Natriuretic Peptide System Research Articles

Endothelium-Derived C-Type Natriuretic Peptide Contributes to Blood Pressure Regulation by Maintaining Endothelial Integrity.

We previously reported the secretion of C-type natriuretic peptide (CNP) from vascular endothelial cells and proposed the existence of a vascular natriuretic peptide system composed of endothelial CNP and smooth muscle guanylyl cyclase-B (GC-B), the CNP receptor, and involved in the regulation of vascular tone, remodeling, and regeneration. In this study, we assessed the functional significance of this system in the regulation of blood pressure in vivo using vascular endothelial cell-specific CNP knockout and vascular smooth muscle cell-specific GC-B knockout mice. These mice showed neither the skeletal abnormality nor the early mortality observed in systemic CNP or GC-B knockout mice. Endothelial cell-specific CNP knockout mice exhibited significantly increased blood pressures and an enhanced acute hypertensive response to nitric oxide synthetase inhibition. Acetylcholine-induced, endothelium-dependent vasorelaxation was impaired in rings of mesenteric artery isolated from endothelial cell-specific CNP knockout mice. In addition, endothelin-1 gene expression was enhanced in pulmonary vascular endothelial cells from endothelial cell-specific CNP knockout mice, which also showed significantly higher plasma endothelin-1 concentrations and a greater reduction in blood pressure in response to an endothelin receptor antagonist than their control littermates. By contrast, vascular smooth muscle cell-specific GC-B knockout mice exhibited blood pressures similar to control mice, and acetylcholine-induced vasorelaxation was preserved in their isolated mesenteric arteries. Nonetheless, CNP-induced acute vasorelaxation was nearly completely abolished in mesenteric arteries from vascular smooth muscle cell-specific GC-B knockout mice. These results demonstrate that endothelium-derived CNP contributes to the chronic regulation of vascular tone and systemic blood pressure by maintaining endothelial function independently of vascular smooth muscle GC-B.

The evolution of natriuretic peptide augmentation in management of heart failure and the role of sacubitril/valsartan.

Heart failure (HF) is one of the leading causes of morbidity, mortality, and health care expenditures in the US and worldwide. For three decades, the pillars of treatment of HF with reduced ejection fraction (HFrEF) were medications that targeted the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS). Prior attempts to augment the natriuretic peptide system (NPS) for the management of HF failed either due to lack of significant clinical benefit or due to the unacceptable side effect profile. This review article will discuss the NPS, the failure of early drugs which targeted the NPS as therapies for HF, and the sequence of events which led to the development of sacubitril plus valsartan (Entresto; LCZ696; Novartis). LCZ696 has been shown to be superior to the standard of care available for treatment of HFrEF in several substantial hard endpoints including heart failure hospitalizations, cardiovascular mortality, and all-cause mortality.

The effects of exercise training and caloric restriction on the cardiac oxytocin natriuretic peptide system in the diabetic mouse.

BackgroundRegular exercise training (ET) and caloric restriction (CR) are the frontline strategies in the treatment of type 2 diabetes mellitus with the aim at reducing cardiometabolic risk. ET and CR improve body weight and glycemic control, and experimental studies indicate that these paradigms afford cardioprotection. In this study, the effects of combined ET and CR on the cardioprotective oxytocin (OT)–natriuretic peptide (NP) system were determined in the db/db mouse, a model of type 2 diabetes associated with insulin resistance, hyperglycemia, and obesity.MethodsFive-week-old male db/db mice were assigned to the following groups: sedentary, ET, and ET + CR. Nonobese heterozygote littermates served as controls. ET was performed on a treadmill at moderate intensity, and CR was induced by reducing food intake by 30% of that consumed by sedentary db/db mice for a period of 8 weeks.ResultsAfter 8 weeks, only ET + CR, but not ET, slightly improved body weight compared to sedentary db/db mice. Regardless of the treatment, db/db mice remained hyperglycemic. Hearts from db/db mice demonstrated reduced expression of genes linked to the cardiac OT–NP system. In fact, compared to control mice, mRNA expression of GATA binding protein 4 (GATA4), OT receptor, OT, brain NP, NP receptor type C, and endothelial nitric oxide synthase (eNOS) was decreased in hearts from sedentary db/db mice. Both ET alone and ET + CR increased the mRNA expression of GATA4 compared to sedentary db/db mice. Only ET combined with CR produced increased eNOS mRNA and protein expression.ConclusionOur data indicate that enhancement of eNOS by combined ET and CR may improve coronary endothelial vasodilator dysfunction in type 2 diabetes but did not prevent the downregulation of cardiac expression in the OT–NP system, possibly resulting from the sustained hyperglycemia and obesity in diabetic mice.

