Angiotensin Receptor-Neprilysin Inhibitor Therapy and Cardiac Remodeling in Heart Failure: Consensus Statement from India

Adverse cardiac remodeling refers to progressive structural and functional modifications in the heart because of increased wall stress in the myocardium, loss of viable myocardium, and neurohormonal stimulation. The guideline-directed medical therapy for Heart failure (HF) includes Angiotensin receptor-neprilysin inhibitor (ARNI) (sacubitril/valsartan), ?-blockers, sodium-glucose co-transporter 2 (SGLT2) inhibitors, and mineralocorticoid receptor antagonists (MRA). ARNI is under-prescribed in India despite its attractive safety and efficacy profile. Therefore, the consensus discusses objectives and topics related to ARNI in the management of cardiac remodeling, and experts shared their views on the early timely intervention of effective dosage of ARNI to improve the diagnosis and enhance mortality and morbidity benefits in cardiac reverse remodeling (CRR).

The Power and Promise of Angiotensin Receptor Neprilysin Inhibitor (ARNI) in Heart Failure Management: National Consensus Statement

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.

Brain stem auditory evoked responses and visual evoked responses in children with tubercular meningitis.

Thirty two patients between 6 months and 14 years of age with tubercular meningitis were evaluated for brain stem auditory evoked response (BAER) and Visual evoked responses (VER), within 7 days of admission. Absolute latencies and interpeak latencies were compared with values obtained from normal children. BAER abnormality was found in 56.25% and VER in 28%children, respectively. BAER abnormality correlated with Glasgow Coma Scale at admission and discharge, stage of meningitis, raised intracranial pressure, seizure activity, and poor outcome. VER abnormality correlated with abnormal fundus findings only.

White spot syndrome virus isolates of tiger shrimp Penaeus monodon (Fabricious) in India are similar to exotic isolates as revealed by polymerase chain reaction and electron microscopy.

Microbiological analysis of samples collected from cases of white spot disease outbreaks in cultured shrimp in different farms located in three regions along East Coast of India viz. Chidambram (Tamil Nadu), Nellore (Andhra Pradesh) and Balasore (Orissa), revealed presence of Vibrio alginolyticus, Vibrio parahaemolyticus, and Aeromonas spp. but experimental infection trials in Penaeus monodon with these isolates did not induce any acute mortality or formation of white spots on carapace. Infection trials using filtered tissue extracts by oral and injection method induced mortality in healthy P. monodon with all samples and 100% mortality was noted by the end of 7 day post-inoculation. Histopathological analysis demonstrated degenerated cells characterized by hypertrophied nuclei in gills, hepatopancreas and lymphoid organ with presence of intranuclear basophilic or eosino-basophilic bodies in tubular cells and intercellular spaces. Analysis of samples using 3 different primer sets as used by other for detection of white spot syndrome virus (WSSV) generated 643, 1447 and 520bp amplified DNA products in all samples except in one instance. Variable size virions with mean size in the range of 110 x 320 +/- 20 nm were observed under electron microscope. It could be concluded that the viral isolates in India involved with white spot syndrome in cultured shrimp are similar to RV-PJ and SEMBV in Japan, WSBV in Taiwan and WSSV in Malaysia, Indonesia, Thailand, China and Japan.

Lupus vulgaris on keloid.

A 28-year-old man presented with multicentric lupus vulgaris on keloids over chest, axilla, neck and back for last 6 months. He had pulmonary tuberculosis. All the laboratory investigations were in favour of clinical diagnosis. The patient responded to antituberculosis therapy.

A comparative study on the effect of felodipine and propranolol on serum lipid profile of rabbits.

Effect of felodipine on serum lipids of rabbits was studied and was compared with that of propranolol. Lipid parameters were estimated at basal (0 wk), end of 4th and 16th week of diet/drug administration by using standard kits for analysis. There was a significant increase in mean serum cholesterol, TG, VLDLc, LDLC and decrease in HDLc, (P<0.05) in the group of rabbits receiving Atherogenic diet (AD)/Propranolol. This effect was maximally observed in rabbits receiving both AD and propranolol. This change was satisfactorily prevented when felodipine was administered from very beginning (P<0.001). In addition, there was a significant increase in HDLc (28.89%) of rabbits receiving felodipine from beginning. Thus both AD and propranolol have dyslipidemic effect and early administration of felodipine favorably changes all lipid parameters.

Restriction fragment analysis of fowlpox virus using Bgl I, Bam HI, Hha I and Sma I restriction endonucleases.

