The role of natriuretic peptides in heart failure

Heart failure is a clinical syndrome associated with progressive cardiac, vascular, and renal dysfunction. Regardless of the initial injury, investigations have demonstrated that neurohormones play an important role in the complex multiorgan and cellular adaptations. Natriuretic peptides play a key role in this process, antagonizing the actions of the renin-angiotensin-aldosterone system, thus promoting vasodilatation and natriuresis. Other important physiologic properties of the natriuretic peptides are prolusitropic, sympathoinhibitory, antiproliferative, anti-ischemic, anti-inflammatory, and antioxidative. Administering exogenous natriuretic peptide is a US Food and Drug Administration-approved therapy for patients with advanced decompensated congestive heart failure. Also, measuring natriuretic peptide levels has diagnostic and prognostic value. More studies are needed to define the full potential of this unique family of endogenous peptides.     

The aging heart, myocardial fibrosis, and its relationship to circulating C-type natriuretic Peptide

Myocardial aging is characterized by left ventricular (LV) fibrosis leading to diastolic and systolic dysfunction. Studies have established the potent antifibrotic and antiproliferative properties of C-type natriuretic peptide (CNP); however, the relationship between circulating CNP, LV fibrosis, and associated changes in LV function with natural aging are undefined. Accordingly, we characterized the relationship of plasma CNP with LV fibrosis and function in 2-, 11-, and 20-month-old male Fischer rats. Further in vitro, we established the antiproliferative actions of CNP and the participation of the clearance receptor using adult human cardiac fibroblasts. Here we establish for the first time that a progressive decline in circulating CNP characterizes natural aging and is strongly associated with a reciprocal increase in LV fibrosis that precedes impairment of diastolic and systolic function. Additionally, we demonstrate in cultured adult human cardiac fibroblasts that the direct antiproliferative actions of high-dose CNP may involve a non-cGMP pathway via the clearance receptor. Together, these studies provide new insights into myocardial aging and the relationship to the antifibrotic and antiproliferative peptide CNP.     

Successful cord blood transplantation in a girl with monosomy 7 myelodysplastic syndrome and reduced numbers of B cells

This report described unrelated umbilical cord blood transplantation for a 3-year-old girl with myelodysplastic syndrome and monosomy 7. The patient had a prolonged course characterized by recurrent infection and slowly progressive pancytopenia. She had reduced numbers of circulating B cells but no decline in immunoglobulin levels. Chemotherapy was not initially recommended because it was contraindicated due to intercurrent lower respiratory tract infection. After 10 months, the girl achieved hematologic remission after induction chemotherapy. The patient then underwent 2-loci HLA-mismatched unrelated donor cord blood transplantation. The time to neutrophil and platelet engraftment was 12 and 23 days post-transplantation, respectively. Acute graft-versus-host disease following transplantation was minimal. She was in continuing hematological remission with full donor chimerism 3 years after transplantation.     

Novel Natriuretic Peptides: New Compounds and New Approaches

The natriuretic peptides (NPs) are a group of structurally similar yet genetically distinct peptides that have diverse actions in cardiovascular, renal, and endocrine homeostasis. Since the discovery of atrial natriuretic peptide in 1981, the diagnostic, prognostic, and therapeutic significance of NPs have been studied extensively in relation to heart failure. Indeed, it now is understood that a hallmark of heart failure is the activation of the cardiac endocrine system, in particular the natriuretic peptide family including atrial natriuretic peptide and B-type natriuretic peptide. Currently, the only approved therapeutic application for NPs is the intravenous treatment of acute decompensated heart failure. However, in recent years there has been considerable research aimed at creating novel NPs and administering them via novel routes. This review focuses on the novel NPs that have been created and on novel approaches for their administration.     

Tracing the protectors path from the germ line to the genome

One of the basic principles that nature uses in evolution is to recycle successful concepts and create new functions by modifying existing units. This conservatism in evolution has resulted in an astonishingly high sequence identity of genes, even between evolutionarily distant species such as the nematode Caenorhabditis elegans and Homo sapiens. The recycling of successful concepts in conjunction with gene duplication events has also led to the existence of highly homologous proteins within the genome of many species. Often, these homologous proteins show similar, yet distinct functions that, in combination with their individual tissue distribution, define their specific physiological role. One prominent example is the p53 protein family, which consists of p53, p63, and p73. Recent advances in understanding the specific biological functions of these members have shed some light onto the evolution of this crucial protein family, from a germ line-specific quality-control factor to a somatic tumor suppressor. Furthermore, structures of the oligomerization domains of the mammalian paralogs, p53 and p73, and invertebrate orthologs, CEP-1 and DMP53, have delineated evolutionary changes and revealed that the oligomerization domain of p53 lacks additional stabilizing structural elements present in all other p53 family members. This suggests that p53 is the most recent evolutionary member of this protein family and predicts a mechanism for p53 activation.     

