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1.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445698

RESUMO

The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease. Short-term RAAS activation controls water and salt retention and causes vasoconstriction, which are beneficial for maintaining cardiac output in low blood pressure and early stage heart failure. However, prolonged RAAS activation is detrimental, leading to structural remodeling and cardiac dysfunction. Natriuretic peptides (NPs) are activated to counterbalance the effect of RAAS and sympathetic nervous system by facilitating water and salt excretion and causing vasodilation. Neprilysin is a major NP-degrading enzyme that degrades multiple vaso-modulatory substances. Although the inhibition of neprilysin alone is not sufficient to counterbalance RAAS activation in cardiovascular diseases (e.g., hypertension and heart failure), a combination of angiotensin receptor blocker and neprilysin inhibitor (ARNI) was highly effective in several clinical trials and may modulate the risk of atrial and ventricular arrhythmias. This review summarizes the possible link between ARNI and cardiac arrhythmias and discusses potential underlying mechanisms, providing novel insights about the therapeutic role and safety profile of ARNI in the cardiovascular system.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Arritmias Cardíacas/fisiopatologia , Neprilisina/antagonistas & inibidores , Antagonistas de Receptores de Angiotensina/metabolismo , Anti-Hipertensivos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Peptídeos Natriuréticos/metabolismo , Peptídeos Natriuréticos/fisiologia , Receptores de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Sistema Nervoso Simpático/fisiopatologia , Tetrazóis/farmacologia
2.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445301

RESUMO

Angiotensin receptor neprilysin inhibitor (ARNI) treatment reduces functional mitral regurgitation (MR) to a greater extent than angiotensin receptor blocker (ARB) treatment alone, but the mechanism is unclear. We evaluated the mechanisms of how ARNI has an effect on functional MR. After inducing functional MR by left circumflex coronary artery occlusion, male Sprague Dawley rats (n = 31) were randomly assigned to receive the ARNI LCZ696, the ARB valsartan, or corn oil only (MR control). Excised mitral leaflets and left ventricle (LV) were analyzed, and valvular endothelial cells were evaluated focusing on molecular changes. LCZ696 significantly attenuated LV dilatation after 6 weeks when compared with the control group (LV end-diastolic volume, 461.3 ± 13.8 µL versus 525.1 ± 23.6 µL; p < 0.05), while valsartan did not (471.2 ± 8.9 µL; p > 0.05 to control). Histopathological analysis of mitral leaflets showed that LCZ696 strongly reduced fibrotic thickness compared to the control group (28.2 ± 2.7 µm vs. 48.8 ± 7.5 µm; p < 0.05). Transforming growth factor-ß and downstream phosphorylated extracellular-signal regulated kinase were also significantly lower in the LCZ696 group. Consequently, excessive endothelial-to-mesenchymal transition (EndoMT) was mitigated in the LCZ696 group compared to the control group and leaflet area was higher (11%) in the LCZ696 group than in the valsartan group. Finally, the MR extent was significantly lower in the LCZ696 group and functional improvement was observed. In conclusion, neprilysin inhibitor has positive effects on LV reverse remodeling and also attenuates fibrosis in MV leaflets and restores adaptive growth by directly modulating EndoMT.


Assuntos
Aminobutiratos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Insuficiência da Valva Mitral/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Valsartana/uso terapêutico , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Animais , Compostos de Bifenilo/farmacologia , Células Cultivadas , Combinação de Medicamentos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Valva Mitral/efeitos dos fármacos , Valva Mitral/patologia , Valva Mitral/fisiologia , Insuficiência da Valva Mitral/diagnóstico , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/fisiopatologia , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/diagnóstico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Neprilisina/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Valsartana/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
4.
BMC Cardiovasc Disord ; 21(1): 324, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215190

RESUMO

BACKGROUND: Treatment of heart failure with reduced ejection fraction (HFrEF) has been revolutionized by angiotensin receptor/neprilysin inhibitor (ARNI). ARNI has been shown to significantly reduce morbidity and mortality in a large, randomized controlled trial. However, real-world evaluation of ARNI with a diverse population is still limited. METHODS: HFrEF patients receiving angiotensin receptor/neprilysin inhibitor (ARNI) or standard HF treatment at a university hospital in Thailand were prospectively followed-up from January 2015 to December 2019. The primary outcome was a composite of all-cause mortality and heart failure hospitalization. Survival analysis and the Cox proportional hazard model were used to compare clinical outcomes between the two groups. RESULTS: During a follow-up period of 12 months, the primary outcome occurred in 10 patients in the ARNI group (11.5%) and 28 in the standard treatment group (28.0%) (hazard ratio 0.34; 95% CI: 0.15-0.80; p = 0.013). After adjustment for confounding factors, ARNI was significantly associated with a significant reduction in the primary outcome (HR 0.32, 95% CI: 0.13-0.82, p = 0.017). In addition, ARNI was also significantly associated with a decrease in the clinical signs and symptoms of HF, including dyspnea, orthopnea, and fatigue. Orthostatic hypotension was more frequently reported among the ARNI group than among the standard treatment group. The rates of target dose achievement were comparable between the two groups. CONCLUSION: In real-world practice, ARNI use was associated with a significant reduction in both clinical outcomes and symptom improvement, while orthostatic hypotension was more common in patients in the ARNI group than in patients in the standard treatment group.


