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The rapidly increasing burden of hypertension is responsible for premature deaths from cardiovascular disease (CVD), renal disease, and stroke, with a tremendous public health and financial burden. Hypertension detection, treatment, and control vary worldwide; it is still low, particularly in low- and middle-income countries (LMICs). High blood pressure (BP) and CVD risk have a strong, linear, and independent association. They contribute to alarming numbers of all-cause and CVD deaths. A major culprit for increased hypertension is sympathetic activity, and further complications of hypertension are heart failure, ischemic heart disease (IHD), stroke, and renal failure. Now, antihypertensive interventions have emerged as a global public health priority to reduce BP-related morbidity and mortality. Calcium channel blockers (CCB) are highly effective vasodilators. and the most common drugs used for managing hypertension and CVD. Cilnidipine, with both L- and N-type calcium channel blocking activity, is a promising 4th generation CCB. It causes vasodilation via L-type calcium channel blockade and inhibits the sympathetic nervous system (SNS) via N-type calcium channel blockade. Cilnidipine, which acts as a dual L/N-type CCB, is linked to a reduced occurrence of pedal edema compared to amlodipine, which solely blocks L-type calcium channels. The antihypertensive properties of cilnidipine are very substantial, with low BP variability and long-acting properties. It is beneficial for hypertensive patients to deal with morning hypertension and for patients with abnormal nocturnal BP due to exaggerated sympathetic nerve activation. Besides its BP-lowering effect, it also exhibits organ protection via sympathetic nerve inhibition and renin-angiotensin-aldosterone system inhibition; it controls heart rate and proteinuria. Reno-protective, neuroprotective, and cardioprotective effects of cilnidipine have been well-documented and demonstrated.
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Bloqueadores dos Canais de Cálcio , Di-Hidropiridinas , Hipertensão , Humanos , Hipertensão/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Di-Hidropiridinas/uso terapêutico , Índia/epidemiologia , Anti-Hipertensivos/uso terapêutico , Consenso , ComorbidadeRESUMO
Heart failure (HF) is a global health concern that is prevalent in India as well. HF is reported at a younger age in Indian patients with comorbidity of type 2 diabetes (T2DM) in approximately 50% of patients. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), originally approved for T2DM, are new guideline-recommended and approved treatment strategies for HF. Extensive evidence highlights that SGLT2i exhibits profound cardiovascular (CV) benefits beyond glycemic control. SGLT2i, in conjunction with other guideline-directed medical therapies (GMDT), has additive effects in improving heart function and reducing adverse HF outcomes. The benefits of SGLT2i are across a spectrum of patients, with and without diabetes, suggesting their potential place in broader HF populations irrespective of ejection fraction (EF). This consensus builds on the updated evidence of the efficacy and safety of SGLT2i in HF and recommends its place in therapy with a focus on Indian patients with HF.
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Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Índia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicaçõesRESUMO
Chronic kidney disease (CKD) is a major contributor to morbidity and mortality in India. CKD often coexists with heart failure (HF), diabetes, and hypertension. All these comorbidities are risk factors for renal impairment. HF and CKD are pathophysiologically intertwined, and the deterioration of one can worsen the prognosis of the other. There is a need for safe renal pharmacological therapies that target both CKD and HF and are also useful in hypertension and diabetes. Neurohormonal activation achieved through the activation of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS), and the natriuretic peptide system (NPS) is fundamental in the pathogenesis and progression of CKD and HF. Angiotensin receptor neprilysin inhibitor (ARNi), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), and selective ß1-blocker (B1B) bisoprolol suppress this neurohormonal activation. They also have many other cardiorenal benefits across a wide range of CKD patients with or without concomitant HF, diabetes, or hypertension. This consensus statement from India explores the place of ARNi, SGLT-2i, and bisoprolol in the management of CKD patients with or without HF and other comorbidities.