Natriuretic Peptides and Analytical Barriers.

The natriuretic peptide system is an endocrine, autocrine and paracrine system that plays an important role in the maintenance of cardiovascular homeostasis. Biomarkers based on these peptides are important diagnostic and prognostic tools for myocardial function. Although natriuretic peptides were discovered more than 2 decades ago, their intricate and complex biology is associated with important questions not yet elucidated. The diversity of circulating forms of natriuretic peptides, the distinct expression of these forms in particular patients, and the heterogeneity of heart failure forms, along with specific assay-related and preanalytic issues, cause assays to be poorly harmonized. This review presents the relevant issues related to the biology of natriuretic peptides and differences between assays with immediate implications for clinical practice.

Sex Differences of the Natriuretic Peptide Polymorphism Associated With Angiographic Coronary Atherosclerosis.

BackgroundPolymorphisms within natriuretic peptide (NP) genes have been associated with clinical outcomes for cardiovascular disease (CVD), but no previous study has compared the effect of these polymorphisms between men and women. This study aimed to investigate the association between single nucleotide polymorphisms (SNPs) in key genes of the NP system and coronary angiographic outcomes, with the focus on the sexual dimorphism in the effects of these SNPs.MethodsPatients undergoing clinically indicated coronary angiography (n = 513, 328 men and 185 women) were consented and genotyped for NPPA rs5065, NPPB rs198389 and NPR2 rs10758325. Patients were stratified into having normal coronaries, non-obstructive coronary artery disease (CAD) or obstructive CAD, based on the highest stenosis in any epicardial artery. Average luminal narrowing across all four arteries was derived to represent the overall atherosclerotic burden.ResultsThe frequency of NPPB rs198389 AA genotype was significantly higher in women with obstructive CAD (P = 0.014). The same association was not observed in males. With respect to atherosclerotic burden, an association was found between the AA genotype and average luminal narrowing in women (P = 0.005), but not in men.ConclusionsThe current study identified an association between an SNP of the NPPB gene and coronary atherosclerotic burden through angiographic evidence in women but not in men. These results suggest that B-type natriuretic peptide (BNP) may have more important involvement in the development of CAD in women compared to men, and as such, genotyping of the NPPB gene may serve as a potential biomarker to identify women with high risk for CAD.

Angiotensin Receptor-Neprilysin Inhibition.

The novel combination sacubitril/valsartan represents a new therapeutic approach in the management of heart failure. With the simultaneous blockage of the enzyme neprilysin (by sacubitril) and angiotensin II receptors (by valsartan), this combination reduces the degradation of natriuretic peptides and other counterregulatory peptide systems while avoiding the deleterious effect of angiotensin II receptors activation and thereby encompasses a beneficial impact of 2 important neurohormonal pathways activated in heart failure. As opposed to previously tested neprilysin inhibitors, sacubitril/valsartan represents a more effective method in reducing morbidity and mortality in heart failure, while preserving a safety profile comparable to well-established, standard, angiotensin-converting enzyme inhibitor's therapy.

Beneficial Effects of Combined AT1 Receptor/Neprilysin Inhibition (ARNI) Versus AT1 Receptor Blockade Alone in the Diabetic Eye.

