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Systemic inflammation and coronary microvascular endothelial dysfunction are essential pathophysiological factors in heart failure (HF) with preserved ejection fraction (HFpEF) that support the use of statins. The pleiotropic properties of statins, such as anti-inflammatory, antihypertrophic, antifibrotic, and antioxidant effects, are generally accepted and may be beneficial in HF, especially in HFpEF. Numerous observational clinical trials have consistently shown a beneficial prognostic effect of statins in patients with HFpEF, while the results of two larger trials in patients with HFrEF have been controversial. Such differences may be related to a more pronounced impact of the pleiotropic properties of statins on the pathophysiology of HFpEF and pro-inflammatory comorbidities (arterial hypertension, diabetes mellitus, obesity, chronic kidney disease) that are more common in HFpEF. This review discusses the potential mechanisms of statin action that may be beneficial for patients with HFpEF, as well as clinical trials that have evaluated the statin effects on left ventricular diastolic function and clinical outcomes in patients with HFpEF.
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Insuficiencia Cardíaca , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Volumen Sistólico , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Volumen Sistólico/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos , Ensayos Clínicos como AsuntoRESUMEN
In this study we analyzed the concentration of lipoprotein(a) (Lp(a)), PCSK9-Lp(a) complexes and the circulating monocyte subsets in coronary atherosclerosis. For this study, 257 patients with coronary atherosclerosis and 68 patients without stenotic atherosclerosis in the coronary, carotid and lower extremity arteries (control group) were enrolled. The monocyte subpopulations (classical CD14++CD16-, intermediate CD14++CD16+ and non-classical CD14+CD16++) were analyzed by direct immunofluorescence and flow cytometry. The Lp(a) and PCSK9-Lp(a) complexes in the serum were detected by ELISA. The concentration of Lp(a) was higher in the coronary atherosclerosis group compared with the controls (23.0 (9.1; 73.3) mg/dL versus 10.7 (4.7; 25.0) mg/dL, p < 0.05). No correlations between the level of Lp(a) and the concentration of the PCSK9-Lp(a) complexes, nor between the level of Lp(a) or PCSK9 and the total number of monocytes, were observed in either group. A slight positive correlation between the concentration of PCSK9-Lp(a) complexes and the absolute level of monocytes was obtained (r = 0.20, p = 0.002) in the patients with atherosclerosis due to the intermediate monocyte subsets (r = 0.33, p = 0.04). According to regression analysis, both the PCSK9-Lp(a) complexes concentration and BMI were related to the absolute number of blood monocytes in patients with atherosclerosis. Further studies are required to determine the pathogenetic contribution of PCSK9-Lp(a) complexes to the development of atherosclerosis.
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(1) Background: Chronic inflammation and fibrosis are key players in cardiac remodeling associated with left ventricular hypertrophy (LVH) and heart failure with a preserved ejection fraction (HFpEF). Monocytes and T-helpers (Th) are involved in both pro-inflammatory and fibrotic processes, while regulatory T-cells (Treg) could be considered to suppress chronic inflammation in the hypertrophied myocardium. We aimed to estimate the relationship between the frequencies of circulating CD4+ T-cell and monocyte subpopulations and the variables of left ventricular (LV) diastolic function in patients with LVH depending on the presence of HFpEF. (2) Methods: We enrolled 57 patients with asymptomatic hypertensive LVH (n = 21), or LVH associated with HFpEF (n = 36). A clinical assessment and echocardiographs were analyzed. CD4+ Treg, activated Th (Th-act), and monocyte (classical, intermediate, and non-classical) subpopulations were evaluated via direct immunofluorescence and flow cytometry. (3) Results: Patients with HFpEF had a lower Treg/Th-act ratio (p = 0.001). Though asymptomatic patients and patients with HFpEF were comparable in terms of both the total monocyte number and monocyte subsets, there were moderate correlations between intermediate monocyte count and conventional and novel echocardiographic variables of LV diastolic dysfunction in patients with HFpEF. (4) Conclusions: In patients with LVH, the clinical deterioration (transition to HFpEF) and progression of LV diastolic dysfunction are probably associated with T-cell disbalance and an increase in intermediate monocyte counts.