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Antagonistas de Receptores de Angiotensina , Bisoprolol , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Índia/epidemiologia , Bisoprolol/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Consenso , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêuticoRESUMO
BACKGROUND: This study aimed to report the surgical outcomes and also evaluating the safety and feasibility of thoracoscopic pericardial window (PW) for recurrent pericardial effusion. MATERIALS AND METHODS: This was a retrospective analysis of eight cases of recurrent pericardial effusion, managed by thoracoscopic method in a tertiary-level thoracic surgery centre over 5 years. A detailed analysis of all perioperative variables, including complications, was carried out. RESULTS: A total of eight patients underwent thoracoscopic PW during the study period. Males (87.5%) were predominant in the cohort. The median age was 54 years (range: 28-78 years). The median duration of symptoms was 2 months (range: 1-3 months). Tuberculosis (50%), malignancy (37.5%) and chronic kidney disease (12.5%) were the causes of recurrent effusion. All patients underwent thoracoscopic procedure with no conversions. The median operative time was 45 min (range: 40-70 min). The median effusion volume drained was 500 ± 100 ml. The median hospital stay was 3 days (range: 2-4 days) with no post-procedural complications. All the patients had complete resolution of symptoms. No recurrence was noted in the median follow-up period of 28 months (range: 6-60 months). CONCLUSIONS: Thoracoscopic PW is a safe and feasible minimally invasive option in the management of recurrent pericardial effusion in selected patients. Surgical fitness, haemodynamic status and estimated survival (in malignant effusion) should be considered before the procedure.
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Single ventricle patients eligible for Fontan completion undergo pre-Fontan catheterization for hemodynamic and anatomic assessment prior to surgery. Cardiac magnetic resonance imaging may be used to evaluate pre-Fontan anatomy, physiology, and collateral burden. We describe our center's outcomes in patients undergoing pre-Fontan catheterization combined with cardiac magnetic resonance imaging. A retrospective review of patients undergoing pre-Fontan catheterization from 10/2018 to 04/2022 at Texas Children's Hospital was performed. Patients were divided into 2 groups: combined cardiac magnetic resonance imaging and catheterization (combined group) and those who underwent catheterization only (catheterization only group). There were 37 patients in the combined group and 40 in the catheterization only group. Both groups were similar in age and weight. Patients undergoing combined procedures received less contrast, and experienced less in-lab time, fluoroscopy time and catheterization procedure time. Median radiation exposure was lower in the combined procedure group but was not statistically significant. Intubation and total anesthesia times were higher in the combined procedure group. Patients undergoing a combined procedure were less likely to have collateral occlusion performed than in the catheterization only group. Bypass time, intensive care unit length of stay, and chest tube duration were similar in both groups at the time of Fontan completion. Combined pre-Fontan assessment decreases catheterization procedure and fluoroscopy time associated with cardiac catheterization at the expense of longer anesthetic times, and results in similar Fontan outcomes compared to when cardiac catheterization alone is utilized.
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BACKGROUND: Fontan baffle punctures and creation of Fontan fenestration for cardiac catheterisation procedures remain challenging especially due to the heavy calcification of prosthetic material and complex anatomy. OBJECTIVES: We sought to evaluate our experience using radiofrequency current via surgical electrocautery needle for Fontan baffle puncture to facilitate diagnostic, electrophysiology, and interventional procedures. METHODS: A retrospective chart review of all Fontan patients (pts) who underwent Fontan baffle puncture using radiofrequency energy via surgical electrocautery from three centres were performed from January 2011 to July 2021. RESULTS: A total of 19 pts underwent 22 successful Fontan baffle puncture. The median age and weight were 17 (3-36 years) and 55 (14-88) kg, respectively. The procedural indications for Fontan fenestration creation included: diagnostic study (n = 1), atrial septostomy and stenting (n = 1), electrophysiology study and ablation procedures (n = 8), Fontan baffle stenting for Fontan failure including protein-losing enteropathy (n = 7), and occlusion of veno-venous collaterals (n = 2) for cyanosis. The type of Fontan baffles included: extra-cardiac conduits (n = 12), lateral tunnel (n = 5), classic atrio-pulmonary connection (n = 1), and intra-cardiac baffle (n = 1). A Fontan baffle puncture was initially attempted using traditional method in 6 pts and Baylis radiofrequency trans-septal system in 2 pts unsuccessfully. In all pts, Fontan baffle puncture using radiofrequency energy via electrocautery needle was successful. The radiofrequency energy utilised was (10-50 W) and required 1-5 attempts for 2-5 seconds. There were no vascular or neurological complications. CONCLUSIONS: Radiofrequency current delivery using surgical electrocautery facilitates Fontan baffle puncture in patients with complex and calcified Fontan baffles for diagnostic, interventional, and electrophysiology procedures.