PurposeDysfunction of the renin-angiotensin system (RAS) contributes to pathogenesis of diabetic retinopathy (DR). Yet RAS blockers have only limited beneficial effects on progression of DR in clinical trials. The natriuretic peptide system offsets RAS, so that enhancing the activity of this system on top of RAS blockade might be beneficial. Neprilysin has an important role in the degradation of natriuretic peptides. Therefore, we hypothesize that dual angiotensin receptor-neprilysin inhibition (ARNI) may outperform angiotensin receptor blocker (ARB) in protection against DR. We tested this hypothesis in streptozotocin-induced diabetic transgenic (mRen2)27 rats.MethodsAdult male diabetic (mRen2)27 rats were followed for 5 or 12 weeks. Treatment with vehicle, irbesartan (ARB), or ARB combined with the neprilysin inhibitor thiorphan (irbesartan+thiorphan [ARNI]) occurred during the final 3 weeks. Retinal cell death, gliosis, and capillary loss were evaluated. Real-time polymerase chain reaction (RT-PCR) analyses were performed to quantify the retinal level of inflammatory cell markers.ResultsBoth ARB- and ARNI-treated groups showed similarly reduced retinal apoptotic cell death, gliosis, and capillary loss compared to the vehicle-treated group in the 5-week study. Treatment with ARNI reduced the expression of inflammatory markers more than ARB treatment in the 5-week study. In the 12-week study, ARNI treatment showed significantly more reduction in apoptotic cell death (51% vs. 25% reduction), and capillary loss (68% vs. 43% reduction) than ARB treatment.ConclusionsTreatment with ARNI provides better protection against DR in diabetic (mRen2)27 transgenic rats, compared to ARB alone. This approach may be a promising treatment option for patients with DR.

Angiotensin receptor neprilysin inhibitor LCZ696: pharmacology, pharmacokinetics and clinical development.

Heart failure still has a significant disease burden with poor outcomes worldwide despite advances in therapy. The standard therapies have been focused on blockade of renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and mineralocorticoid antagonists and the sympathetic nervous system with β-blockers. The natriuretic peptide system is a potential counter-regulatory system that promotes vasodilatation and natriuresis. Angiotensin receptor neprilysin inhibitors are a new class drug capable of blocking the renin-angiotensin-aldosterone system and enhancing the natriuretic peptide system to improve neurohormonal balance. The success of the PARADIGM-HF trial with LCZ696 and its approval for heart failure treatment is likely to generate a paradigm shift. This review summarises the current knowledge of LCZ696 with a focus on pharmacology, pharmacokinetics and pharmacodynamics, mechanisms of action, clinical efficacy and safety.

Focus on the Novel Cardiovascular Drug LZC696: from Evidence to Clinical Consideration.

LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is comprised of the angiotensin receptor blocker valsartan and the neprilysin inhibitor pro-drug sacubitril (AHU377). After oral administration, AHU377 is rapidly metabolized to the active neprilysin inhibitor LBQ657. LCZ696 exerts its effects of diuresis, natriuresis, vasodilation and aldosterone secretion inhibition through simultaneous renin-angiotensin-aldosterone system (RAAS) blockade and natriuretic peptides system (NPS) enhancement. Powerful evidence including PARAMETER and PRARDIGM-HF trials have shown that LCZ696 outperforms RAAS inhibition in treating patients with hypertension and heart failure with reduced ejection fraction (HFrEF), and is well tolerated. In addition, accumulating evidence also suggests its potential use in heart failure with preserved ejection fraction (HFpEF), chronic kidney disease (CKD), post-myocardium infarction (post-MI) and stroke. Both the FDA and CHMP have approved LCZ696 for treatment of HFrEF. Despite all this, some special issues (e.g. use in specific subgroups, adverse events, contraindications and cost-effectiveness analysis) should be considered before its implementation in clinical practice.

From ARB to ARNI in Cardiovascular Control.

Coexistence of hypertension, diabetes mellitus and chronic kidney disease synergistically aggravates the risk of cardiovascular and renal morbidity and mortality. These high-risk, multi-morbid patient populations benefit less from currently available anti-hypertensive treatment. Simultaneous angiotensin II type 1 receptor blockade and neprilysin inhibition (‘ARNI’) with valsartan/sacubitril (LCZ696) might potentiate the beneficial effects of renin-angiotensin-aldosterone inhibition by reinforcing its endogenous counterbalance, the natriuretic peptide system. This review discusses effects obtained with this approach in animals and humans. In animal models of hypertension, either alone or in combination with myocardial infarction or diabetes, ARNI consistently reduced heart weight and cardiac fibrosis in a blood pressure-independent manner. Additionally, LCZ696 treatment reduced proteinuria, focal segmental glomerulosclerosis and retinopathy, thus simultaneously demonstrating favourable effects on microvascular complications. These results were confirmed in patient populations. Besides blood pressure reductions in hypertensive patients and greatly improved (cardiovascular) mortality in heart failure patients, ventricular wall stress and albuminuria were reduced particularly in diabetic patients. The exact underlying mechanism remains unknown, but may involve improved renal haemodynamics and reduced glomerulosclerosis, e.g. related to a rise in natriuretic peptide levels. However, the assays of these peptides are hampered by methodological artefacts. Moreover, since sacubitrilat is largely renally cleared, drug accumulation may occur in patients with impaired renal function and thus hypotension is a potential side effect in patients with chronic kidney disease. Further caution is warranted since neprilysin also degrades endothelin-1 and amyloid beta in animal models. Accumulation of the latter may increase the risk of Alzheimer’s disease.

