Ligand-Dependent Downregulation of Guanylyl Cyclase/Natriuretic Peptide Receptor-A: Role of miR-128 and miR-195.

Cardiac hormones act on the regulation of blood pressure (BP) and cardiovascular homeostasis. These hormones include atrial and brain natriuretic peptides (ANP, BNP) and activate natriuretic peptide receptor-A (NPRA), which enhance natriuresis, diuresis, and vasorelaxation. In this study, we established the ANP-dependent homologous downregulation of NPRA using human embryonic kidney-293 (HEK-293) cells expressing recombinant receptor and MA-10 cells harboring native endogenous NPRA. The prolonged pretreatment of cells with ANP caused a time- and dose-dependent decrease in 125I-ANP binding, Guanylyl cyclase (GC) activity of receptor, and intracellular accumulation of cGMP leading to downregulation of NPRA. Treatment with ANP (100 nM) for 12 h led to an 80% decrease in 125I-ANP binding to its receptor, and BNP decreased it by 62%. Neither 100 nM c-ANF (truncated ANF) nor C-type natriuretic peptide (CNP) had any effect. ANP (100 nM) treatment also decreased GC activity by 68% and intracellular accumulation cGMP levels by 45%, while the NPRA antagonist A71915 (1 µM) almost completely blocked ANP-dependent downregulation of NPRA. Treatment with the protein kinase G (PKG) stimulator 8-(4-chlorophenylthio)-cGMP (CPT-cGMP) (1 µM) caused a significant increase in 125I-ANP binding, whereas the PKG inhibitor KT 5823 (1 µM) potentiated the effect of ANP on the downregulation of NPRA. The transfection of miR-128 significantly reduced NPRA protein levels by threefold compared to control cells. These results suggest that ligand-dependent mechanisms play important roles in the downregulation of NPRA in target cells.

Genetic Disruption of Guanylyl Cyclase/Natriuretic Peptide Receptor-A Triggers Differential Cardiac Fibrosis and Disorders in Male and Female Mutant Mice: Role of TGF-ß1/SMAD Signaling Pathway.

The global targeted disruption of the natriuretic peptide receptor-A (NPRA) gene (Npr1) in mice provokes hypertension and cardiovascular dysfunction. The objective of this study was to determine the mechanisms regulating the development of cardiac fibrosis and dysfunction in Npr1 mutant mice. Npr1 knockout (Npr1-/-, 0-copy), heterozygous (Npr1+/-, 1-copy), and wild-type (Npr1+/+, 2-copy) mice were treated with the transforming growth factor (TGF)-ß1 receptor (TGF-ß1R) antagonist GW788388 (2 µg/g body weight/day; ip) for 28 days. Hearts were isolated and used for real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemical analyses. The Npr1-/- (0-copy) mice showed a 6-fold induction of cardiac fibrosis and dysfunction with markedly induced expressions of collagen-1α (3.8-fold), monocyte chemoattractant protein (3.7-fold), connective tissue growth factor (CTGF, 5.3-fold), α-smooth muscle actin (α-SMA, 6.1-fold), TGF-ßRI (4.3-fold), TGF-ßRII (4.7-fold), and phosphorylated small mothers against decapentaplegic (pSMAD) proteins, including pSMAD-2 (3.2-fold) and pSMAD-3 (3.7-fold), compared with wild-type mice. The expressions of phosphorylated extracellular-regulated kinase ERK1/2 (pERK1/2), matrix metalloproteinases-2, -9, (MMP-2, -9), and proliferating cell nuclear antigen (PCNA) were also significantly upregulated in Npr1 0-copy mice. The treatment of mutant mice with GW788388 significantly blocked the expression of fibrotic markers, SMAD proteins, MMPs, and PCNA compared with the vehicle-treated control mice. The treatment with GW788388 significantly prevented cardiac dysfunctions in a sex-dependent manner in Npr1 0-copy and 1-copy mutant mice. The results suggest that the development of cardiac fibrosis and dysfunction in mutant mice is predominantly regulated through the TGF-ß1-mediated SMAD-dependent pathway.

Outcomes following balloon mitral valvuloplasty in pregnant females with mitral stenosis and significant sub valve disease with severe decompensated heart failure.

BACKGROUND: Mitral stenosis may present with decompensated heart failure during pregnancy. Many patients do have advanced sub valve disease and present late with decompensated state. The outcomes of balloon mitral valvuloplasty (BMV) in such advanced sub valve disease with severe heart failure in pregnancy has not been specifically studied till now. METHODS: A descriptive study looking at the immediate and long-term outcomes of pregnant patients with MS who presented with severe heart failure and sub valve disease who had undergone BMV. RESULTS: Ninety-six patients were studied. The mean gestational age was 23.4 ± 10.9 weeks .Mean SpO2 was 89% at admission,17% were in cardiogenic shock and 33.33 were on mechanical ventilation. The mean Wilkin's score was 9.71 ± 2.1 and sub valve score was 3.3 ± 0.12. BMV was successful in 77 (80.2%) patients and failed in 19. In 5.2% cases, acute severe MR occurred. There were 11 maternal deaths (six in failed and five in success group). A successful obstetric outcome was seen in 71 patients in success (92%) and 11/19 (57%) in failed (P < 0.001). The obstetric outcomes were better in success versus failure group. Anova post hoc analysis showed sustained gradient reductions at 1 and 5 year follow-up (P = 0.03) in success group. CONCLUSIONS: BMV offers substantial improvement in clinical outcomes among pregnant patients with MS and heart failure even with severe sub valve disease. The morality rate among failed was high at 31%. The obstetric outcomes were poor after a failed BMV. Outcomes following balloon mitral valvuloplasty in pregnant females with mitral stenosis and significant sub valve disease with severe decompensated heart failure.