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Técnica de Fontan , Cardiopatias Congênitas , Humanos , Cardiopatias Congênitas/complicações , Estudos Retrospectivos , Coração , Cateterismo Cardíaco , Eletrocoagulação , Resultado do TratamentoRESUMO
;Heart failure (HF) is a huge global public health task due to morbidity, mortality, disturbed quality of life, and major economic burden. It is an area of active research and newer treatment strategies are evolving. Recently angiotensin receptor-neprilysin inhibitor (ARNI), a class of drugs (the first agent in this class, Sacubitril-Valsartan), reduces cardiovascular mortality and morbidity in chronic HF patients with reduced left ventricular ejection fraction (LVEF). Positive therapeutic effects have led to a decrease in cardiovascular mortality and HF hospitalizations (HFH), with a favorable safety profile, and have been documented in several clinical studies with an unquestionable survival benefit with ARNI, Sacubitril-Valsartan. This consensus statement of the Indian group of experts in cardiology, nephrology, and diabetes provides a comprehensive review of the power and promise of ARNI in HF management and an evidence-based appraisal of the use of ARNI as an essential treatment strategy for HF patients in clinical practice. Consensus in this review favors an early utility of Sacubitril-Valsartan in patients with HF with reduced EF (HFrEF), regardless of the previous therapy being given. A lower rate of hospitalizations for HF with Sacubitril-Valsartan in HF patients with preserved EF who are phenotypically heterogeneous suggests possible benefits of ARNI in patients having 40-50% of LVEF, frequent subtle systolic dysfunction, and higher hospitalization risk.
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Insuficiência Cardíaca , Humanos , Insuficiência Cardíaca/tratamento farmacológico , Neprilisina/farmacologia , Volume Sistólico/fisiologia , Tetrazóis/uso terapêutico , Tetrazóis/farmacologia , Qualidade de Vida , Função Ventricular Esquerda , Antagonistas de Receptores de Angiotensina/uso terapêutico , Antagonistas de Receptores de Angiotensina/farmacologia , Resultado do Tratamento , Anti-Hipertensivos/uso terapêutico , Combinação de MedicamentosRESUMO
In India, heart failure (HF) is an important health concern affecting younger age groups than the western population. A limited number of Indian patients receive guideline-directed medical therapy (GDMT). Selective ß-1 blockers (BB) are one of the GDMTs in HF and play an important role by decreasing the sympathetic overdrive. The BB reduces heart rate (HR) reverse the adverse cardiac (both ventricular and atrial), vascular, and renovascular remodeling seen in HF. Bisoprolol, a ß-1 blocker, has several advantages and can be used across a wide spectrum of HF presentations and in patients with HF and comorbid conditions such as coronary artery disease (CAD), atrial fibrillation (AF), post-myocardial infarction (MI), uncontrolled diabetes, uncontrolled hypertension, and renal impairment. Despite its advantages, bisoprolol is not optimally utilized for managing HF in India. This consensus builds on updated evidence on the efficacy and safety of bisoprolol in HF and recommends its place in therapy with a focus on Indian patients with HF.