The role of natriuretic peptides in diabetes and its complications.

This review aimed to summarize recent findings on the role of natriuretic peptides (NPs) in diabetes and its important complications. Although the treatment of diabetes mellitus has benefited from recent advances, aggressive glycemic control can increase the risk of hypoglycemia and weight gain. Therefore, innovative therapies are required to address this issue. Natriuretic peptides (NPs) may have such novel therapeutic potential. NPs comprise a family of structurally related peptides, including atrial, brain, C-type, and dendroaspis. Each of these NPs has a wide range of specific functions to regulate and maintain cardiovascular, renal, and endocrine homeostasis. NPs exert their effects by interacting with three receptor subtypes including NPR-A, NPR-B, and NPR-C. The coronary NP system has been suggested to be involved in regulating water and salt balance, as well as vascular remodeling. In this review, we provide evidence that NPs play an important role in diabetes mellitus and its related complications including macrovascular and microvascular disorders. NPs hold promise as markers for early diagnosis, risk assessment, and intervention guidance in diabetes and its complications and may thus improve diabetes care.

Role of corin in the regulation of blood pressure.

Corin is a transmembrane protease that activates atrial natriuretic peptide (ANP), an important hormone in regulating salt-water balance and blood pressure. This review focuses on the regulation of corin function and potential roles of corin defects in hypertensive, heart, and renal diseases. Proprotein convertase subtilisin/kexin-6 has been identified as a primary enzyme that converts zymogen corin to an active protease. Genetic variants that impair corin intracellular trafficking, cell surface expression, and zymogen activation have been found in patients with hypertension, cardiac hypertrophy, and pre-eclampsia. Reduced corin expression has been detected in animal models of cardiomyopathies and in human failing hearts. Low levels of circulating soluble corin have been reported in patients with heart disease and stroke. Corin, ANP and natriuretic peptide receptor-A mRNAs, and proteins have been colocalized in human renal segments, suggesting a corin-ANP autocrine function in the kidney. Corin is a key enzyme in the natriuretic peptide system. The latest findings indicate that corin-mediated ANP production may act in a tissue-specific manner to regulate cardiovascular and renal function. Corin defects may contribute to major diseases such as hypertension, heart failure, pre-eclampsia, and kidney disease.

Hypertension in Patients with Heart Failure with Reduced Ejection Fraction.

Hypertension (HTN) is a well-known health problem associated with considerable morbidity and mortality and it is an important risk factor for the development of heart failure (HF). These findings support the need for optimizing the antihypertensive strategies to prevent the progression to HF. Interestingly, the progression from HTN to HF, among other things, may be a consequence of inappropriate over-activation of the renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system (SNS), and the natriuretic peptide system (NPS). In the present review, we will discuss the pathophysiological aspects of the progression from HTN to HF with reduced ejection fraction (HFrEF) and we will focus on the evolution of different pharmacological therapies which are reported to be effective in reducing BP and improving HF outcomes, paying particular attention to the recent trials that have demonstrated the efficacy of the combined therapy of RAAS blockade and Neprilysin (NEP) inhibitor in lowering BP and mediating several beneficial actions within cardiovascular tissues, such as avoiding the worsening of HF.

Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy.

