Physiological and pathophysiological roles of the KCNK3 potassium channel in the pulmonary circulation and the heart.

Potassium channel subfamily K member 3 (KCNK3), encoded by the KCNK3 gene, is part of the two-pore domain potassium channel family, constitutively active at resting membrane potentials in excitable cells, including smooth muscle and cardiac cells. Several physiological and pharmacological mediators, such as intracellular signalling pathways, extracellular pH, hypoxia and anaesthetics, regulate KCNK3 channel function. Recent studies show that modulation of KCNK3 channel expression and function strongly influences pulmonary vascular cell and cardiomyocyte function. The altered activity of KCNK3 in pathological situations such as atrial fibrillation, pulmonary arterial hypertension and right ventricular dysfunction demonstrates the crucial role of KCNK3 in cardiovascular homeostasis. Furthermore, loss of function variants of KCNK3 have been identified in patients suffering from pulmonary arterial hypertension and atrial fibrillation. This review focuses on current knowledge of the role of the KCNK3 channel in pulmonary circulation and the heart, in healthy and pathological conditions.

Heart Failure with Preserved Ejection Fraction: a Pharmacotherapeutic Update.

While guidelines for management of heart failure with reduced ejection fraction (HFrEF) are consensual and have led to improved survival, treatment options for heart failure with preserved ejection fraction (HFpEF) remain limited and aim primarily for symptom relief and improvement of quality of life. Due to the shortage of therapeutic options, several drugs have been investigated in multiple clinical trials. The majority of these trials have reported disappointing results and have suggested that HFpEF might not be as simply described by ejection fraction as previously though. In fact, HFpEF is a complex clinical syndrome with various comorbidities and overlapping distinct phenotypes that could benefit from personalized therapeutic approaches. This review summarizes the results from the most recent phase III clinical trials for HFpEF and the most promising drugs arising from phase II trials as well as the various challenges that are currently holding back the development of new pharmacotherapeutic options for these patients.

Therapeutic Approaches in Pulmonary Arterial Hypertension with Beneficial Effects on Right Ventricular Function-Preclinical Studies.

Pulmonary hypertension (PH) is a progressive condition that affects the pulmonary vessels, but its main prognostic factor is the right ventricle (RV) function. Many mice/rat models are used for research in PAH, but results fail to translate to clinical trials. This study reviews studies that test interventions on pulmonary artery banding (PAB), a model of isolated RV disfunction, and PH models. Multiple tested drugs both improved pulmonary vascular hemodynamics in PH models and improved RV structure and function in PAB animals. PH models and PAB animals frequently exhibited similar results (73.1% concordance). Macitentan, sildenafil, and tadalafil improved most tested pathophysiological parameters in PH models, but almost none in PAB animals. Results are frequently not consistent with other studies, possibly due to the methodology, which greatly varied. Some research groups start treating the animals immediately, and others wait up to 4 weeks from model induction. Treatment duration and choice of anaesthetic are other important differences. This review shows that many drugs currently under research for PAH have a cardioprotective effect on animals that may translate to humans. However, a uniformization of methods may increase comparability between studies and, thus, improve translation to clinical trials.

Urocortins as biomarkers in cardiovascular disease.

The urocortins (Ucns) belong to the corticotropin-releasing factor (CRF) family of peptides and have multiple effects within the central nervous and the cardiovascular systems. With growing evidence indicating significant cardioprotective properties and cardiovascular actions of these peptides, the question arises as to whether the plasma profiles of the Ucns are altered in pathologic settings. While reports have shown conflicting results and findings have not been corroborated in multiple independent cohorts, it seems likely that plasma Ucn concentrations are elevated in multiple cardiovascular conditions. The degree of increase and accurate determination of circulating values of the Ucns requires further validation.

Bmpr2 Mutant Rats Develop Pulmonary and Cardiac Characteristics of Pulmonary Arterial Hypertension.