Assuntos
Aminobutiratos/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Padrões de Prática Médica/tendências , Inibidores de Proteases/uso terapêutico , Valsartana/uso terapêutico , Adulto , Idoso , Aminobutiratos/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Compostos de Bifenilo/efeitos adversos , Combinação de Medicamentos , Uso de Medicamentos/tendências , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Hospitalização/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Inibidores de Proteases/efeitos adversos , Recuperação de Função Fisiológica , Estudos Retrospectivos , Tailândia , Fatores de Tempo , Resultado do Tratamento , Valsartana/efeitos adversos
5.
Kardiologiia ; 61(6): 4-10, 2021 Jul 01.
Artigo em Russo, Inglês | MEDLINE | ID: mdl-34311683

RESUMO

Major principles for treatment of chronic heart failure with reduced left ventricular ejection fraction <40% (HFrEF) include a "triple neurohormonal blockade" as a main approach. However, in recent 6 years, two new classes of drugs for the treatment of HFrEF have appeared, which beneficially influence the prognosis. These drugs are angiotensin receptor neprilysin inhibitors (ARNI) and type 2 sodium-glucose cotransporter 2 (SGLT2) inhibitors.Aim    To compare the net effect of simultaneous treatment with ARNI and SGLT2 inhibitors with the triple neurohormonal blockade in stable or decompensated patients with CHF based on Russian data.Material and methods    We analyzed the risk of death per 100 patient-years in patients with HFrEF. Stable patients were followed up at the A.L. Myasnikov Institute of Cardiology (presently, A.L. Myasnikov Research Institute of Clinical Cardiology of the National Medical Research Center of Cardiology) from 2006 through 2007; data from the EPOCH-Decompensation-CHF study were used for decompensated patients (12.2 % and 36.8 %, respectively).Results    When patients with stable HFrEF were successively switched from renin-angiotensin-aldosterone system (RAAS) inhibitors to ARNI (-16 %) and subsequently supplemented with SGLT2 (-13 %) the risk of death per 100 patient-years decreased from 12.2 % to 8.9 % (total risk decreased by 27 %; to save one patient the ARNI+ SGLT2 combination has to be prescribed to 30 patients). The estimated risk of death upon discharge from the hospital for the patients with decompensated CHF switched from RAAS inhibitors to ARNI (-16 %) and subsequently supplemented with SGLT2 (-13 %) was 26.9 deaths per 100 patient-years, whereas the number of patients to be treated for saving one life was only 10. Based on available data that demonstrate a greater effect of ARNI+ SGLT2 in patients immediately after CHF aggravation, the risk of death was recalculated. According to this analysis, the death rate per 1000 patient-years decreased from 36.8 to 19.9 % (relative risk decrease, 46 %), and to save one life only 6 patients had to be treated after they have achieved compensation of HFrEF.Conclusions    This analysis shows the importance of early initiation of the ARNI+ SGLT2 therapy in patients with both decompensated and with stable HFrEF.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca , Neprilisina , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Angiotensinas , Glucose , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Neprilisina/antagonistas & inibidores , Prognóstico , Federação Russa , Sódio , Volume Sistólico , Função Ventricular Esquerda
6.
Cochrane Database Syst Rev ; 5: CD012721, 2021 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-34022072

