase activity was significantly higher in patients with lower EFs and was higher with increasing NYHA class(P< 0.001). Conclusion: Myocardial GRK2 expression and activity are mirrored by lymphocyte levels of this kinase, and its elevation in HF is associated with the loss of β-AR responsiveness and appears to increase with disease severity. Therefore, lymphocytes may provide a surrogate for monitoring cardiac GRK2 in human HF.