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Antagonistas de Receptores Adrenérgicos beta 1 , Bisoprolol , Insuficiência Cardíaca , Humanos , Bisoprolol/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Índia , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , ConsensoRESUMO
PURPOSE OF REVIEW: Overlapping hemodynamics in constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM) often pose difficulties in establishing accurate diagnosis. Echocardiography is the first-line imaging modality used for this purpose, but no single echocardiographic parameter is sufficiently robust for distinguishing between the two conditions. The newer developments may improve the diagnostic accuracy of echocardiography in this setting. RECENT FINDINGS: Recent studies have validated multiparametric algorithms, based on conventional echocardiographic parameters, which enable high sensitivity and specificity for distinguishing between CP and RCM. In addition, myocardial deformation analysis using speckle-tracking echocardiography has revealed distinct pattern of abnormalities in the two conditions. CP is characterized by impaired left ventricular apical rotation with relatively preserved longitudinal strain, esp. of ventricular and atrial septum. In contrast, RCM results in global and marked impairment of left ventricular longitudinal strain with initially preserved circumferential mechanics. Combining multiple echocardiographic parameters into step-wise algorithms and incorporation of myocardial deformation analysis help improve the diagnostic accuracy of echocardiography for distinguishing between CP and RCM. The use of machine-learning may allow easy integration of a wide range of echocardiographic and clinical parameters to permit accurate, automated diagnosis, with less dependence on the user expertise.
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Ecocardiografia , HumanosRESUMO
Aortic aneurysm in children is rare, but has been described in the tuberous sclerosis complex (TSC) population. While surgical repair has been utilized as the primary means of intervention, we present the first known case reporting exclusion of a descending thoracic aortic aneurysm with percutaneous covered stent implantation in a pediatric patient with TSC. A review of the literature is also included herein.
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Aneurisma da Aorta Torácica , Implante de Prótese Vascular , Procedimentos Endovasculares , Esclerose Tuberosa , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/etiologia , Aneurisma da Aorta Torácica/cirurgia , Criança , Humanos , Stents , Resultado do Tratamento , Esclerose Tuberosa/complicaçõesRESUMO
Lipid-lowering therapy plays a crucial role in reducing adverse cardiovascular (CV) events in patients with established atherosclerotic cardiovascular disease (ASCVD) and familial hypercholesterolemia. Lifestyle interventions along with high-intensity statin therapy are the first-line management strategy followed by ezetimibe. Only about 20-30% of patients who are on maximally tolerated statins reach recommended low-density lipoprotein cholesterol (LDL-C) goals. Several factors contribute to the problem, including adherence issues, prescription of less than high-intensity statin therapy, and de-escalation of statin dosages, but in patients with very high baseline LDL-C levels, including those with familial hypercholesterolemia and those who are intolerant to statins, it is critical to expand our arsenal of LDL-C-lowering medications. Moreover, in the extreme risk group of patients with an LDL-C goal of ≤30 mg/dL according to the Lipid Association of India (LAI) risk stratification algorithm, there is a significant residual risk requiring the addition of non-statin drugs to achieve LAI recommended targets. This makes bempedoic acid a welcome addition to the existing non-statin therapies such as ezetimibe, bile acid sequestrants, and PCSK9 inhibitors. A low frequency of muscle-related side effects, minimal drug interactions, a significant reduction in high-sensitivity C-reactive protein (hsCRP), and a lower incidence of new-onset or worsening diabetes make it a useful adjunct for LDL-C lowering. However, the CV outcomes trial results are still pending. In this LAI consensus document, we discuss the pharmacology, indications, contraindications, advantages, and evidence-based recommendations for the use of bempedoic acid in clinical practice.