RESUMO

BACKGROUND: Beta-blockers and inhibitors of the renin-angiotensin-aldosterone system improve survival and reduce morbidity in people with heart failure with reduced left ventricular ejection fraction (LVEF); a review of the evidence is required to determine whether these treatments are beneficial for people with heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: To assess the effects of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor neprilysin inhibitors, and mineralocorticoid receptor antagonists in people with HFpEF. SEARCH METHODS: We updated searches of CENTRAL, MEDLINE, Embase, and one clinical trial register on 14 May 2020 to identify eligible studies, with no language or date restrictions. We checked references from trial reports and review articles for additional studies.  SELECTION CRITERIA: We included randomised controlled trials with a parallel group design, enrolling adults with HFpEF, defined by LVEF greater than 40%. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 41 randomised controlled trials (231 reports), totalling 23,492 participants across all comparisons. The risk of bias was frequently unclear and only five studies had a low risk of bias in all domains. Beta-blockers (BBs) We included 10 studies (3087 participants) investigating BBs. Five studies used a placebo comparator and in five the comparator was usual care. The mean age of participants ranged from 30 years to 81 years. A possible reduction in cardiovascular mortality was observed (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.62 to 0.99; number needed to treat for an additional benefit (NNTB) 25; 1046 participants; three studies), however, the certainty of evidence was low. There may be little to no effect on all-cause mortality (RR 0.82, 95% CI 0.67 to 1.00; 1105 participants; four studies; low-certainty evidence). The effects on heart failure hospitalisation, hyperkalaemia, and quality of life remain uncertain. Mineralocorticoid receptor antagonists (MRAs) We included 13 studies (4459 participants) investigating MRA. Eight studies used a placebo comparator and in five the comparator was usual care. The mean age of participants ranged from 54.5 to 80 years. Pooled analysis indicated that MRA treatment probably reduces heart failure hospitalisation (RR 0.82, 95% CI 0.69 to 0.98; NNTB = 41; 3714 participants; three studies; moderate-certainty evidence). However, MRA treatment probably has little or no effect on all-cause mortality (RR 0.91, 95% CI 0.78 to 1.06; 4207 participants; five studies; moderate-certainty evidence) and cardiovascular mortality (RR 0.90, 95% CI 0.74 to 1.11; 4070 participants; three studies; moderate-certainty evidence). MRA treatment may have little or no effect on quality of life measures (mean difference (MD) 0.84, 95% CI -2.30 to 3.98; 511 participants; three studies; low-certainty evidence). MRA treatment was associated with a higher risk of hyperkalaemia (RR 2.11, 95% CI 1.77 to 2.51; number needed to treat for an additional harmful outcome (NNTH) = 11; 4291 participants; six studies; high-certainty evidence). Angiotensin-converting enzyme inhibitors (ACEIs) We included eight studies (2061 participants) investigating ACEIs. Three studies used a placebo comparator and in five the comparator was usual care. The mean age of participants ranged from 70 to 82 years. Pooled analyses with moderate-certainty evidence suggest that ACEI treatment likely has little or no effect on cardiovascular mortality (RR 0.93, 95% CI 0.61 to 1.42; 945 participants; two studies), all-cause mortality (RR 1.04, 95% CI 0.75 to 1.45; 1187 participants; five studies) and heart failure hospitalisation (RR 0.86, 95% CI 0.64 to 1.15; 1019 participants; three studies), and may result in little or no effect on the quality of life (MD -0.09, 95% CI -3.66 to 3.48; 154 participants; two studies; low-certainty evidence). The effects on hyperkalaemia remain uncertain. Angiotensin receptor blockers (ARBs) Eight studies (8755 participants) investigating ARBs were included. Five studies used a placebo comparator and in three the comparator was usual care. The mean age of participants ranged from 61 to 75 years. Pooled analyses with high certainty of evidence suggest that ARB treatment has little or no effect on cardiovascular mortality (RR 1.02, 95% 0.90 to 1.14; 7254 participants; three studies), all-cause mortality (RR 1.01, 95% CI 0.92 to 1.11; 7964 participants; four studies), heart failure hospitalisation (RR 0.92, 95% CI 0.83 to 1.02; 7254 participants; three studies), and quality of life (MD 0.41, 95% CI -0.86 to 1.67; 3117 participants; three studies). ARB was associated with a higher risk of hyperkalaemia (RR 1.88, 95% CI 1.07 to 3.33; 7148 participants; two studies; high-certainty evidence). Angiotensin receptor neprilysin inhibitors (ARNIs) Three studies (7702 participants) investigating ARNIs were included. Two studies used ARBs as the comparator and one used standardised medical therapy, based on participants' established treatments at enrolment. The mean age of participants ranged from 71 to 73 years. Results suggest that ARNIs may have little or no effect on cardiovascular mortality (RR 0.96, 95% CI 0.79 to 1.15; 4796 participants; one study; moderate-certainty evidence), all-cause mortality (RR 0.97, 95% CI 0.84 to 1.11; 7663 participants; three studies; high-certainty evidence), or quality of life (high-certainty evidence). However, ARNI treatment may result in a slight reduction in heart failure hospitalisation, compared to usual care (RR 0.89, 95% CI 0.80 to 1.00; 7362 participants; two studies; moderate-certainty evidence). ARNI treatment was associated with a reduced risk of hyperkalaemia compared with valsartan (RR 0.88, 95% CI 0.77 to 1.01; 5054 participants; two studies; moderate-certainty evidence). AUTHORS' CONCLUSIONS: There is evidence that MRA and ARNI treatment in HFpEF probably reduces heart failure hospitalisation but probably has little or no effect on cardiovascular mortality and quality of life. BB treatment may reduce the risk of cardiovascular mortality, however, further trials are needed. The current evidence for BBs, ACEIs, and ARBs is limited and does not support their use in HFpEF in the absence of an alternative indication. Although MRAs and ARNIs are probably effective at reducing the risk of heart failure hospitalisation, the treatment effect sizes are modest. There is a need for improved approaches to patient stratification to identify the subgroup of patients who are most likely to benefit from MRAs and ARNIs, as well as for an improved understanding of disease biology, and for new therapeutic approaches.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , Volume Sistólico , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Insuficiência Cardíaca/mortalidade , Hospitalização , Humanos , Pessoa de Meia-Idade , Neprilisina/antagonistas & inibidores , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
Ren Fail ; 43(1): 315-324, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33541194