BACKGROUND: Monoallelic mutations in the gene encoding bone morphogenetic protein receptor 2 ( Bmpr2) are the main genetic risk factor for heritable pulmonary arterial hypertension (PAH) with incomplete penetrance. Several Bmpr2 transgenic mice have been reported to develop mild spontaneous PAH. In this study, we examined whether rats with the Bmpr2 mutation were susceptible to developing more severe PAH. METHODS: The zinc finger nuclease method was used to establish rat lines with mutations in the Bmpr2 gene. These rats were then characterized at the hemodynamic, histological, electrophysiological, and molecular levels. RESULTS: Rats with a monoallelic deletion of 71 bp in exon 1 (Δ 71 rats) showed decreased BMPRII expression and phosphorylated SMAD1/5/9 levels. Δ 71 Rats develop age-dependent spontaneous PAH with a low penetrance (16%-27%), similar to that in humans. Δ 71 Rats were more susceptible to hypoxia-induced pulmonary hypertension than wild-type rats. Δ 71 Rats exhibited progressive pulmonary vascular remodeling associated with a proproliferative phenotype and showed lower pulmonary microvascular density than wild-type rats. Organ bath studies revealed severe alteration of pulmonary artery contraction and relaxation associated with potassium channel subfamily K member 3 (KCNK3) dysfunction. High levels of perivascular fibrillar collagen and pulmonary interleukin-6 overexpression discriminated rats that developed spontaneous PAH and rats that did not develop spontaneous PAH. Finally, detailed assessments of cardiomyocytes demonstrated alterations in morphology, calcium (Ca2+), and cell contractility specific to the right ventricle; these changes could explain the lower cardiac output of Δ 71 rats. Indeed, adult right ventricular cardiomyocytes from Δ 71 rats exhibited a smaller diameter, decreased sensitivity of sarcomeres to Ca2+, decreased [Ca2+] transient amplitude, reduced sarcoplasmic reticulum Ca2+ content, and short action potential duration compared with right ventricular cardiomyocytes from wild-type rats. CONCLUSIONS: We characterized the first Bmpr2 mutant rats and showed some of the critical cellular and molecular dysfunctions described in human PAH. We also identified the heart as an unexpected but potential target organ of Bmpr2 mutations. Thus, this new genetic rat model represents a promising tool to study the pathogenesis of PAH.

Cardiovascular Effects of Urocortin-2: Pathophysiological Mechanisms and Therapeutic Potential.

Urocortin-2 (Ucn-2) is a peptide of the corticotrophin releasing factor-related family with several effects within the cardiovascular system. A variety of molecular mechanisms has been proposed to underlie some of these effects, although others remain mostly hypothetical. Growing interest in the cardiovascular properties of this peptide promoted several pre-clinical studies in the settings of heart failure and ischemia, as well as some experiments in the fields of systemic and pulmonary arterial hypertension. Most of these studies report promising results, with Ucn-2 showing therapeutic potential in these settings, and few clinical trials to date are trying to translate this potential to human cardiovascular disease. Ucn-2 also appears to have potential as a biomarker of diagnostic/prognostic relevance in cardiovascular disease, this being a recent field in the study of this peptide needing further corroboration. Regarding the increasing amount of evidence in Ucn-2 investigation, this work aims to make an updated review on its cardiovascular effects and molecular mechanisms of action and therapeutic potential, and to identify some research barriers and gaps in the study of this cardioprotective peptide.

Update on pathophysiology and preventive strategies of anthracycline-induced cardiotoxicity.

Anthracycline chemotherapy has a prominent role in treating many forms of cancer. Unfortunately, cardiotoxic side effects represent a serious limitation to their use, with doxorubicin being the leading drug of the group. Indeed, anthracycline-induced cardiomyopathy is an important public health concern because it may not be detected for many years and remains a lifelong threat. Even after decades of investigation, neither the exact mode of action of anthracyclines nor the pathways leading to their side effect are fully understood. It is increasingly important to establish collaboration between oncologists and cardiologists to improve the management of cancer patient receiving anthracyclines. This article reviews the clinical course, pathogenesis, cardiac monitoring and new concepts in diagnosing and preventing anthracycline-induced cardiotoxicity.

Neuregulin-1 attenuates right ventricular diastolic stiffness in experimental pulmonary hypertension.