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Anticolesterolemiantes , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipoproteinemia Tipo II , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol , Ácidos Dicarboxílicos , Ezetimiba/farmacologia , Ezetimiba/uso terapêutico , Ácidos Graxos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/induzido quimicamente , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pró-Proteína Convertase 9RESUMO
One strategy for the development of a next generation influenza vaccine centers upon using conserved domains of the virus to induce broader and long-lasting immune responses. The production of artificial proteins by mimicking native-like structures has shown to be a promising approach for vaccine design against diverse enveloped viruses. The amino terminus of influenza A virus matrix 2 ectodomain (M2e) is highly conserved among influenza subtypes, and previous studies have shown M2e-based vaccines are strongly immunogenic, making it an attractive target for further exploration. We hypothesized that stabilizing M2e protein in the mammalian system might influence the immunogenicity of M2e with the added advantage to robustly produce the large scale of proteins with native-like fold and hence can act as an efficient vaccine candidate. In this study, we created an engineered construct in which the amino terminus of M2e is linked to the tetramerizing domain tGCN4, expressed the construct in a mammalian system, and tested for immunogenicity in BALB/c mice. We have also constructed a stand-alone M2e construct (without tGCN4) and compared the protein expressed in mammalian cells and in Escherichia coli using in vitro and in vivo methods. The mammalian-expressed protein was found to be more stable, more antigenic than the E. coli protein, and form higher-order oligomers. In an intramuscular protein priming and boosting regimen in mice, these proteins induced high titers of antibodies and elicited a mixed Th1/Th2 response. These results highlight the mammalian-expressed M2e soluble proteins as a promising vaccine development platform.
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Vírus da Influenza A Subtipo H1N1/metabolismo , Proteínas da Matriz Viral/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Escherichia coli/metabolismo , Células HEK293 , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Vacinas contra Influenza/imunologia , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Domínios Proteicos , Multimerização Proteica , Estabilidade Proteica , Estrutura Secundária de Proteína , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Células Th1/citologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/citologia , Células Th2/imunologia , Células Th2/metabolismo , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/metabolismoRESUMO
BACKGROUND: Tricuspid valve injury can occur during implantation of a SAPIEN valve in the pulmonary position. We describe our experience using a long Gore DrySeal (GDS) sheath to protect the tricuspid valve during advancement of the Commander delivery system. METHODS: Retrospective single center review of all patients who underwent placement of a SAPIEN valve in the right ventricular outflow tract between January 2016 and April 2020. Patients were divided into two groups: delivery of the valve using standard technique (Group I), and with the use of a GDS (Group II), for comparison. RESULTS: There were 48 patients in total: 25 in Group I and 23 in Group II. In Group II, the first 10 patients had a 29 mm S3 placed through a 26 French (Fr), 65 cm GDS. We then performed additional crimping of the S3 onto the balloon after the balloon catheter was withdrawn to position the valve on the balloon outside the body. Subsequently, seven had a 29 mm S3 placed through a 24 Fr GDS, and four had a 26 mm S3 placed through a 22 Fr GDS including one weighing 16 kg. Two had a 23 mm S3 placed through a 22Fr GDS as the 20Fr GDS was not available in our lab. Severe tricuspid valve injury occurred in 2/25 (8%) of Group I patients and 0/23 of Group II patients. CONCLUSION: Use of a long GDS may protect the tricuspid valve from injury during implantation of the S3 valve in the pulmonary position, and is technically feasible in smaller patients.