RESUMO

Salt-sensitive (SS) hypertension is accompanied with severe cardiorenal complications. In this condition, elevated blood pressure (BP) resulting from salt retention is associated with counterintuitively lower levels of atrial natriuretic peptide (ANP). In plasma, ANP is degraded by the neprilysin; therefore, pharmacological inhibition of this metalloprotease (i.e., with sacubitril) can be employed to increase ANP level. We have shown earlier that sacubitril in combination with valsartan (75 µg/day each) had beneficial effects on renal function in Dahl SS rats. The goal of this study was to evaluate the effects of a higher dose of sacubitril on renal damage in this model. To induce hypertension, male Dahl SS rats were fed a 4% NaCl diet (HS) for 21 days, and were administered sacubitril (125 µg/day) or vehicle via s.c. osmotic pumps. At the end of the HS challenge, both groups exhibited similar outcomes for GFR, heart weight, plasma electrolytes, BUN, and creatinine. Sacubitril exacerbated kidney hypertrophy, but did not affect levels of renal fibrosis. We also observed aggravated glomerular lesions and increased formation of protein casts in the sacubitril-treated animals compared to controls. Thus, in Dahl SS rats, administration of sacubitril without renin-angiotensin-system blockage had adverse effects on renal disease progression, particularly in regards to glomerular damage and protein cast formation. We can speculate that while ANP levels are increased because of neprilysin inhibition, there are off-target effects of sacubitril, which are detrimental to renal function in the SS hypertensive state.


Assuntos
Aminobutiratos/efeitos adversos , Compostos de Bifenilo/efeitos adversos , Hipertensão/tratamento farmacológico , Glomérulos Renais/efeitos dos fármacos , Neprilisina/antagonistas & inibidores , Insuficiência Renal/patologia , Aminobutiratos/administração & dosagem , Animais , Fator Natriurético Atrial/sangue , Fator Natriurético Atrial/metabolismo , Compostos de Bifenilo/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Hipertensão/sangue , Hipertensão/complicações , Glomérulos Renais/patologia , Masculino , Neprilisina/metabolismo , Ratos , Ratos Endogâmicos Dahl , Insuficiência Renal/sangue , Insuficiência Renal/etiologia , Insuficiência Renal/prevenção & controle
8.
High Blood Press Cardiovasc Prev ; 28(2): 167-175, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33599965

RESUMO

INTRODUCTION: Sacubitril/valsartan (S-V) has been shown to reduce clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). This benefit has been mostly attributed to an improvement in systolic function. AIM: This study aimed to evaluate longitudinal changes in several echocardiographic parameters of diastolic function in a cohort of patients with HFrEF receiving S-V. METHODS: Echocardiographic parameters of consecutive patients receiving S-V, such as diastolic dysfunction (DD) grade and other individual diastolic and systolic function parameters, were prospectively collected at baseline and at 6-month follow-up. New York Heart Association (NYHA) functional class was also recorded. RESULTS: 65 patients (73.9% males; 61.5 ± 13 years) with HFrEF in NYHA class II-IV were evaluated. There was a significant reduction in DD grade after treatment with maximal tolerated doses (p < 0.001). Patients with advanced DD showed the most significant improvements: 75% and 60% of patients with initial grade 3 and 2, respectively, had better grade after 6 months of S-V. Moreover, there was a reduction in E/e' ratio (p = 0.004), left atrial longitudinal strain (p = 0.002), and an improvement of left ventricle ejection fraction (p < 0.001) and NYHA functional class (p = 0.001). Among those subjects who improved their functional class, a higher percentage improved their DD grade (39.3%, p = 0.025) in comparison with those not improving their NYHA class (25%, p = 0.434). CONCLUSIONS: In addition to an improvement in systolic function parameters, patients with HFrEF receiving S-V improved their diastolic function. This echocardiographic improvement is particularly relevant in those patients with better NYHA class at 6-month follow-up.


Assuntos
Aminobutiratos/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/uso terapêutico , Volume Sistólico/efeitos dos fármacos , Tetrazóis/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Aminobutiratos/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Diástole , Combinação de Medicamentos , Ecocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores de Proteases/efeitos adversos , Recuperação de Função Fisiológica , Tetrazóis/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
9.
Eur J Pharmacol ; 894: 173851, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33422508

RESUMO

Sacubitril/valsartan (Entresto™; LCZ696) is the first angiotensin receptor-neprilysin inhibitor (ARNI) drug approved by the US and EU for heart failure (HF) and especially recommended for hypertensive HF (HHF). Sacubitril inhibits the enzyme neprilysin (NEP) which produces both beneficial and adverse effects in the human body. While LCZ696 causes beneficial cardiovascular effects, it may induce memory and cognitive dysfunction, or even exacerbate Alzheimer's disease (AD). This article reviewed data reported by experimental and clinical studies that examined NEP inhibitors and their dementia-related side effects. Based on the literature, LCZ696 increases the risk of memory and cognitive dysfunctions, and clinical trials failed to show compelling evidence for LCZ696 safety for the brain. Together, it was concluded that more experimental and clinical studies with particular focus on LCZ696 side effects on ß-amyloid (Aß) degradation are needed to assess LCZ696 safety for the cognitive function, especially in case of long-term administration.