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Left atrial (LA) dysfunction seems to play a central role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), is associated with disease severity and poor outcomes and potentially impacts management. Identifying LA myopathy can help guide tailored therapy for HFpEF. Echocardiography allows the accurate measurement of atrial size and function, where LA strain appears to be a sensitive measure of intrinsic LA myopathy. Several therapies and devices that decompress of left atrium are being tested for HFpEF. Further investigation is required to understand the specific atrial effects of statins, mineralocorticoid receptor antagonists, and other therapies.
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Insuficiencia Cardíaca , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Atrios Cardíacos/diagnóstico por imagen , Humanos , Antagonistas de Receptores de Mineralocorticoides , Volumen Sistólico/fisiología , Función Ventricular IzquierdaRESUMEN
Pulmonary hypertension (PH) is common in patients with heart failure with preserved ejection fraction (HFpEF). A chronic increase in mean left atrial pressure leads to passive remodeling in pulmonary veins and capillaries and modest PH (isolated postcapillary PH, Ipc-PH) and is not associated with significant right ventricular dysfunction. In approximately 20% of patients with HFpEF, "precapillary" alterations of pulmonary vasculature occur with the development of the combined pre- and post-capillary PH (Cpc-PH), pertaining to a poor prognosis. Current data indicate that pulmonary vasculopathy may be at least partially reversible and thus serves as a therapeutic target in HFpEF. Pulmonary vascular targeted therapies, including phosphodiesterase (PDE) inhibitors, may have a valuable role in the management of patients with PH-HFpEF. In studies of Cpc-PH and HFpEF, PDE type 5 inhibitors were effective in long-term follow-up, decreasing pulmonary artery pressure and improving RV contractility, whereas studies of Ipc-PH did not show any benefit. Randomized trials are essential to elucidate the actual value of PDE inhibition in selected patients with PH-HFpEF, especially in those with invasively confirmed Cpc-PH who are most likely to benefit from such treatment.
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(1) Background: The structural and functional features of the natural history of asymptomatic hypertensive left ventricular hypertrophy (LVH) are not clearly defined. (2) Objective: To determine structural and functional changes in asymptomatic hypertensive LVH, as well as the incidence and predictors of the transition to different phenotypes of heart failure (HF) after a long-term follow-up. (3) Methods: Based on the assessment of chart reviews, we retrospectively selected 350 asymptomatic patients with hypertensive concentric LVH and LV ejection fraction (EF) ≥ 50%. After a median follow-up of 8.1 years, 223 patients had a re-assessment. The final diagnosis (HF with reduced EF [HFrEF], or HF with preserved EF [HFpEF]) was established according to current recommendations. (4) Results: After a follow-up, only 13% of patients remained asymptomatic, 72% developed HFpEF, and 15% developed HFrEF. The transition to HFpEF was associated with an increase in LV diastolic dysfunction grade in 62% of patients. Multivariable analysis identified age, duration of hypertension, interval changes in LV mass, and a lack of statin treatment as independent predictors of HFpEF. Among 34 patients who developed HFrEF, 16 patients (7% of the whole group) had no interval myocardial infarction, corresponding to an internal mechanism of systolic dysfunction. All these 16 patients had mild systolic dysfunction (LVEF > 40%). Baseline LVEF and LV end-diastolic dimension, and interval atrial fibrillation were identified as predictors of internal HFrEF. (5) Conclusions: The majority of patients with asymptomatic LVH developed HFpEF after long-term follow-up, which was associated with the deterioration of LV diastolic dysfunction and a lack of statin treatment. In contrast, the transition to HFrEF was infrequent and characterized by mild LV systolic dysfunction.