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Cateterismo Cardíaco/instrumentação , Traumatismos Cardíacos/prevenção & controle , Implante de Prótese de Valva Cardíaca/instrumentação , Próteses Valvulares Cardíacas , Hemodinâmica , Valva Pulmonar/cirurgia , Insuficiência da Valva Tricúspide/prevenção & controle , Valva Tricúspide/fisiopatologia , Adolescente , Adulto , Valvuloplastia com Balão , Cateterismo Cardíaco/efeitos adversos , Criança , Feminino , Traumatismos Cardíacos/diagnóstico por imagem , Traumatismos Cardíacos/etiologia , Traumatismos Cardíacos/fisiopatologia , Implante de Prótese de Valva Cardíaca/efeitos adversos , Humanos , Masculino , Desenho de Prótese , Valva Pulmonar/diagnóstico por imagem , Valva Pulmonar/fisiopatologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Valva Tricúspide/diagnóstico por imagem , Valva Tricúspide/lesões , Insuficiência da Valva Tricúspide/diagnóstico por imagem , Insuficiência da Valva Tricúspide/etiologia , Insuficiência da Valva Tricúspide/fisiopatologia , Adulto JovemRESUMO
A 25-year-old female, with systemic lupus erythematosus and antiphospholipid antibody syndrome, presented with exertional dyspnoea. Echocardiography showed a large (2.0 cm × 1.1 cm), echogenic, heterogeneous mass in the left ventricular outflow tract, under the aortic valve, attached to the ventricular aspect of the anterior mitral leaflet. Tiny flagellar, frond-like structures were seen attached to the surface of the mass. There was mitral regurgitation. These echocardiographic features were suggestive of a papillary fibroelastoma, but the histopathology of the excised mass revealed it to be a thrombus, which was consistent with a diagnosis of non-bacterial thrombotic endocarditis (NBTE). This case represents a rare histopathologically confirmed NBTE presenting as an unusually large mass in the left ventricular outflow tract.
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Síndrome Antifosfolipídica , Lúpus Eritematoso Sistêmico , Adulto , Ecocardiografia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/complicações , Valva Mitral/diagnóstico por imagemRESUMO
Rare variants in the T-box transcription factor 4 gene (TBX4) have recently been recognised as an emerging cause of paediatric pulmonary hypertension (PH). Their pathophysiology and contribution to persistent pulmonary hypertension in neonates (PPHN) are unknown. We sought to define the spectrum of clinical manifestations and histopathology associated with TBX4 variants in neonates and children with PH.We assessed clinical data and lung tissue in 19 children with PH, including PPHN, carrying TBX4 rare variants identified by next-generation sequencing and copy number variation arrays.Variants included six 17q23 deletions encompassing the entire TBX4 locus and neighbouring genes, and 12 likely damaging mutations. 10 infants presented with neonatal hypoxic respiratory failure and PPHN, and were subsequently discharged home. PH was diagnosed later in infancy or childhood. Three children died and two required lung transplantation. Associated anomalies included patent ductus arteriosus, septal defects, foot anomalies and developmental disability, the latter with a higher prevalence in deletion carriers. Histology in seven infants showed abnormal distal lung development and pulmonary hypertensive remodelling.TBX4 mutations and 17q23 deletions underlie a new form of developmental lung disease manifesting with severe, often biphasic PH at birth and/or later in infancy and childhood, often associated with skeletal anomalies, cardiac defects, neurodevelopmental disability and other anomalies.
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Deleção de Genes , Hipertensão Pulmonar/genética , Proteínas com Domínio T/genética , Adolescente , Adulto , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Variação Genética , Heterozigoto , Humanos , Lactente , Recém-Nascido , Pulmão/crescimento & desenvolvimento , Transplante de Pulmão , Masculino , Mutação , Fenótipo , Resistência Vascular , Adulto JovemRESUMO