Assuntos
Encefalopatias/induzido quimicamente , Insuficiência Cardíaca/tratamento farmacológico , Hipertensão/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Aminobutiratos/efeitos adversos , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/farmacologia , Comprometimento Cognitivo Relacionado à Quimioterapia/metabolismo , Combinação de Medicamentos , Humanos , Valsartana/efeitos adversos , Valsartana/farmacologia
10.
Am Heart J ; 235: 82-96, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33497697

RESUMO

BACKGROUND: In patients with heart failure and reduced ejection fraction (HFrEF), angiotensin converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB), or angiotensin receptor neprilysin inhibitor (ARNI), mineralocorticoid receptor antagonists (MRA), and beta-blockers (ßB) are underutilized. It is unknown if patients with and without comorbidities have similar ACEi/ARB/ARNI, MRA, and ßB prescription patterns. METHODS: Baseline data from the CHAMP-HF (Change the Management of Patients with Heart Failure) registry were categorized by history of atrial fibrillation, asthma/chronic lung disease, obstructive sleep apnea, and depression. Using multivariate hierarchical logistic models, associations of ACEi/ARB/ARNI, MRA and ßB medication use and dose by comorbidities were assessed after adjusting for patient characteristics. RESULTS: Of 4,815 HFrEF patients from 152 CHAMP-HF sites, ACEi/ARB/ARNI use was lower in patients with more comorbidities, and generally, MRA use was low and ßB use was high. In adjusted analyses, patients with HFrEF and comorbid obstructive sleep apnea, vs. without, were more likely to be prescribed ARNI (OR [95% CI]: 1.25 [1.00, 1.55]); P = .047 and MRA (1.31 [1.11, 1.55]); P = .002 and less likely to be prescribed ACEi (0.74 [0.63, 0.88]); P < .001. Patients with atrial fibrillation, vs. without, were less likely to receive ACEi/ARB (0.82 [0.71, 0.95]); P = .006 and any study medication (0.81 [0.67, 0.97]); P = .020. Comorbid lung disease and history of depression were not associated with HFrEF prescriptions. CONCLUSIONS: Renin-angiotensin-aldosterone blockade therapy prescription and dose varied by comorbidity status, but ßB therapy did not. In quality efforts, leaders need to consider use and dosing of prescriptions in light of prevalent comorbidities.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Neprilisina/antagonistas & inibidores , Sistema Renina-Angiotensina/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Idoso , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos
11.
Int J Cardiovasc Imaging ; 37(1): 165-173, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32815051

RESUMO

The sacubitril/valsartan combination is an important agent used in the treatment of heart failure with reduced ejection fraction (HFrEF). Pulmonary artery stiffness (PAS) is an index developed to evaluate the pulmonary vascular bed. Changes in pulmonary vascular structures in HFrEF patients can affect PAS. In this study, we aimed to investigate the effect of sacubitril/valsartan on PAS in HFrEF patients. One hundred fifty HFrEF patients, who received sacubitril/valsartan therapy and continued for at least 6 months without interruption, were examined retrospectively. N-terminal pro-B-type natriuretic peptide levels (NT-proBNP), NYHA classes, Minnesota Living with Heart Failure Questionnaire (MLWHFQ) scores, New York Heart Association (NYHA) functional classes and echocardiograpic parameters such as left ventricular ejection fraction (LVEF), mean pulmonary artery pressure (mPAP), right ventricle myocardial performance index (RV-MPI), Tricuspid annular plane systolic excursion (TAPSE), right ventricular fractional area change (RV-FAC) and PAS changes were evaluated before and 6 months after sacubitril/valsartan treatment. PAS was calculated by using the maximal frequency shift and acceleration time of the pulmonary artery flow trace measured in the echocardiogram. PAS values were significantly reduced (23.8 ± 2.8 vs 19.1 ± 3.1 kHz/ms, p < 0.001) after the sacubitril/valsartan treatment. Sacubitril/valsartan treatment was associated with significant improvements in NYHA class and MLWHFQ scores; significant reductions in the NT-proBNP levels, mPAP, and RV-MPI, and significant increases in LVEF, TAPSE, and RV-FAC (p < 0.05). The significant reduction in the PAS value was significantly correlated with the improvements in the MLWFQ scores, NT-proBNP levels, mPAP, RV-MPI, TAPSE and RV-FAC. In HFrEF patients, switching from angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy to sacubitril/valsartan may result in reduction in PAS.


Assuntos
Aminobutiratos/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Tetrazóis/uso terapêutico , Rigidez Vascular/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Aminobutiratos/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Estudos Transversais , Combinação de Medicamentos , Ecocardiografia Doppler de Pulso , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteases/efeitos adversos , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Estudos Retrospectivos , Tetrazóis/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
12.
Curr Opin Nephrol Hypertens ; 30(1): 123-130, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33148948

RESUMO

PURPOSE OF REVIEW: Chronic kidney disease (CKD) is associated with increased risk of progression to end-stage kidney disease and cardiovascular events. There is limited evidence that available treatments have beneficial effects on cardiorenal outcomes in all people with nondiabetic CKD. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential to improve outcomes for patients with CKD. RECENT FINDINGS: NEPi enhances the activity of the natriuretic peptide system producing natriuresis, diuresis and inhibition of the renin-angiotensin system and sympathetic nervous system. Sacubitril/valsartan is the first Angiotensin receptor-neprilysin inhibitor (ARNI) to be produced and has been shown to substantially improve cardiovascular outcomes in heart failure and delay progression of kidney disease in this population. Although ARNIs have not shown similar effects on kidney function in the short-to-medium term in people with CKD, they are associated with substantial reductions in cardiac biomarkers and blood pressure in CKD. SUMMARY: These data suggest that NEPi with an ARNI could benefit patients with CKD by reducing the risk of cardiovascular disease and have the possibility of retarding the progression of CKD (hence delaying the need for renal replacement therapy).