We have previously shown that treatment with recombinant human neuregulin-1 (rhNRG-1) improves pulmonary arterial hypertension (PAH) in a monocrotaline (MCT)-induced animal model, by decreasing pulmonary arterial remodelling and endothelial dysfunction, as well as by restoring right ventricular (RV) function. Additionally, rhNRG-1 treatment showed direct myocardial anti-remodelling effects in a model of pressure loading of the RV without PAH. This work aimed to study the intrinsic cardiac effects of rhNRG-1 on experimental PAH and RV pressure overload, and more specifically on diastolic stiffness, at both the ventricular and cardiomyocyte level. We studied the effects of chronic rhNRG-1 treatment on ventricular passive stiffness in RV and LV samples from MCT-induced PAH animals and in the RV from animals with compensated and decompensated RV hypertrophy, through a mild and severe pulmonary artery banding (PAB). We also measured passive tension in isolated cardiomyocytes and quantified the expression of myocardial remodelling-associated genes and calcium handling proteins. Chronic rhNRG-1 treatment decreased passive tension development in RV and LV isolated from animals with MCT-induced PAH. This decrease was associated with increased phospholamban phosphorylation, and with attenuation of the expression of cardiac maladaptive remodelling markers. Finally, we showed that rhNRG-1 therapy decreased RV remodelling and cardiomyocyte passive tension development in PAB-induced RV hypertrophy animals, without compromising cardiac function, pointing to cardiac-specific effects in both hypertrophy stages. In conclusion, we demonstrated that rhNRG-1 treatment decreased RV intrinsic diastolic stiffness, through the improvement of calcium handling and cardiac remodelling signalling.

Improvement in left intraventricular pressure gradients after aortic valve replacement in aortic stenosis patients.

NEW FINDINGS: What is the central question of this study? Normal diastolic and systolic intraventricular pressure gradients are decreased when left ventricular filling and/or emptying are compromised. We hypothesized that in patients with severe aortic valve stenosis, a condition that interferes with ventricular filling and emptying, those gradients would be disturbed. What is the main finding and its importance? We showed the existence of intraventricular pressure gradients throughout the cardiac cycle in the human left ventricle. Moreover, we demonstrated, for the first time, that diastolic and systolic gradients, which are markers of normal ventricular filling and emptying, respectively, improved in patients with severe aortic valve stenosis immediately after valve replacement. The present study was conducted to characterize left intraventicular pressure gradients, which are markers of normal cardiac function, in patients with severe aortic stenosis, a condition that interferes with ventricular filling and emptying. In 10 patients (four male; mean age 71.3 ± 4.8 years old) undergoing aortic valve replacement, two high-fidelity pressure catheters were inserted inside the cavity of the left ventricle through an apical puncture and positioned in the apex and outflow tract below the aortic valve. Pressures were continuously acquired and gradients calculated as apical minus outflow tract pressure, before and immediately after aortic valve replacement. During early filling, we recorded a negative intraventricular gradient along the basal portion of the left ventricle in the apical direction (-0.82 ± 0.45 mmHg), which increased to -3.97 ± 0.42 mmHg after aortic valve replacement. In late filling, intraventricular flow was now directed towards the outflow tract, with a positive pressure gradient both before (+1.23 ± 0.37 mmHg) and after surgery (+2.12 ± 0.58 mmHg). During systole, before surgery we observed a positive pressure gradient between the apex and outflow tract during both rapid (+1.60 ± 0.21 mmHg) and slow ejection phases (+1.68 ± 0.12 mmHg), whereas after aortic valve replacement the positive gradient (+1.54 ± 0.15 mmHg) during rapid ejection was inverted (-3.92 ± 0.34 mmHg) during the slow ejection phase. We demonstrated that in patients with severe aortic stenosis both diastolic and systolic intraventricular pressure gradients are significantly attenuated but can be restored immediately after aortic valve replacement. The assessment and measurement of intraventricular pressure gradients and their modulation in pathophysiological conditions may provide novel insights into cardiac physiology.

Angiotensin-(1-7) modulates angiotensin II-induced vasoconstriction in human mammary artery.