INTRODUCTION: High-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, is known to be elevated in patients with erectile dysfunction (ED). However, its role in predicting therapeutic response to phosphodiesterase-5 inhibitors is incompletely understood. AIM: The aim of this study was to understand the relationship among hs-CRP, mechanism of ED, and therapeutic response of ED to tadalafil, a phosphodiesterase-5 inhibitor. METHODS: A total of 282 men (mean age 36.6 ± 12.0 years) with ED were included. All subjects underwent detailed evaluation, including estimation of a 6-item abbreviated version of the International Index of Erectile Function (IIEF-6) score, penile Doppler studies, and measurement of hs-CRP. IIEF-6 scoring and hs-CRP measurement were repeated after 6 weeks of tadalafil therapy (10 mg/day). The patients were categorized into vasculogenic and nonvasculogenic ED groups based on penile Doppler findings. MAIN OUTCOME MEASURE: The main outcome measure was the therapeutic response to tadalafil, in relation to the mechanism of ED and hs-CRP levels. RESULTS: Vasculogenic ED was much less common (23.8% of the subjects) than non-vasculogenic ED. Subjects with vasculogenic ED were older, had higher prevalence of cardiovascular risk factors, had more severe (mean IIEF-6 score 9.2 ± 4.6 vs 14.8 ± 4.7; P < .001) and longer duration ED, and responded less favorably to therapy (response rate 10.4% vs 75.0%; P < .001). Those showing improvement with tadalafil had lower hs-CRP at baseline (median 1.5 mg/L [interquartile range 0.9-2.3] vs 2.0 mg/L [interquartile range 1.1-3.1; P = .034]) and had proportionately greater reduction in its level. However, on multivariate analysis, only shorter duration of ED (P = .008), non-vasculogenic origin (P = .025), and higher IIEF-6 score at baseline (P = .013) were independent predictors of response to treatment. CLINICAL IMPLICATIONS: Serum hs-CRP is elevated in patients who are less likely to respond to vasodilator therapy but does not have an independent predictive value for this purpose. STRENGTHS & LIMITATIONS: This is the largest study to evaluate the relationship among the mechanism of ED, serum hs-CRP level, and therapeutic response of ED to tadalafil. All patients underwent a penile Doppler study to characterize the type of ED. The limitations were nonrandomized nature of the study and nearly 22% dropout rate. CONCLUSION: Serum hs-CRP level is higher in vasculogenic ED compared with non-vasculogenic ED, and is associated with poorer response to tadalafil therapy. However, this association is not independent of underlying risk factors and mechanism of ED. Jamaluddin, Bansal M, Srivastava GK, et al. Role of Serum High-Sensitivity C-Reactive Protein as a Predictor of Therapeutic Response to Tadalafil in Patients With Erectile Dysfunction: A Prospective Observational Study. J Sex Med 2019;16:1912-1921.
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Proteína C-Reativa/análise , Disfunção Erétil/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Tadalafila/uso terapêutico , Vasodilatadores/uso terapêutico , Adulto , Carbolinas/uso terapêutico , Relação Dose-Resposta a Droga , Disfunção Erétil/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Estudos Prospectivos , Resultado do TratamentoRESUMO
The burden of atherosclerotic cardiovascular (CV) disease is alarmingly high and increasing in our country. Dyslipidemia is one of the major modifiable risk factors, and INTERHEART study showed that dyslipidemia had the highest population attributable risk for myocardial infarction. In the management of dyslipidemia, low-density lipoprotein cholesterol (LDL-C) is the primary therapeutic target. In addition to therapeutic lifestyle changes, statins and ezetimibe effectively lower LDL-C and consequently improve CV outcomes. However, there are situations where these drugs fall short of achieving the target or they may not be well tolerated.