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Doenças Cardiovasculares , Neprilisina , Insuficiência Renal Crônica/tratamento farmacológico , Valsartana/uso terapêutico , Aminobutiratos/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Compostos Benzidrílicos/uso terapêutico , Compostos de Bifenilo/farmacologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Doença Crônica , Modelos Animais de Doenças , Progressão da Doença , Combinação de Medicamentos , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Humanos , Camundongos , Peptídeos Natriuréticos/fisiologia , Neprilisina/antagonistas & inibidores , Neprilisina/fisiologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Sistema Renina-Angiotensina/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Valsartana/farmacologia
13.
Biomed Pharmacother ; 133: 110824, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378988

RESUMO

BACKGROUND: LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNi), is reported to play a cardioprotective role after acute myocardial infarction (AMI). Angiotensin-converting enzyme inhibitors(ACEIs) have similar roles. However, it is unclear whether the combination of the two drugs has a better protective effect. The purpose of this study was to investigate the effect of this combination therapy after AMI. METHODS: Male C57BL/6 J mice subjected to ligation of left anterior descending artery were treated for 4 weeks with LCZ696, ACEI(benazepril), or both(combination therapy) after induction of MI. Cardiac function, hemodynamics, and inflammatory factors were evaluated at 1 st day, 14th day, and 28th day. Heart weight and myocardial fibrosis were measured at the end of the experiment. RESULTS: Blood pressure was lower in all treatment groups than in the control group. The combination therapy group had the strongest antihypertensive effect. Compared with LCZ696 or benazepril, treatment with combination therapy increased ejection fraction, fractional shortening, and cardiac output and decreased N-terminal pro-B-type natriuretic peptide(NT-proBNP). The ratios of heart weight to body weight in all treatment groups were less than that in the control group. Compared with the control and LCZ696 group, the fibrotic area in the combination therapy group was suppressed and had a lower level of TGF-ß1 in the left ventricle. The plasma concentration of bradykinin and renin in the combination therapy group were highest among groups at 14th and 28th day. CONCLUSIONS: LCZ696 in combination with benazepril showed better positive effects in modulating heart failure and myocardial fibrosis after acute AMI in mice and affect some inflammatory markers.


Assuntos
Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Benzazepinas/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/complicações , Miocárdio/patologia , Inibidores de Proteases/farmacologia , Tetrazóis/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Combinação de Medicamentos , Quimioterapia Combinada , Fibrose , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Neprilisina/antagonistas & inibidores , Renina/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
14.
Circ Cardiovasc Qual Outcomes ; 13(12): e007070, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33302715

RESUMO

BACKGROUND: Out-of-pocket medication costs for patients who have heart failure with reduced ejection fraction may be an important part of shared decision-making, but cost has generally been excluded from clinical discussions. This study reports patients' perspectives on a decision aid for sacubitril/valsartan that explicitly addresses out-of-pocket costs. METHODS: Structured, in-depth interviews were conducted with 20 patients with heart failure with reduced ejection fraction from 2 medical centers to elicit their views on a publicly available decision aid for sacubitril/valsartan that explicitly incorporates considerations related to out-of-pocket costs. Qualitative descriptive analysis was conducted. RESULTS: Key themes identified were general enthusiasm for decision aids for medication decisions, openness on the part of patients to incorporation of cost into decision-making and the decision aid, requests for greater specificity regarding patient-specific cost, and challenges communicating evidence of benefit in a way that allows patients to make cost-benefit analyses for themselves. Patients also raised questions regarding logistical challenges of incorporating a decision aid into the normal clinical and decision-making workflow. CONCLUSIONS: Patients were receptive to the inclusion of out-of-pocket cost as relevant in a decision aid for sacubitril/valsartan. Key challenges to effective integration of cost in these decisions include developing mechanisms for acquiring reliable patient-specific cost estimates and addressing patients' difficulties (and sometimes skepticism) applying trial evidence to their own situation. In addition, implementation strategies are important to develop to facilitate decision aid integration for routine medical decisions into clinic workflow.