PURPOSE: The renin-angiotensin system plays a key role in cardiovascular pathophysiology and one of its members, angiotensin-(1-7) (ANG-(1-7)), is now recognized as a peptide with the ability to counter-regulate angiotensin II (ANGII) effects. We sought to investigate ANG-(1-7) actions in human vessels, particularly its effect on ANGII-induced vasoconstriction in human mammary arteries (HMA). METHODS: Samples of HMA from patients submitted to coronary revascularization (22 patients, mean age 67 years) were cut into small rings, mounted in a myograph bath system, normalized and allowed to contract and dilate isometrically. In baseline experiments, the rings were incubated with ANG-(1-7) or vehicle, followed by increasing concentrations of ANGII. This protocol was repeated in the presence of A-779, PD123177, losartan and after mechanical endothelium removal. Western blot analysis and immunofluorescence were also performed in order to verify the presence of Mas receptor in HMA. RESULTS: ANG-(1-7) significantly attenuated ANGII-induced contraction, producing a maximal inhibition of approximately 65.2%. This effect was not abolished by A-779, PD123177 or endothelium removal. In the presence of losartan, ANGII response was attenuated and no differences were observed between ANG-(1-7) and vehicle treated rings. Finally, we observed, for the first time, that the Mas receptor is expressed in HMA endothelium. CONCLUSIONS: ANG-(1-7) significantly attenuates ANGII-induced vasoconstriction and, although the Mas receptor is expressed in HMA, this effect seems to be independent of its activation. Additionally, AT2 receptor and endothelium are not involved in this mechanism, which suggests a direct effect on smooth muscle cells.

Biosensors for natriuretic peptides in cardiovascular diseases. A review.

Heart failure (HF) is a complex clinical syndrome associated with high rates of morbidity and mortality. Over the years, it has been crucial to find accurate biomarkers capable of doing a precise monitor of HF and provide an early diagnosis. Of these, it has been established an important role of natriuretic peptides in HF assessment. Moreover, the development of biosensors has been garnering interest as new diagnostic medical tools. In this review we first provide a general overview of HF, its pathogenesis, and diagnostic features. We then discuss the role of natriuretic peptides in heart failure by characterizing them and point out their potential as biomarkers. Finally, we adress the evolution of biosensors development and the available natriuretic peptides biosensors for disease monitoring.

Corticotropin-releasing hormone and obesity: From fetal life to adulthood.

Obesity is among the most common chronic disorders, worldwide. It is a complex disease that reflects the interactions between environmental influences, multiple genetic allelic variants, and behavioral factors. Recent developments have also shown that biological conditions in utero play an important role in the programming of energy homeostasis systems and might have an impact on obesity and metabolic disease risk. The corticotropin-releasing hormone (CRH) family of neuropeptides, as a central element of energy homeostasis, has been evaluated for its role in the pathophysiology of obesity. This review aims to summarize the relevance and effects of the CRH family of peptides in the pathophysiology of obesity spanning from fetal life to adulthood.

The Ketone Bridge Between the Heart and the Bladder: How Fast Should We Go?

Metabolic syndrome (MS) is associated with both cardiovascular and bladder dysfunction. Insulin resistance (IR) and central obesity, in particular, are the main risk factors. In these patients, vicious pathological cycles exacerbate abnormal carbohydrate metabolism and sustain an inflammatory state, with serious implications for both the heart and bladder. Ketone bodies serve as an alternative energy source in this context. They are considered a "super-fuel" because they generate adenosine triphosphate with less oxygen consumption per molecule, thus enhancing metabolic efficiency. Ketone bodies have a positive impact on all components of MS. They aid in weight loss and glycemic control, lower blood pressure, improve lipid profiles, and enhance endothelial function. Additionally, they possess direct anti-inflammatory, antioxidant, and vasodilatory properties. A shared key player in dysfunction of both the heart and bladder dysfunction is the formation of the NLRP3 inflammasome, which ketone bodies inhibit. Interventions that elevate ketone body levels-such as fasting, a ketogenic diet, ketone supplements, and sodium-glucose cotransporter 2 inhibitors-have been shown to directly affect cardiovascular outcomes and improve lower urinary tract symptoms derived from MS. This review explores the pathophysiological basis of the benefits of ketone bodies in cardiac and bladder dysfunction.