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Inibidores Enzimáticos/uso terapêutico , Inibidores de PCSK9 , Anticolesterolemiantes , LDL-Colesterol , Índia , Pró-Proteína Convertase 9/metabolismoRESUMO
BACKGROUND: HIV-1 Env gp160 is cleaved to form gp120 and gp41 and the functional HIV-1 Env is a trimer of non-covalently associated heterodimeric subunits, gp120 and gp41. The cleaved, native, trimeric form of Envs expose only broadly neutralizing antibody (bNAb) epitopes while occluding epitopes targeted by non-neutralizing antibodies (non-NAbs). We and others have previously observed that efficient cleavage of Envs into their constituent subunits co-relates with specific binding to bNAbs and poor binding to non-neutralizing antibodies (non-NAbs). Such Envs have been identified from clades A, B and C which make up a majority of globally circulating HIV-1 strains. Frequently, the C-terminal tail (CT) of Envs is deleted to enhance expression and stabilize soluble Env-based vaccine immunogens. Deletion of CT of efficiently cleaved Indian clade C Env 4-2.J41 results in recognition by both NAbs and non-NAbs. It is to be noted that uncleaved Envs bind to both NAbs and non-NAbs. So we investigated whether altered antigenicity upon CT deletion of efficiently cleaved Envs is due to inefficient cleavage or conformational change as the mechanism by which the CT regulates the ectodomain (ET) integrity is not well understood. RESULTS: We studied the effect of CT deletion in four membrane bound efficiently cleaved Envs, A5 (clade A), 4-2.J41 (clade C), JRFL and JRCSF (clade B). Deletion of CT of the Envs, JRCSF and 4-2.J41, but not JRFL and A5 alter their ET antigenicity/conformation without affecting the cleavage efficiency. We carried out a series of deletion mutation in order to determine the region of the CT required for restoring native-like antigenicity/conformation of the ET of 4-2.J41 and JRCSF. Extending the CT up to aa753 in 4-2.J41 and aa759 in JRCSF, which includes a conserved hydrophilic domain (CHD), restores native-like conformation of these Envs on the plasma membrane. However, CT-deletion in 4-2.J41 and JRCSF at the pseudovirus level has either no or only modest effect on neutralization potency. CONCLUSION: Here, we report that the CHD in the CT of Env plays an important role in regulating the ET integrity of a subset of efficiently cleaved, functional Envs on the cell surface.
Assuntos
Membrana Celular/metabolismo , HIV-1/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Anticorpos Neutralizantes/imunologia , Epitopos/química , Epitopos/imunologia , Células HEK293 , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/química , HIV-1/genética , Humanos , Ligação Proteica/imunologia , Conformação Proteica , Domínios Proteicos , Deleção de Sequência , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismoRESUMO
Human immunodeficiency virus 1 (HIV-1) diversity is a significant challenge in developing a vaccine against the virus. B/C recombinants have been found in India and other places but are the predominant clade prevalent in China. HIV-1 envelopes (Envs) are the target of broadly neutralizing antibodies (bNAbs) which develop spontaneously in some HIV-1 infected patients. It has been previously reported with efficiently cleaved clade A, B and C Envs that preferential binding of Envs to bNAbs as opposed to non-NAbs, a desirable property for immunogens, is correlated with efficient cleavage of the Env precursor polypeptide into constituent subunits. These Envs are suitable for designing immunogens as soluble proteins, virus-like particles or for delivery by viral vectors/plasmid DNA. However, a B/C recombinant Env with similar properties has not been reported. Here we show that the chimeric, recombinant B/C clade Env LT5.J4b12C is efficiently cleaved on the plasma membrane and selectively binds to bNAbs.
Assuntos
Membrana Celular/metabolismo , HIV-1/genética , Proteólise , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo , Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , HIV-1/isolamento & purificação , Humanos , Índia , Ligação Proteica , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologiaRESUMO
Echocardiography, given its safety, easy availability, and the ability to permit a comprehensive assessment of cardiac structure and function, is an indispensable tool in the evaluation and management of patients with heart failure (HF). From initial phenotyping and risk stratification to providing vital data for guiding therapeutic decision-making and monitoring, echocardiography plays a pivotal role in the care of HF patients. The recent advent of multiparametric approaches for myocardial deformation imaging has provided valuable insights in the pathogenesis of HF, elucidating distinct patterns of myocardial dysfunction and events that are associated with progression from subclinical stage to overt HF. At the same time, miniaturization of echocardiography has further expanded clinical application of echocardiography, with the use of pocket cardiac ultrasound as an adjunct to physical examination demonstrated to improve diagnostic accuracy and risk stratification. Furthermore, ongoing advances in the field of big data analytics promise to create an exciting opportunity to operationalize precision medicine as the new approach to healthcare delivery that aims to individualize patient care by integrating data extracted from clinical, laboratory, echocardiographic, and genetic assessments. The present review summarizes the recent advances in the field of echocardiography, with emphasis on their role in HF phenotyping, risk stratification, and optimizing clinical outcomes.