Prenatal exposure to diagnostic ultrasound impacts blood-brain barrier permeability in rats

The central nervous system vasculature consists of a tightly sealed endothelium that forms the blood-brain barrier (BBB); these blood vessels are impermeable to large-molecular-size agents. The aim of this study was to determine the influence of prenatal ultrasound exposure on blood-brain barrier (BBB) integrity as measured by the permeation of Evans blue (EB) through the BBB during the postnatal development of the rat. Diagnostic levels of ultrasound (2.89 MHz, mechanical index = 1.1, acoustic output power = 70.5 mW) for 1 h and 2 h per day, for 9 consecutive days were used on Sprague-Dawley rats. Offspring were assessed postnatally on days 10, 17, 24 and 38. Our analysis of over 139 animals reveals that, when exposed to diagnostic levels of ultrasound during embryonic development, a statistically significant amount of EB extravasation into the cerebrum and cerebellum could be detected on postnatal day 10 but not later. In addition, small changes in pup body weight, cerebrum weight and cerebellum weight were observed after relatively prolonged ultrasound exposure on all postnatal days. Taken together, these results emphasize the need for further investigation of the effects of ultrasound exposure during the potentially vulnerable period of intense BBB development in the human fetus.     

B-type natriuretic peptide: beyond a diagnostic

The concept of the heart as an endocrine organ has been attractive since the discovery of atrial natriuretic peptide. This review focuses on the second discovered natriuretic peptide from the heart - B-type natriuretic peptide (BNP), widely used as a tool in the diagnosis of heart failure (HF). Controversy remains regarding its use as a therapeutic agent in HF. This article places into perspective some of the debate and provides insights into the therapeutics of BNP and the importance of its second messenger 3'5' cyclic guanosine monophosphate, which also is the second messenger for nitric oxide and is modulated by renal phosphodiesterases.     

Sonographically guided antegrade common femoral artery access.

OBJECTIVE: To evaluate the feasibility of sonographically guided antegrade common femoral artery puncture and superficial femoral artery access. METHODS: Fifty antegrade common femoral artery punctures and superficial femoral artery access procedures were performed under sonographic guidance alone in 30 consecutive patients (24 male and 6 female; mean age, 55.1 +/- 25.7 years; range, 13-85 years). The indications were (1) insertion of a vascular sheath for balloon angioplasty in 42 attempts (24 patients with lower leg ischemia) and (2) insertion of an angiographic catheter for 1-shot intra-arterial chemoinfusion therapy in 8 attempts (6 patients with distal femoral osteosarcomas). RESULTS: Technical success was achieved in 28 of 30 patients or 48 (96%) of 50 procedures (95% confidence interval, 80.39-98.32). The average procedure time +/- SD (excluding the failures) was 3 +/- 1 minutes (range, 2-6 minutes). In the 2 failures (2 [4%] of 50) in which common femoral artery punctures were accomplished, further superficial femoral artery cannulations were completed under fluoroscopic road map angiographic guidance. A small groin hematoma was noted in 1 patient. No arteriovenous fistula or pseudoaneurysm was encountered. CONCLUSIONS: Sonographically guided antegrade common femoral artery puncture and selective cannulation of the superficial femoral artery are feasible and safe. They may be used as adjunctive modalities in difficult cases of common femoral artery access.     

Urgency to treat patients with chronic hepatitis C in Asia

Chronic hepatitis C (CHC) infection poses a global healthcare burden, being associated with serious complications if untreated. The prevalence of hepatitis C virus (HCV) infection is highest in areas of Central, South, and East Asia; over 50% of HCV patients worldwide live in the region, where HCV genotypes 1b, 2, 3, and 6 are the most prevalent. Treatment outcomes for chronic hepatitis C vary by ethnicity, and Asian patients achieve higher sustained virologic response rates following interferon (IFN)‐based therapy than non‐Asians. However, low efficacy, poor safety profile, and subcutaneous administration limit the use of IFN‐based therapies. Superior virologic outcomes have been observed with different classes of direct‐acting antivirals (DAAs) alone or in combination, and several all‐oral DAA regimens are available in Asia. These regimens have shown excellent efficacy and favorable tolerability in clinical trials, yet there is a need for further studies of DAAs in a real world context, particularly in Asia. Furthermore, IFN‐free treatment may not be accessible for many patients in the region, and IFN‐based regimens remain an option in some countries. There is a need to improve current clinical practices for HCV management in Asia, including effective screening, disease awareness, and prevention programs, and to further understand the cost‐effectiveness of IFN‐free regimens. The evolution of potent treatments makes HCV eradication a possibility that should be available to all patients. However, access to these therapies in Asian countries has been slow, primarily because of economic barriers that continue to present a hurdle to optimal treatment.     

How Does Aging Affect Presentation and Management of Biliary Stones?

Common bile duct (CBD) stones are common in elderly adults, but the effect of aging on the presentation of CBD stones remains to be evaluated. Recent studies have demonstrated that the clinical presentation of CBD stones may vary with age. Younger adults may present with classical biliary colic symptoms, whereas elderly adults may have no unapparent clinical features. Younger adults with CBD stones were significantly more likely to have abnormal liver function tests than those without. The sensitivity and accuracy of transabdominal ultrasound scans in screening for CBD stones increases with age. Antibiotic agents should be promptly administered to individuals with CBD stones complicated by cholangitis, but the effects of pharmacotherapy on renal function should be considered in elderly adults. Endoscopic retrograde cholangiopancreatography (ERCP) is considered to be first‐line treatment for CBD stones, and endoscopic biliary sphincterotomy (EST) or endoscopic papillary balloon dilation (EPBD) along with ERCP is an adequate biliary drainage method in individuals with CBD stones. EPBD has a lower bleeding risk but higher post‐ERCP risk of pancreatitis than EST. Longer‐duration (>1 minute) EPBD may be preferred over EST because it is associated with a comparable risk of pancreatitis but a lower rate of overall complications, although recurrent cholangitis or unfavorable outcomes will increase during CBD dilation or in the presence of residual CBD stones.