Intraventricular pressure gradients throughout the cardiac cycle: effects of ischaemia and modulation by afterload.

The aim of the present study was to characterize the intraventricular pressure gradients (IVPGs) througout the cardiac cycle, to correlate them with myocardial segmental asynchrony and to evaluate the effects of ischaemia and modulation by afterload. Open-chest anaesthetized rabbits (n = 6) were instrumented with pressure-tip micromanometers placed in the apex and outflow tract of the left ventricular (LV) cavity and with sonomicrometer crystals placed in the apex and base of the LV free wall to measure IVPGs and myocardial segment length changes during basal, afterloaded (aortic cross-clamping) and ischaemic conditions (left anterior descending coronary artery ligation). During early diastole (rapid filling), we recorded an IVPG (4.6 ± 0.7 mmHg) from the cardiac base towards the apex followed by an apex-to-outflow pressure gradient (3.6 ± 0.2 mmHg). During systole, we recorded an IVPG (0.6 ± 0.1 mmHg) from apex to outflow during early rapid ejection, which inverted during late slow ejection. Interestingly, the maximal rate of LV pressure fall occurred earlier and relaxation rate was faster in the base than in the apex. While shortening of basal segments was complete at the end of ejection, apical segments always showed a significant amount of postsystolic shortening. The IVPGs were entirely lost during ischaemia and attenuated by afterload elevations. During ischaemia, systolic shortening of the apical segment decreased, while postsystolic shortening increased. The present study confirms the existence of diastolic and systolic IVPGs in the LV and demonstrates, for the first time, that this normal gradient pattern is related to physiological asynchrony between basal and apical myocardial segments. Moreover, we show that the IVPG, a marker of normal left ventricular function, can be attenuated, lost entirely or even reversed after regional acute ischaemia and afterload elevations.

Pulmonary Valve Replacement: A New Paradigm with Tissue Engineering.

Prevalence of congenital heart diseases worldwide is around 9 per 1000 newborns, 20% of which affect the pulmonary valve or right ventricular outflow tract. As survival after surgical repair of these defects has improved over time, there is the need to address the long-term issues of older children and young adults with "repaired" congenital heart diseases. In recent decades, the most used types of valves are the mechanical and bioprosthetic valves. Despite improving patients' quality of life, these effects are suboptimal due to their limitations, such as the inability to grow and adapt to hemodynamic changes. These issues have led to the search for living valve solutions through tissue engineering to respond to these challenges. This article aims to review the performance of traditional pulmonary valves and understand how tissue engineering-based valves can improve the management of these patients.

Cardiovascular effects of relaxin-2: therapeutic potential and future perspectives.

The hormone relaxin-2 has emerged as a promising player in regulating the physiology of the cardiovascular system. Through binding to the relaxin family peptide receptor 1 (RXFP1), this hormone elicits multiple physiological responses including vasodilation induction, reduction of inflammation and oxidative stress, and angiogenesis stimulation. The role of relaxin-2, or its recombinant human form known as serelaxin, has been investigated in preclinical and clinical studies as a potential therapy for cardiovascular diseases, especially heart failure, whose current therapy is still unoptimized. However, evidence from past clinical trials has been inconsistent and further research is needed to fully understand the potential applications of relaxin-2. This review provides an overview of serelaxin use in clinical trials and discusses future directions in the development of relaxin-2 mimetics, which may offer new therapeutic options for patients with heart failure.

Candidate microRNAs as prognostic biomarkers in heart failure: A systematic review.

