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1.
Cardiorenal Syndrome and Heart Failure-Challenges and Opportunities.
Yogasundaram, H, Chappell, MC, Braam, B, Oudit, GY
The Canadian journal of cardiology. 2019;(9):1208-1219
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Abstract
Cardiorenal syndromes (CRS) describe concomitant bidirectional dysfunction of the heart and kidneys in which 1 organ initiates, perpetuates, and/or accelerates decline of the other. CRS are common in heart failure and universally portend worsened prognosis. Despite this heavy disease burden, the appropriate diagnosis and classification of CRS remains problematic. In addition to the hemodynamic drivers of decreased renal perfusion and increased renal vein pressure, induction of the renin-angiotensin-aldosterone system, stimulation of the sympathetic nervous system, disruption of balance between nitric oxide and reactive oxygen species, and inflammation are implicated in the pathogenesis of CRS. Medical therapy of heart failure including renin-angiotensin-aldosterone system inhibition and β-adrenergic blockade can blunt these deleterious processes. Renovascular disease can accelerate the progression of CRS. Volume overload and diuretic resistance are common and complicate the management of CRS. In heart failure and CRS being treated with diuretics, worsening creatinine is not associated with worsened outcome if clinical decongestion is achieved. Adjunctive therapy is often required in the management of volume overload in CRS, but evidence for these therapies is limited. Anemia and iron deficiency are importantly associated with CRS and might amplify decline of cardiac and renal function. End-stage cardiac and/or renal disease represents an especially poor prognosis with limited therapeutic options. Overall, worsening renal function is associated with significantly increased mortality. Despite progress in the area of CRS, there are still multiple pathophysiological and clinical aspects of CRS that need further research to eventually develop effective therapeutic options.
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A review of the mechanism of action, metabolic profile and haemodynamic effects of sodium-glucose co-transporter-2 inhibitors.
Brown, E, Rajeev, SP, Cuthbertson, DJ, Wilding, JPH
Diabetes, obesity & metabolism. 2019;:9-18
Abstract
Inhibition of glucose transport in the kidney, to produce glucosuria and thus directly lower blood glucose seems a remarkably simple way to treat diabetes (type 1 or type 2). The development of sodium-glucose co-transporter-2 (SGLT2) inhibitors and their subsequent clinical development has on one hand shown this to be true, but at another level has helped reveal a complex web of interacting effects starting in the kidney and modulating multiple metabolic pathways in a variety of other organs. These underlie the now clear benefits of this class of drugs in the management of type 2 diabetes from glucose lowering, weight loss and blood pressure reduction through to the reductions in cardiovascular and renal complications observed in long-term outcomes trials. They also explain some of the adverse effects that have emerged, including the risk of diabetic ketoacidosis. This review describes the effects of SGLT2 inhibition in relation to this complex physiology, and shows how this can favourably alter the pathophysiology of type 2 diabetes.
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Risk Factor Variability and Cardiovascular Outcome: JACC Review Topic of the Week.
Messerli, FH, Hofstetter, L, Rimoldi, SF, Rexhaj, E, Bangalore, S
Journal of the American College of Cardiology. 2019;(20):2596-2603
Abstract
Until recently, intraindividual visit-to-visit variability of cardiovascular risk factors has been dismissed as random fluctuation. This simplistic concept was challenged by demonstrating that visit-to-visit blood pressure variability, independent of average blood pressure, was a powerful risk factor for stroke. Subsequently, variability of other cardiovascular risk factors such as cholesterol, glycemia, and body weight was documented to increase risk independent of their absolute values. Variability of these risk factors has been demonstrated to be a powerful predictor for all-cause and cardiovascular mortality, stroke, coronary artery disease, heart failure, end-stage renal disease, and dementia. With the notable exception of heart rate, cardiovascular risk factors must now be defined by 2 components: the magnitude and duration of sustained risk factor elevation and, equally important, the variability of the same risk factor over time.
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Interventions to prevent hemodynamic instability during renal replacement therapy in critically ill patients: a systematic review.