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Aims: The authors examined the phenotype of circulating monocytes in patients with coronary atherosclerosis depending on age. Methods: A total of 121 patients were categorized into three groups according to the severity of coronary atherosclerosis assessed by angiography and into two groups depending on age above/below the median 60.0 (range: 56.0-66.0). Classical CD14++CD16-, intermediate CD14++CD16+ and non-classical CD14+CD16+ monocytes were analyzed via direct immunofluorescence and flow cytometry. Results and conclusions: In patients >60 years of age, the severity of atherosclerosis was associated with the decreased number of classical monocytes in the blood. In patients under 60 years of age, this relationship was not observed. The authors hypothesize that the contribution of different subtypes of blood monocytes to the development of atherosclerosis may vary with age.
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BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is frequently complicated by pulmonary hypertension (PH). A pulmonary vascular contribution could be considered as a substantial therapeutic target in HFpEF and PH and combined pre- and postcapillary PH (Cpc-PH). METHODS: We enrolled 50 patients with HFpEF and Cpc-PH who were determined by echocardiography to have pulmonary artery systolic pressure (PASP) > 40 mmHg, pulmonary vascular resistance > 3 Wood units, and/or transpulmonary gradient > 15 mmHg. RESULTS: The patients were assigned to the phosphodiesterase 5 (PDE5) inhibitor sildenafil group (25 mg TID for 3 months followed by 50 mg TID for 3 months; n = 30) or the control group (n = 20). In the sildenafil group after 6 months, the 6-min walk distance increased by 50 m (95% CI, 36 to 64 m); substantial improvement in NYHA functional class and exercise capacity during diastolic stress test were revealed; decreases in early mitral inflow to mitral annulus relaxation velocities ratio by 2.4 (95% CI, - 3.3 to - 1.4) and PASP by 17.0 mmHg (95% CI, 20.4 to 13.5) were observed; right ventricular systolic function (M-mode tricuspid annular plane systolic excursion) increased by 0.42 cm (95% CI, 0.32 to 0.52 cm; P < 0.01 for all). No changes occurred in the control group. CONCLUSIONS: In a subset of patients with HFpEF and Cpc-PH assessed by echocardiography, PDE5 inhibition was associated with an improvement in exercise capacity, pulmonary haemodynamic parameters, and right ventricular function. The role of sildenafil needs to be considered in randomized trials in selected patients with HFpEF with invasively confirmed Cpc-PH. TRIAL REGISTRATION: Russian National Information System of Research, Development and Technology Data of Civilian Usage (NIS, https://rosrid.ru), registration number 01201257849 . Registered 20 April 2012. This manuscript adheres to the CONSORT guidelines.
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Presión Arterial/efectos de los fármacos , Tolerancia al Ejercicio/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Arteria Pulmonar/efectos de los fármacos , Citrato de Sildenafil/uso terapéutico , Volumen Sistólico/efectos de los fármacos , Vasodilatadores/uso terapéutico , Función Ventricular Derecha/efectos de los fármacos , Anciano , Femenino , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Humanos , Hipertensión/diagnóstico por imagen , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa 5/efectos adversos , Proyectos Piloto , Arteria Pulmonar/fisiopatología , Recuperación de la Función , Federación de Rusia , Citrato de Sildenafil/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Vasodilatadores/efectos adversosRESUMEN
Objective. Immune processes play a significant role in atherosclerosis plaque progression. Regulatory T cells and T helpers 17 were shown to possess anti- and pro-atherogenic activity, respectively. We aimed to investigate the balance of circulating Treg and Th17 in stable angina patients with different stages of coronary atherosclerosis. Methods. Treg, Th17 and Th1 cell frequencies were studied in 117 patients via direct immunofluorescence staining and flow cytometry. Group 1 had intact coronary arteries. Group 2 and Group 3 had undergone previous coronary stenting; in Group 2 no coronary atherosclerosis progression was found, in Group 3 patients had disease progression in non-invaded coronary arteries. Group 4 had severe coronary atherosclerosis. Results. The frequencies of CD4+CD25highCD127low, CD4+foxp3+, and CD4+IL10 + T cells were decreased, and CD4+IL17 + T cells frequencies were increased in group 4 vs. 1. Treg/Th17 ratios were declined in groups 3 and 4 vs. groups 1 and 2. IL-10 level was lower while hsCRP and sCD25 levels were higher in group 4 vs. 1. Conclusion. We assume that the imbalance in pro- and anti-inflammatory/atherogenic lymphocyte subpopulations is associated with atherosclerosis progression.