Assuntos
Aminobutiratos/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Tomada de Decisão Compartilhada , Técnicas de Apoio para a Decisão , Custos de Medicamentos , Gastos em Saúde , Insuficiência Cardíaca/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Valsartana/uso terapêutico , Idoso , Aminobutiratos/economia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/economia , Compostos de Bifenilo/economia , Colorado , Análise Custo-Benefício , Combinação de Medicamentos , Feminino , Georgia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/economia , Insuficiência Cardíaca/fisiopatologia , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Neprilisina/antagonistas & inibidores , Participação do Paciente , Satisfação do Paciente , Inibidores de Proteases/economia , Resultado do Tratamento , Valsartana/economia
15.
Molecules ; 25(24)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33321720

RESUMO

BACKGROUND: the pharmacological treatment and/or maintenance of remission in inflammatory bowel diseases (IBDs) is currently one of the biggest challenges in the field of gastroenterology. METHOD: our aim was the synthesis of homo- and heterodimers of natural enkephalinase inhibitors (opiorphin; sialorphin; spinorphin) and the in vitro characterization of their effect on the degradation of enkephalin by neutral endopeptidase (NEP) and stability in human plasma. We investigated the in vivo heterodimer of Cys containing analogs of sialorphin and spinorphin (peptide X) in a mouse model of colitis. The extent of inflammation was evaluated based on the microscopic score; macroscopic score; ulcer score, colonic wall thickness, colon length and quantification of myeloperoxidase activity. RESULTS: we showed that the homo- and heterodimerization of analogs of sialorphin, spinorphin and opiorphin containing Cys residue at the N-terminal position resulted in dimeric forms which in vitro exhibited higher inhibitory activity against NEP than their parent and monomeric forms. We showed that peptide X was more stable in human plasma than sialorphin and spinorphin. Peptide X exerts potent anti-inflammatory effect in the mouse model of colitis. CONCLUSION: we suggest that peptide X has the potential to become a valuable template for anti-inflammatory therapeutics for the treatment of gastrointestinal (GI) tract inflammation.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Neprilisina/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Anti-Inflamatórios/farmacocinética , Produtos Biológicos/farmacocinética , Biomarcadores , Fenômenos Químicos , Colite/tratamento farmacológico , Dimerização , Modelos Animais de Doenças , Estabilidade de Medicamentos , Inibidores Enzimáticos/farmacocinética , Humanos , Imuno-Histoquímica , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Peptídeos/química , Peptídeos/farmacologia
16.
Int J Mol Sci ; 21(22)2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33203141

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger "cytokine storm" leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on "multi-targeted" therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Pneumonia Viral/tratamento farmacológico , Aminobutiratos/administração & dosagem , Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/administração & dosagem , Animais , COVID-19 , Infecções por Coronavirus/metabolismo , Combinação de Medicamentos , Humanos , Neprilisina/metabolismo , Pandemias , Pneumonia Viral/metabolismo , Tetrazóis/administração & dosagem , Tetrazóis/uso terapêutico , Valsartana/administração & dosagem , Valsartana/uso terapêutico
17.
Open Heart ; 7(2)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33020255

RESUMO

BACKGROUND: Sacubitril/valsartan is an effective treatment for heart failure with reduced ejection fraction (HFrEF) based on clinical trial data. However, little is known about its use or impact in real-world practice. The aim of this study was to describe our routine clinical experience of switching otherwise optimally treated patients with HFrEF to sacubitril/valsartan with respect to patient outcomes such as quality of life (QoL) and echocardiographic variables. METHODS AND RESULTS: From June 2017 to May 2019, 80 consecutive stable patients with HFrEF on established and maximally tolerated guideline-directed HF therapies were initiated on sacubitril/valsartan with bimonthly uptitration. Clinical assessment, biochemistry, echocardiography and QoL were compared pretreatment and post-treatment switching. We were able to successfully switch 89% of patients from renin-angiotensin axis inhibitors to sacubitril/valsartan (71 of 80 patients). After 3 months of switch therapy, we observed clinically significant and incremental improvements in blood pressure (systolic blood pressure 123 vs 112 mm Hg, p<0.001; diastolic blood pressure 72 vs 68 mm Hg, p=0.004), New York Heart Association functional classification score (2.3 vs 1.9, p<0.001), Minnesota Living with Heart Failure Questionnaire score (46 vs 38, p=0.016), left ventricular ejection fraction (26% vs 33%, p<0.001) and left ventricular end systolic diameter (5.2 vs 4.9 cm, p=0.013) compared with baseline. There were no significant changes in renal function or serum potassium. CONCLUSION: This study provides real-world clinical practice data demonstrating incremental improvements in functional and echocardiographic outcomes in optimally treated patients with HFrEF switched to sacubitril/valsartan. The data provide evidence beyond that observed in clinical trial settings of the potential benefits of sacubitril/valsartan when used as part of a multidisciplinary heart failure programme.