BACKGROUND: Heart failure (HF) is a high prevalent syndrome with significant burden worldwide. B-type natriuretic peptide (BNP) and N-terminal proBNP are the gold standard biomarkers in HF management. Although useful in clinical practice, they have limitations as their expression can be influenced by ventricular function, aging, obesity, renal failure and atrial arrhythmias. MicroRNAs have recently emerged as potential diagnostic and prognostic biomarkers, given that they are related to cell growth, proliferation, differentiation, and metabolism. An increasing amount of research has highlighted some microRNAs for their potential as HF biomarkers. However, different study designs, methods and study groups have led to inconsistent results. METHODS AND RESULTS: We performed a systematic search of available literature on Pubmed and Scopus reporting the prognostic value of microRNAs in HF, followed by a review of risk of bias, according to Quadas Group Standards. Simultaneously, microRNAs' potential as differential diagnosis and severity biomarkers was also analyzed. Studies have described circulating microRNA as potential diagnostic, prognostic, and severity markers. Mir-622, -519 and -499 were significantly related to HF with reduced ejection fraction, whereas miR-22-3p revealed greater ability as a severity biomarker. Let-7i-5p, miR-223-5p, miR-423-5p, miR-21, miR-1306-5p and miR-122 serum expressions presented a consistent correlation with HF prognosis. Furthermore, identified miR targets were associated with signaling pathways already known to be involved in HF progression. CONCLUSION: Several miRs were related to HF pathophysiology and demonstrated potential as biomarkers for disease progression. MicroRNAs have a promising role in HF, and although unquestionable, we require a deeper and broader understanding of their role and function for future research.

Role of Ion Channel Remodeling in Endothelial Dysfunction Induced by Pulmonary Arterial Hypertension.

Endothelial dysfunction is a key player in advancing vascular pathology in pulmonary arterial hypertension (PAH), a disease essentially characterized by intense remodeling of the pulmonary vasculature, vasoconstriction, endothelial dysfunction, inflammation, oxidative stress, and thrombosis in situ. These vascular features culminate in an increase in pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past years, there has been a great development in our understanding of pulmonary endothelial biology related to the genetic and molecular mechanisms that modulate the endothelial response to direct or indirect injury and how their dysregulation can promote PAH pathogenesis. Ion channels are key regulators of vasoconstriction and proliferative/apoptotic phenotypes; however, they are poorly studied at the endothelial level. The current review will describe and categorize different expression, functions, regulation, and remodeling of endothelial ion channels (K+, Ca2+, Na+, and Cl- channels) in PAH. We will focus on the potential pathogenic role of ion channel deregulation in the onset and progression of endothelial dysfunction during the development of PAH and its potential therapeutic role.

Emerging Roles of Micrornas in Veterinary Cardiology.

Over the last years, the importance of microRNAs (miRNAs) has increasingly been recognised. Each miRNA is a short sequence of non-coding RNA that influences countless genes' expression and, thereby, contributes to several physiological pathways and diseases. It has been demonstrated that miRNAs participate in the development of many cardiovascular diseases (CVDs). This review synopsises the most recent studies emphasising miRNA's influence in several CVDs affecting dogs and cats. It provides a concise outline of miRNA's biology and function, the diagnostic potential of circulating miRNAs as biomarkers, and their role in different CVDs. It also discusses known and future roles for miRNAs as potential clinical biomarkers and therapeutic targets. So, this review gives a comprehensive outline of the most relevant miRNAs related to CVDs in Veterinary Medicine.

An Overview of Circulating Pulmonary Arterial Hypertension Biomarkers.

Pulmonary arterial hypertension (PAH), also known as Group 1 Pulmonary Hypertension (PH), is a PH subset characterized by pulmonary vascular remodeling and pulmonary arterial obstruction. PAH has an estimated incidence of 15-50 people per million in the United States and Europe, and is associated with high mortality and morbidity, with patients' survival time after diagnosis being only 2.8 years. According to current guidelines, right heart catheterization is the gold standard for diagnostic and prognostic evaluation of PAH patients. However, this technique is highly invasive, so it is not used in routine clinical practice or patient follow-up. Thereby, it is essential to find new non-invasive strategies for evaluating disease progression. Biomarkers can be an effective solution for determining PAH patient prognosis and response to therapy, and aiding in diagnostic efforts, so long as their detection is non-invasive, easy, and objective. This review aims to clarify and describe some of the potential new candidates as circulating biomarkers of PAH.