Current Vascular Pharmacology - Volume 14, Issue 1, 2016

Several cellular and molecular mechanisms have been implicated in the development of myocardial dysfunction and low cardiac output in pediatric patients undergoing heart surgery. Ischemia- reperfusion injury with alterations in calcium homeostasis as well as mitochondrial function has been strongly related to myocyte damage and heart failure in this population. In this article, we will review the main mechanisms of postoperative cardiac dysfunction at cellular and molecular levels and the subsequent protective strategies. In addition, we will describe cellular features of the neonatal or immature myocardium and will suggest possible protective management strategies. This article addresses the first of eight topics comprising the special issue entitled “Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery”.

Low cardiac output syndrome frequently complicates the post-operative care of infants and children following cardiac surgery. The onset of low cardiac output follows a predictable course in the hours following cardiopulmonary bypass, as myocardial performance declines in the face of an elevated demand for cardiac output. When demand outstrips supply, shock ensues, and early recognition and intervention can decrease mortality. Multifactorial in etiology, this article will discuss the pathophysiology of low cardiac output syndrome, including myocardial depression following bypass, altered cardiac loading conditions, and inflammation driving a hypermetabolic state. Contributions from altered neurohormonal, thyroid, and adrenal axes will also be discussed. Sources included the clinical experiences of four cardiac intensivists, supported throughout by primary sources and relevant reviews obtained through PubMed searches and from seminal textbooks in the field. This article addresses the second of eight topics comprising the special issue entitled “Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery”.

Rational use of vasodilators to induce afterload reduction is predicated on a thorough knowledge of the constituents of afterload and of the role ventriculoarterial coupling plays in determining their effects. Afterload reduction therapy should be goal directed with the intent to improve stroke volume and tissue oxygen delivery rather than to decrease blood pressure per se. This review will summarize the components comprising circulatory system afterload and will use ventriculoarterial coupling concepts to demonstrate the variable but predictable effects of vasodilator therapy on hemodynamics and tissue oxygen delivery. This article addresses the third of eight topics comprising the special issue entitled “Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery”.

Following surgery for congenital heart disease, patients develop a predictable and progressive decline in cardiac output known as low cardiac output syndrome. During low cardiac output states, a compensatory response to increase systemic perfusion occurs both innately and as part of the postoperative pharmacologic support strategies intended to increase or sustain adequate oxygen delivery. The result typically involves a rise in systemic vascular resistance and heart rate. These and other responses may actually limit the ability of the recently operated heart to provide sufficient cardiac output to meet the oxygen demands of the body. In order to improve systemic oxygen delivery, clinicians have increasingly employed systemic vasodilator therapy to reduce afterload and improve ventriculoarterial coupling. This review will summarize currently utilized pharmacologic agents that promote systemic vasodilation and improve cardiac output through afterload reduction. This article addresses the fourth of eight topics comprising the special issue entitled “Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery”.

Pulmonary hypertension is among the causes of low cardiac output syndrome after neonatal and pediatric cardiac surgery. In the setting of transient postoperative myocardial dysfunction, even a moderate elevation of pulmonary pressure can result in heart dysfunction and circulatory collapse. Although, specific pharmacological manipulation of pulmonary vascular resistance is frequently required in the perioperative period, there is no widely standardized management. In this review, a systematic literature search of PubMed and MEDLINE databases using relevant terms was performed. All clinical trials and relevant manuscripts, along with important physiological, pharmacological, and evidence-based considerations involving the use of pulmonary vasodilators in the management of low cardiac output syndrome after cardiac surgery were reviewed. This article addresses the fifth of eight topics comprising the special issue entitled “Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery”.

Postoperative low cardiac output syndrome has been shown to have both a central and a peripheral vascular involvement. Therefore, inodilators which provide with a combination of positive inotropic and vasodilating therapy, conceptually should be an ideal form of treatment. However, contradictory data on these drugs exist. Phosphodiesterase inhibitors (e.g. milrinone) and more recently calcium sensitizers (e.g. levosimendan) have been most commonly used groups in the clinical setting. This review will summarize the pharmacology of inodilators with a special foccus on current clinical evidence. This article addresses the sixth of eight topics comprising the special issue entitled “Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery”.

Pharmacological manipulation of afterload is often used in the management of single ventricle patients, both in the acute post-operative setting and more chronically. After the first stage of palliation the pulmonary and systemic circulations are in parallel and afterload reduction is often used to increase total cardiac output and systemic oxygen delivery. The effectiveness of this approach is likely to be dependent on the intrinsic contractile state of the myocardium as well as the post-operative vascular tone. A variety of clinical studies and theoretical models support this approach. The use of afterload reduction in this context must be balanced with the need to maintain a critical systemic blood pressure for organ perfusion and to promote pulmonary blood flow. After the second and third stages of palliation the use of acute afterload reduction is less complex and primarily directed at promoting cardiac output when it is low and/or controlling high blood pressure. Second stage palliation is particularly unique in that the cerebral and pulmonary circulations are in series and respond differently to many manipulations designed to control vascular resistance. The incidence of long-term circulatory failure in single ventricle patients has led to frequent use of afterload reducing agents in this population but data to suggest that this improves overall outcomes is lacking. Newer studies suggest there may be a role for drugs that reduce pulmonary vascular resistance. This chapter will discuss the principles of manipulation of systemic vascular resistance, or afterload, following each of the three stages of single ventricle reconstruction. This article addresses the seventh of eight topics comprising the special issue entitled “Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery”.