Fowlpox virus vaccine strain and two field isolates collected from out breaks of disease were purified from cell culture using sucrose gradient ultracentrifugation. The viral DNAs were digested with Bgl I, Bam HI, Hha I and Sma I restriction endonucleases and the fragment pattern was analysed on 0.7% agarose gel. Bgl I digestion produced 54 fragments of size ranging from 31.50 to 0.60 kb, having similar electrophoretic mobilities in both the vaccine strain and two field isolates. Only 9 well resolved and one unresolved or partially digested fragment were obtained after Bam HI digestion. A total number of 29 and 41 fragments were obtained with Hha I and Sma I respectively. Almost similar restriction fragment pattern was observed in vaccine strain and the field isolates. The total genomic size was calculated to be between 265.00 and 302.91 kb. The three viruses were found to be genetically similar.

Fowlpox virus structural protein immunogens and characterization of single band polypeptide.

A fowlpox virus isolate obtained from an outbreak of disease in a vaccinated poultry flock was propagated in chicken embryo fibroblast cell culture. Analysis of purified virus polypeptide on 7.5-15% gradient polyacrylamide gel revealed 45 structural polypeptides after Coomassie blue staining. The mol.wt. of polypeptides ranged between 225.53 and 10.50 kDa with total mol.wt. of 2650 kDa. Variable numbers of immunogenic virion polypeptides were detected in immunoblot with fowlpox virus infected chicken sera collected at different time intervals. A total of 29 polypeptides reacted with sera collected at 1st week post-infection and the number gradually declined to 27, 26, 20, 17 and 15 when reacted with 2nd, 3rd, 4th, 5th and 6th week post-infection sera, respectively. Reaction with fowlpox virus hyperimmune sera revealed 35 immunogenic polypeptides. A number of major and minor immunogens were detected. Antisera against seven major single band polypeptides including one double band polypeptide showed very low reactivity both in ELISA and serum neutralization test. Involvement of multigenic components in virus neutralization is indicated.

Comparative immunological and genomic characterization of fowlpox virus isolates.

Chickens infected with fowlpox virus (FPV) IVRI vaccine strain and two field isolates collected from clinical cases of disease (Bareilly isolate and Panchmahal isolate) produced humoral antibody response after 2nd week post-infection, with a noticeable variation in degree of immune response. Serum antibody titre peaked at 4th week post-infection with a titre of 25,600, 25,600 and 51,200 being detected in ELISA and neutralization index of 2.75, 2.43 and 3.12 in serum neutralization test (SNT) with IVRI vaccine strain, Panchmahal isolate and Bareilly isolate, respectively. Cellular immune response was detected as early as 1st week post-infection by leukocyte migration inhibition test (LMIT). Per cent migration inhibition too peaked at 4th week with a value of 40.30 +/- 3.45, 36.93 +/- 4.11 and 45.45 +/- 3.66 being detected with the three viruses respectively. The Hind III and Hae III restriction fragment profile of viral DNA showed almost similar pattern both in vaccine strain and two field isolates. Hind III digestion produced 47 well resolved fragments of sizes between 24.30 and 1.20 kb and the total genomic size was estimated to be between 305.81 and 306.06 kb. Hae III digestion revealed 34 well resolved fragments of sizes between 27.55 and 1.32 kb. The three viruses could not be differentiated on the basis of their genomic restriction pattern. However immunogenic and antigenic differences were noticed by ELISA and SNT tests.

Structural proteins of fowlpox virus vaccine strain and field isolates.

Structural polypeptides of IVRI vaccine strain and two field isoaltes of Fowlpox virus (Bareilly isolate and Panchmahal isolate) were analysed on SDS-PAGE and by immunoblotting technique. In 5%-20% gradient acrylamide gel 31, 29 and 31 polypeptide bands and in 7.5%-15% gradient gel 45, 37 and 39 polypeptide bands were detected after Coomassie blue staining respectively for Bareilly isolate, Panchmahal isolate and IVRI vaccine strain. The molecular weight (MW) of the polypeptides ranged from 226.10 to 10.30 kDa with total MW of 2650.12, 2259.50, and 2378.68 kDa respectively for the three viruses. The immunoblot revealed 35, 29 and 30 immunogenic polypeptides indicating most virion polypeptides to be immunogenic in nature. Although most polypeptides had similar electrophoretic pattern both in SDS-PAGE and immunoblotting, still the three viruses could be differentiated. The viruses were found to be antigenically different with Panchmahal isolate lacking the polypeptides 81.15, 76.33, 39.30, 37.50 and 29.35 kDa and the vaccine strain lacking 76.33, 37.50 and 29.35 kDa polypeptides as were present in Bareilly isolate.

Modification of vascular response to synthetic oxytocin by oestrogen in rabbit.

Intravenously administered oxytocin caused a dose-related fall in blood pressure of the rabbit. When oxytocin was administered in oestrogen-primed animals, the depressor response was converted to a pressor one "Oxytocin reversal". The "oxytocin reversal." was abolished after treatment with dihydroergotamine, hexamethonium or adrenalectomy. The "oxytocin reversal" did not appear in reserpinized animals.