Natriuretic peptides (NPs) promote diuresis, natriuresis and vasodilation in early chronic heart failure (CHF), countering renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system (SNS) overstimulation. Despite dramatic increases in circulating NP concentrations as CHF progresses, their effects become blunted. Increases in diuresis, natriuresis, and vasodilation after administration of exogenous atrial (ANP) or brain (BNP) natriuretic peptides are attenuated in patients with advanced CHF compared with controls. Several major factors may account for the reduced effectiveness of the natriuretic peptide system (NPS) in CHF. First, there is reduced availability of active forms of NPs, namely BNP. Second, target organ responsiveness becomes diminished. Third, the counter‐regulatory hormones of the RAAS and SNS, and endothelin‐1 become over‐activated. Therefore, pharmacological approaches to enhance the functional effectiveness of the NPS in CHF have been explored in recent years. In terms of clinical outcomes, studies of synthetic BNP, or of neprilysin inhibitors alone or associated with an angiotensin converting enzyme inhibitor, have been controversial for several reasons. Recently, however, encouraging results have been obtained with the angiotensin receptor neprilysin inhibitor sacubitril/valsartan. The available data show that treatment with sacubitril/valsartan is associated with increased levels of NPs and their intracellular mediator cyclic guanosine monophosphate, suggesting improved functional effectiveness of the NPS, in addition to beneficial effects on mortality and morbidity outcomes. Therefore, combined targeting of the NPS and RAAS with sacubitril/valsartan emerges as the current optimal approach for redressing the neurohormonal imbalance in CHF.

Lipids, Statins and Heart Failure: An Update.

Heart failure (HF) is characterized by cardiac functional and structural alterations, progressively leading to clinical symptoms and signs. Certain neurohormonal systems (i.e. the sympathetic nervous system, the reninangiotensin-aldosterone system and the natriuretic peptide system) as well as interactions between endothelial, monocytes/macrophages and myocardial cells are involved in the process. The present narrative review discusses the relationships between lipids, statins and HF. Lipid metabolism is involved in cardiac function. Inflammation, oxidative stress, endothelial and platelet dysfunction, activation of neurohormonal systems, adverse cardiac remodeling, haemodynamic disorders and arrhythmogenesis predispose to HF development and progression. Statins have been shown to reduce HF incidence possibly via their pleiotropic actions on the above mentioned mechanisms. Other cardiovascular (CV) risk factors affecting HF prevalence and outcomes include metabolic syndrome, non-alcoholic fatty liver disease, chronic kidney disease, hyperuricaemia, epicardial fat and increased arterial stiffness that are improved following statin therapy. Lipid disorders are involved in HF development and progression. Statins may beneficially affect these disorders as well as other CV risk factors linked to HF. However, the impact of statins in patients with established HF has yet to be determined. Further studies are needed to unveil potential benefits of statin therapy (or some statins) in specific groups of HF patients.

Insulin resistance in chronic kidney disease: a systematic review.

Insulin resistance (IR) is an early metabolic alteration in chronic kidney disease (CKD) patients, being apparent when the glomerular filtration rate is still within the normal range and becoming almost universal in those who reach the end stage of kidney failure. The skeletal muscle represents the primary site of IR in CKD, and alterations at sites beyond the insulin receptor are recognized as the main defect underlying IR in this condition. Estimates of IR based on fasting insulin concentration are easier and faster but may not be adequate in patients with CKD because renal insufficiency reduces insulin catabolism. The hyperinsulinemic euglycemic clamp is the gold standard for the assessment of insulin sensitivity because this technique allows a direct measure of skeletal muscle sensitivity to insulin. The etiology of IR in CKD is multifactorial in nature and may be secondary to disturbances that are prominent in renal diseases, including physical inactivity, chronic inflammation, oxidative stress, vitamin D deficiency, metabolic acidosis, anemia, adipokine derangement, and altered gut microbiome. IR contributes to the progression of renal disease by worsening renal hemodynamics by various mechanisms, including activation of the sympathetic nervous system, sodium retention, and downregulation of the natriuretic peptide system. IR has been solidly associated with intermediate mechanisms leading to cardiovascular (CV) disease in CKD including left ventricular hypertrophy, vascular dysfunction, and atherosclerosis. However, it remains unclear whether IR is an independent predictor of mortality and CV complications in CKD. Because IR is a modifiable risk factor and its reduction may lower CV morbidity and mortality, unveiling the molecular mechanisms responsible for the pathogenesis of CKD-related insulin resistance is of importance for the identification of novel therapeutic targets aimed at reducing the high CV risk of this condition.

Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III-rationale, trial design and baseline data.