Parasystole in a mahaim accessory pathway.

Automaticity has been described in Mahaim pathways, both spontaneously and during radiofrequency ablation. We describe an unusual case of automatic rhythm from a Mahaim pathway presenting as parasystole. The parasystolic beats were also found to initiate tachycardia, resulting in initial presentation with incessant tachycardia and tachycardia induced cardiomyopathy.

Sequential Anterograde and Retrograde Conduction Block during Radiofrequency Ablation of an Accessory Pathway.

We present an interesting image showing sequential loss of anterograde, and subsequently, retrograde conduction during radiofrequency ablation of an accessory pathway. We discuss the possible mechanisms and prior literature concerning this interesting finding.

Seckel syndrome with severe sinus bradycardia.

Seckel syndrome is an uncommon form of microcephalic dwarfism. The authors report a young boy with Seckel syndrome who presented with severe sinus bradycardia with symptoms of syncope and presyncope. Implantation of a permanent pacemaker was necessary in view of the severe symptoms. Although uncommon, cardiac abnormalities have been rarely reported in Seckel syndrome. This is the one of the few reports of rhythm abnormalities in this condition.

Hereditary Hemorrhagic Telangiectasia with Unusual Associations.

We describe a report of an elderly lady who was hospitalized with progressive worsening of breathlessness and fatigue of one month's duration. Clinical evaluation of the patient revealed hereditary hemorrhagic telangiectasia, interstitial lung disease, pulmonary hypertension without left heart failure, and bilateral gluteal calcinosis cutis. Initially, CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome was considered in view of the telangiectasia and calcinosis cutis, but a strong autosomal inheritance pattern and endoscopies (nasal and upper gastrointestinal) favored a diagnosis of hereditary hemorrhagic telangiectasia with rare associations.

Balloon valvuloplasty in rheumatic aortic valve stenosis: immediate and long-term results.

To study the immediate and long-term results of balloon aortic valvuloplasty (BAV) in a large cohort of patients with rheumatic valvular aortic stenosis. Single tertiary care center retrospective data analysis of immediate and long-term outcomes in patients following BAV from 2000 to 2008. Ninety-two patients with rheumatic aortic stenosis (AS) were studied who underwent BAV. Mean age of patients was 21.7 years (95 % CI 14.3-28.9) with mean follow-up period of 5.7 years (±SD 1.3). Intervention resulted in successful BAV (more than 50 % reduction in baseline gradient) in 79 (85.9 %) subjects (Group A) and partially successful BPV (<50 % reduction in baseline gradient) in 8 (8.7 %) subjects (Group B). BAV failed in 5 (5.4 %) subjects (Group C). Concomitant balloon mitral valvuloplasty was done in 23/92 cases. Mean left ventricular systolic pressure decreased from 165.6 (95 % CI 142.7-196.3) to 110.9 mmHg (95 % CI 92.1-129.6), (P < 0.001) and mean aortic valve (AV) gradient from 50.7 (95 % CI 35.12-66.22) to 27.2 mmHg (95 % CI 25.83-31.23), (P < 0.001). The mean change in ejection fraction and mean AV gradient were significantly different between success (Groups A and B) and failure groups (P < 0.001). Different grades of aortic regurgitation were noted in 32 (34.78 %) patients post BAV (severe regurgitation in 2.18 %). Anova post hoc analysis showed sustained gradient reductions at 1- and 5-year follow-up (P > 0.05). The need for surgery was much lower in Group A (2.5 %) compared to Group B (50 %) and C (100 %). BAV is an effective treatment strategy in dominant AS in multi valvular rheumatic disease situations. Combined aortic and mitral valvuloplasty was performed in one-fourth of study patients.

A life threatening rash, an unexpected cause.

We describe a 74-year-old man with purpura fulminans and altered sensorium following an acute febrile illness. Intensive sepsis management was to no avail, until institution of doxycycline therapy following confirmation of scrub typhus. Empirical doxycycline needs to be considered in endemic areas for patients presenting with purpura fulminans.

Atypical mycobacterial infection in hairy cell leukemia treated with cladribine.

We report a case of hairy cell leukemia who improved after cladribine but succumbed to disseminated atypical mycobacterial infection 2 months after completing cladribine.

Hairy cell leukemia masquerading as infective endocarditis.

Hairy cell leukemia is a chronic lymphoproliferative disorder affecting middle-aged adults, with the median age of 50-55 years. We report a case of hairy cell leukemia who presented with fever, splinter haemorrhages and moderate splenomegaly, simulating infective endocarditis. There was bicytopenia at presentation and hairy cells were seen in the peripheral blood.