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Aterosclerosis/inmunología , Enfermedad de la Arteria Coronaria/inmunología , Linfocitos T Reguladores/citología , Células Th17/citología , Anciano , Aterosclerosis/patología , Enfermedad de la Arteria Coronaria/patología , Vasos Coronarios/patología , Citocinas/metabolismo , Progresión de la Enfermedad , Femenino , Citometría de Flujo , Factores de Transcripción Forkhead/metabolismo , Humanos , Inmunosupresores/uso terapéutico , Inflamación/patología , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Subunidad alfa del Receptor de Interleucina-7/metabolismo , Masculino , Microscopía Fluorescente , Persona de Mediana EdadRESUMEN
Rapamycin contributes to the expansion of regulatory T cells (Tregs) in vitro. We investigated CD4(+)CD25(high)CD127(low) Treg level dynamics as well as the major parameters of cell immunity and sCD25 and highly sensitive C-reactive protein (hsCRP) concentrations in the blood of patients after coronary stenting (CS) with sirolimus (rapamycin)-eluting stents (SES; n = 43). The relation between initial Treg values and the severity of coronary atherosclerosis was observed. Treg and sCD25 levels were increased 1 month after CS versus baseline values and versus data in the control group (coronary angiography [CA], n = 20). A positive correlation between Treg and sCD25 levels was reported, whereas no relation was observed with the length of SES implanted. HsCRP level was increased during the first 7 days and returned to baseline values 1 month after CS/CA. Treg content is lower in patients with multivessel CAD. Elevated levels of Tregs and sCD25 after SES implantation might occur because of the immunomodulating effect of rapamycin.
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Angina de Pecho/patología , Angina de Pecho/terapia , Angioplastia Coronaria con Balón , Stents Liberadores de Fármacos , Factores Inmunológicos/farmacología , Sirolimus/farmacología , Linfocitos T Reguladores , Anciano , Angina de Pecho/inmunología , Angioplastia de Balón Asistida por Láser , Proteína C-Reactiva/inmunología , Linfocitos T CD4-Positivos/inmunología , Femenino , Humanos , Subunidad alfa del Receptor de Interleucina-2/inmunología , Subunidad alfa del Receptor de Interleucina-7/inmunología , Subgrupos Linfocitarios/efectos de los fármacos , Subgrupos Linfocitarios/inmunología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Factores de TiempoRESUMEN
Our previous studies have revealed the abundant expression of T-cadherin--a glycosylphosphatidylinositol (GPI)-anchored member of cadherin superfamily--in endothelial and mural cells in the heart and vasculature. The upregulation of T-cadherin in vascular proliferative disorders such as atherosclerosis and restenosis suggests the involvement of T-cadherin in vascular growth and remodeling. However, the functional significance of this molecule in the vasculature remains unknown. The effect of T-cadherin on angiogenesis in vivo was evaluated using Matrigel implant model. We demonstrate that T-cadherin overexpression in L929 cells injected in Matrigel inhibits neovascularization of the plug. In vitro T-cadherin inhibits the directional migration of endothelial cells, capillary growth, and tube formation but has no effect on endothelial cell proliferation, adhesion, or apoptosis in vitro. These data suggest that T-cadherin expressed in the stroma could act as a negative guidance cue for the ingrowing blood vessels and thus could have an important potential therapeutic application.