Assuntos
Aminobutiratos/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Substituição de Medicamentos , Insuficiência Cardíaca/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Volume Sistólico/efeitos dos fármacos , Tetrazóis/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Aminobutiratos/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Combinação de Medicamentos , Ecocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/efeitos adversos , Qualidade de Vida , Recuperação de Função Fisiológica , Estudos Retrospectivos , Tetrazóis/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
18.
Drugs Aging ; 37(11): 779-785, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33084001

RESUMO

This paper presents a brief overview of the complex interaction between age, hypertension, the renin-angiotensin-aldosterone system (RAAS), inflammation, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Coronavirus disease 2019 (COVID-19) is more frequent and more severe in comorbid elderly patients, especially those with hypertension, diabetes, obesity, or cardiovascular diseases. There are concerns regarding the use of RAAS inhibitors in patients with COVID-19. Some physicians have considered the need for interrupting RAAS inhibition in order to reduce the possibility of SARS-CoV2 entering lung cells after binding to angiotensin-converting enzyme 2 (ACE2) receptors. We offer a different point of view in relation to the need for continuing to use RAAS inhibitors in patients with COVID-19. We focused our article on elderly patients because of the distinctive imbalance between the immune response, which is depressed, and the exacerbated inflammatory response, 'inflammaging', which makes the geriatric patient an appropriate candidate for therapeutic strategies aimed at modulating the inflammatory response. Indeed, COVID-19 is an inflammatory storm that starts and worsens during the course of the disease. During the COVID-19 pandemic, various therapeutic approaches have been tested, including antiviral drugs, interferon, anti-interleukins, hydroxychloroquine, anti-inflammatories, immunoglobulins from recovered patients, and heparins. Some of these therapeutic approaches did not prove to be beneficial, or even induced serious complications. Based on current evidence, in the early stages of the disease modulation of the inflammatory response through the inhibition of neprilysin and modulation of the RAAS could affect the course and outcome of COVID-19.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Betacoronavirus , Infecções por Coronavirus , Hipertensão/tratamento farmacológico , Inflamação , Pandemias , Pneumonia Viral , Idoso , Enzima de Conversão de Angiotensina 2 , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , COVID-19 , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/imunologia , Humanos , Fatores Imunológicos/farmacologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Neprilisina/antagonistas & inibidores , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Sistema Renina-Angiotensina/efeitos dos fármacos , SARS-CoV-2
19.
Lancet ; 396(10254): 819-829, 2020 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-32877652

RESUMO

BACKGROUND: Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials. METHODS: We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran's Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model. FINDINGS: Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77-0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76-0·98; p=0·027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0·74, 0·68-0·82; p<0·0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0·75, 0·68-0·84; p<0·0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43-0·90; p=0·013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race. INTERPRETATION: The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF. FUNDING: Boehringer Ingelheim.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Glucosídeos/efeitos adversos , Insuficiência Cardíaca/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Volume Sistólico/efeitos dos fármacos , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Índice de Massa Corporal , Estudos de Casos e Controles , Causas de Morte/tendências , Ensaios Clínicos como Assunto , Morte , Diabetes Mellitus Tipo 2/complicações , Quimioterapia Combinada , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/classificação , Insuficiência Cardíaca/fisiopatologia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina/antagonistas & inibidores , Avaliação de Resultados da Assistência ao Paciente , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
20.
Cells ; 9(9)2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32967374

RESUMO

During the last three decades, timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous intervention (pPCI) has allowed amazing improvements in outcomes with a more than halving in 1-year ST-elevation myocardial infarction (STEMI) mortality. However, mortality and left ventricle (LV) remodeling remain substantial in these patients. As such, novel therapeutic interventions are required to reduce myocardial infarction size, preserve LV systolic function, and improve survival in reperfused-STEMI patients. Myocardial ischemia-reperfusion injury (MIRI) prevention represents the main goal to reach in order to reduce STEMI mortality. There is currently no effective therapy for MIRI prevention in STEMI patients. A significant reason for the weak and inconsistent results obtained in this field may be the presence of multiple, partially redundant, mechanisms of cell death during ischemia-reperfusion, whose relative importance may depend on the conditions. Therefore, it is always more recognized that it is important to consider a "multi-targeted cardioprotective therapy", defined as an additive or synergistic cardioprotective agents or interventions directed to distinct targets with different timing of application (before, during, or after pPCI). Given that some neprilysin (NEP) substrates (natriuretic peptides, angiotensin II, bradykinin, apelins, substance P, and adrenomedullin) exert a cardioprotective effect against ischemia-reperfusion injury, it is conceivable that antagonism of proteolytic activity by this enzyme may be considered in a multi-targeted strategy for MIRI prevention. In this review, by starting from main pathophysiological mechanisms promoting MIRI, we discuss cardioprotective effects of NEP substrates and the potential benefit of NEP pharmacological inhibition in MIRI prevention.


Assuntos
Aminobutiratos/uso terapêutico , Angiotensina II/genética , Cardiotônicos/uso terapêutico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Neprilisina/antagonistas & inibidores , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Tetrazóis/uso terapêutico , Adrenomedulina/genética , Adrenomedulina/metabolismo , Angiotensina II/metabolismo , Animais , Apelina/genética , Apelina/metabolismo , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Bradicinina/genética , Bradicinina/metabolismo , Combinação de Medicamentos , Regulação da Expressão Gênica , Humanos , Camundongos , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Neprilisina/genética , Neprilisina/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST/enzimologia , Infarto do Miocárdio com Supradesnível do Segmento ST/genética , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Substância P/genética , Substância P/metabolismo , Análise de Sobrevida , Remodelação Ventricular/efeitos dos fármacos
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