BackgroundPatients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis.MethodsUK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor–neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but <60 mL/min/1.73 m2 and urine albumin:creatinine ratio (uACR) >20 mg/mmol or eGFR ≥20 but <45 mL/min/1.73 m2 (regardless of uACR) were invited to be screened. Following a 4- to 7-week pre-randomization single-blind placebo run-in phase (during which any current renin–angiotensin system inhibitors were stopped), willing and eligible participants were randomly assigned either sacubitril/valsartan or irbesartan and followed-up for 12 months. The primary aim was to compare the effects of sacubitril/valsartan and irbesartan on measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD.ResultsBetween November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m2 and the median uACR was 58.5 mg/mmol.ConclusionsUK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD.

SP 04-1 THE ROLE OF NATRIURETIC PEPTIDES IN THE PATHOGENESIS OF CARDIOVASCULAR DISEASES

SP 04-1 THE ROLE OF NATRIURETIC PEPTIDES IN THE PATHOGENESIS OF CARDIOVASCULAR DISEASES

Serum proatrial natriuretic peptide does not increase with higher systolic blood pressure in obese men

ObjectiveObese persons have low circulating natriuretic peptide (NP) concentrations. It has been proposed that this ‘natriuretic handicap’ could play a role in obesity-related hypertension. The normal physiological response of the...

247 - Molecular Phenotyping of the Natriuretic Peptide and Renin-Angiotensin Systems in the Post-Myocardial Infarction Left Ventricle and Scar

Background: Myocardial infarction (MI) is a major consequence of ischemic heart disease and progression from MI to heart failure (HF) continues to increase. Indeed, the formation and extent of LV scarring due to MI contributes to HF progression and represents a target of therapeutic intervention, as the scar contains living fibroblast like cells. Further, studies continue to support the role of the renin-angiotensin system (RAS) contributing to adverse post-MI fibrotic remodeling, which are opposed by the cardioprotective actions of the natriuretic peptide system (NPS). While the cellular responses of the RAS and NPS have been studied in the viable post-MI myocardium, it is unknown whether the RAS and NPS are expressed, and altered, in the LV scar that is increasingly recognized as a biologically active tissue. Hypothesis: This study tested the hypothesis that NPS receptors and their endogenous ligands and components of the RAS are present and altered in the post-MI scar. Methods: MI was induced by left coronary artery ligation in wistar rats and sham-operated (S) rats served as controls (n = 10/group). LV structure and function was assessed at 4 weeks post-MI and included hypertrophy, EF and interstitial fibrosis (remote region) by picrosirius red staining. Microarray analysis (Affymetrix Rat Genome GeneChip and GeneSifter software) was performed on 3 sets of LV tissue: 1) scar; 2) remote region distal to the scar and 3) sham-operated LV. Transcriptional identification and changes in the NPS [natriuretic peptide (NP) ligands: ANP, BNP, CNP; natriuretic peptide receptors (NPR): NPR-A, NPR-B and NPR-C] and RAS components [renin, angiotensinogen, angiotensin converting enzyme (ACE), angiotensin II receptor (ATR)1 and ATR2] were assessed in LV tissues. Data are presented as Mean ± SE. *P < .05 between groups. Results: MI was characterized by a significant increase in LV hypertrophy (S: 2.06 ± 0.03, MI: 2.57 ± 0.07 mg/g*) as well as LV fibrosis (S: 2.4 ± 0.1, MI:4.5 ± 0.6%*) and a significant decrease in EF (S:79 ± 1, MI:49 ± 4%*). Microarray analysis indicated the expression of all genes related to the NPS and RAS in LV scar and the remote region tissue. Notably, ANP was significantly up-regulated in both the LV scar and remote region compared to sham LV, while the ATR1, ACE and NPR-B genes were significantly up-regulated in the scar compared to other LV tissues. Conclusion: We report that the NPS (anti-hypertrophic, anti-fibrotic, and anti-apoptotic) and RAS (pro- hypertrophic, pro-fibrotic and pro-apoptotic) are molecularly activated within the scar, in addition to the viable myocardium. Moreover, this activation may contribute to the structural and functional integrity as well as remodeling of the heart following MI. These findings suggest key differential molecular modulation of the NPS and RAS in the regulation post-MI fibrotic remodeling, which may provide strategic insights into the development of novel scar-modifying therapies to prevent the progression to HF.