Pediatric cardiac surgery patients commonly suffer from alterations in vascular tone in the early post-operative period. Pharmacologic manipulation of systemic vascular resistance (SVR) can be complex in a variety of special patient situations including extremes of age, presence of left sided valvar lesions and the use of mechanical circulatory support. Familiarity with how these special circumstances alter SVR and the response to pharmacologic intervention will allow for tailored therapy and hopefully, optimized outcomes. This article addresses the eighth topic of the special issue entitled “Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery”.

Sirtuins (SIRTs) are a class of nicotine adenine dinucleotide (NAD+)-dependent proteins which participate in numerous molecular pathways involved in various age-related human diseases, such as type II diabetes, cardiovascular (CV) diseases and cancer. They have a major role in apoptosis, inflammation, oxidative stress and metabolism regulation, traits that have a great impact on CV physiology and pathology. Their unique profile of NAD+ energy dependency makes them an appealing target for human intervention in cellular and metabolic processes. This review focuses on the recent advances of SIRTs research aiming to shed light on the emerging roles of SIRTs in the pathophysiology of CV and metabolic diseases.

MicroRNAs (miRs) are small non-coding regulatory RNAs that control gene expression. They are involved in the pathogenesis of several diseases, including vascular and cardiac diseases. Their involvement is related to alterations of lipid metabolism, endothelial dysfunction, vascular smooth muscle cell phenotype, atherosclerosis-related low-grade inflammation of the arteries, cardiac hypertrophy or remodelling and heart failure. The manipulation of miRs may eventually be used to prevent or treat vascular or cardiac disease. Available drugs (some statins and renin-angiotensin-system inhibitors, alone or in combination) have beneficial off-target effects mediated through miRs; thus, these drugs may have advantages over other regimens. Inhibition of overexpression of “unfavourable” miRs can be potentially accomplished by silencing them with antisense oligonucleotides, masking, sponges, erasers or decoys. In contrast, down-regulation of “protective” miRs can be tackled by the administration of miR mimics. These approaches may represent a new therapeutic approach to vascular disease; miR manipulation research started recently and is developing rapidly. There is still a long way to go before clinical implementation; at present only one study is in phase II. Thus, the therapeutic manipulation of miRs is not yet the philosopher stone for the prevention or treatment of vascular or cardiac diseases. More research is needed.

Stroke is an acute condition characterized by a sudden decrease in blood flow to brain tissue, resulting in immediate deprivation of both glucose and oxygen. Different mechanisms are involved in the pathogenesis of stroke, but increasing evidence suggests that one of the processes worsening clinical outcome is inflammation with the synthesis and the release of pro-inflammatory cytokines that activate several cells contributing to the progression of brain injury. Monoclonal antibody therapy has proved useful and safe for the treatment of several systemic diseases. In contrast, the evidence is limited for the treatment of stroke. More studies are needed in order to standardize the method of treatment and establish if it is safe and effective.

Angiogenesis is a key process by which new capillary blood vessels are formed, sustaining the supply of oxygen and other nutrients to the body allowing its growth and wound healing, among others. However, angiogenesis also associates with pathological processes, such us tumor growth. Vascular endothelial cells produce different matrix remodeling enzymes such as matrix metalloproteinases and a-disintegrin and metalloproteinases, which have both positive and negative effects on angiogenesis, regulating the cell environment and signaling. However, little is known about the regulation of the activity of these proteases during vascular development. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a membrane-anchored inhibitor of different matrix metalloproteinases and a-disintegrin and metalloproteinases, being a critical regulator of extracellular matrix remodeling and signaling pathway, particularly Notch, which is critical for the maturation of the growing vessels. Reck knockout mice die in utero showing vascular developmental defects and massive hemorrhages. These defects were not observed in knockout mice for secreted-soluble matrix metalloproteinase inhibitors pointing to an exclusive role of RECK in vascular development and maturation since its location at the plasma membrane. Despite the above, the exact role of RECK in this process has not been clarified. This review is focused to summarize the available information on the role of RECK as membrane anchored matrix metalloproteinases and a-disintegrin and metalloproteinases inhibitor, proposing a hypothesis by which RECK play key roles in the physiology and pathophysiology of the angiogenesis processes.

Clopidogrel and aspirin are commonly prescribed anti-platelet medications indicated for patients who have experienced, or are at risk for, ischemic cardiovascular events. The Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study was designed to characterize determinants of clopidogrel and dual anti-platelet therapy (DAPT) response in a healthy cohort of Old Order Amish from Lancaster, PA. Following a loading dose, clopidogrel was taken once a day for 7 days. One hour after the last dose of clopidogrel, 325 mg of aspirin was given. Ex vivo platelet aggregometry was performed at baseline, post-clopidogrel, and post-DAPT. Platelet aggregation measurements were significantly lower after both interventions for all agonists tested (p <0.05), although there was large inter-individual variation in the magnitude of anti-platelet response. Female sex and older age were associated with higher platelet aggregation at all three time-points. Change in aggregation was correlated among the various agonists at each time point. Heritability (h2) of change in platelet aggregation was significant for most traits at all time-points (range h2=0.14-0.57). Utilization of a standardized, short-term intervention provided a powerful approach to investigate sources of variation in platelet aggregation response due to drug therapy. Further, this short-term intervention approach may provide a useful paradigm for pharmacogenomics studies.