Douvris, A, Malhi, G, Hiremath, S, McIntyre, L, Silver, SA, Bagshaw, SM, Wald, R, Ronco, C, Sikora, L, Weber, C, et al
Critical care (London, England). 2018;(1):41
Abstract
BACKGROUND Hemodynamic instability related to renal replacement therapy (HIRRT) may increase the risk of death and limit renal recovery. Studies in end-stage renal disease populations on maintenance hemodialysis suggest that some renal replacement therapy (RRT)-related interventions (e.g., cool dialysate) may reduce the occurrence of HIRRT, but less is known about interventions to prevent HIRRT in critically ill patients receiving RRT for acute kidney injury (AKI). We sought to evaluate the effectiveness of RRT-related interventions for reducing HIRRT in such patients across RRT modalities. METHODS A systematic review of publications was undertaken using MEDLINE, MEDLINE in Process, EMBASE, and Cochrane's Central Registry for Randomized Controlled Trials (RCTs). Studies that assessed any intervention's effect on HIRRT (the primary outcome) in critically ill patients with AKI were included. HIRRT was variably defined according to each study's definition. Two reviewers independently screened abstracts, identified articles for inclusion, extracted data, and evaluated study quality using validated assessment tools. RESULTS Five RCTs and four observational studies were included (n = 9; 623 patients in total). Studies were small, and the quality was mostly low. Interventions included dialysate sodium modeling (n = 3), ultrafiltration profiling (n = 2), blood volume (n = 2) and temperature control (n = 3), duration of RRT (n = 1), and slow blood flow rate at initiation (n = 1). Some studies applied more than one strategy simultaneously (n = 5). Interventions shown to reduce HIRRT from three studies (two RCTs and one observational study) included higher dialysate sodium concentration, lower dialysate temperature, variable ultrafiltration rates, or a combination of strategies. Interventions not found to have an effect included blood volume and temperature control, extended duration of intermittent RRT, and slower blood flow rates during continuous RRT initiation. How HIRRT was defined and its frequency of occurrence varied widely across studies, including those involving the same RRT modality. Pooled analysis was not possible due to study heterogeneity. CONCLUSIONS Small clinical studies suggest that higher dialysate sodium, lower temperature, individualized ultrafiltration rates, or a combination of these strategies may reduce the risk of HIRRT. Overall, for all RRT modalities, there is a paucity of high-quality data regarding interventions to reduce the occurrence of HIRRT in critically ill patients.
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A perspective on diuretic resistance in chronic congestive heart failure.
Shah, N, Madanieh, R, Alkan, M, Dogar, MU, Kosmas, CE, Vittorio, TJ
Therapeutic advances in cardiovascular disease. 2017;(10):271-278
Abstract
Chronic congestive heart failure (CHF) is a complex disorder characterized by inability of the heart to keep up the demands on it, followed by the progressive pump failure and fluid accumulation. Although the loop diuretics are widely used in heart failure (HF) patients, both pharmacodynamic and pharmacokinetic alterations are thought to be responsible for diuretic resistance in these patients. Strategies to overcome diuretic resistance include sodium intake restriction, changes in diuretic dose and route of administration and sequential nephron diuretic therapy. In this review, we discuss the definition, prevalence, mechanism of development and management strategies of diuretic resistance in HF patients.
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Therapy of acute kidney injury in the perioperative setting.
Romagnoli, S, Ricci, Z, Ronco, C
Current opinion in anaesthesiology. 2017;(1):92-99
Abstract
PURPOSE OF REVIEW The current review analyzes the current pharmacologic approaches in cardiac surgery-associated acute kidney injury and renal replacement/support therapies. RECENT FINDINGS Hemodynamic management and promising therapies, including atrial natriuretic peptide, calcium sensitizer inodilators, and mesenchymal stem cells have been discussed. Encouraging results from pre-emptive renal replacement therapies have been also addressed. SUMMARY Cardiac surgery is responsible for the highest risk of renal dysfunction with respect to other surgical settings. A number of different and coacting insults, including toxins, renal hypoperfusion, ischemia-reperfusion injury, and systemic inflammation, are leading causes of this frequent complication. Intense research is ongoing on the treatment of established cardiac surgery-associated acute kidney injury and, in this view, a holistic approach including preoperative data, risk stratification, prevention, timely diagnosis, and aggressive intervention can limit the burdening consequences of renal dysfunction in these patients. Although no specific pharmacologic and nonpharmacologic strategy can be currently recommended outside clinical research, the prompt identification of renal dysfunction and the application of multimodal treatments are fundamental aspects. Right ventricular dysfunction and increased central venous pressure, frequently affecting cardiac surgery patients, potentially lead to congestive renal dysfunction. Hemodynamic management covers a central role in these cases.
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Effect of perioperative goal-directed hemodynamic therapy on postoperative recovery following major abdominal surgery-a systematic review and meta-analysis of randomized controlled trials.
Sun, Y, Chai, F, Pan, C, Romeiser, JL, Gan, TJ
Critical care (London, England). 2017;(1):141
Abstract
BACKGROUND Goal-directed hemodynamic therapy (GDHT) has been used in the clinical setting for years. However, the evidence for the beneficial effect of GDHT on postoperative recovery remains inconsistent. The aim of this systematic review and meta-analysis was to evaluate the effect of perioperative GDHT in comparison with conventional fluid therapy on postoperative recovery in adults undergoing major abdominal surgery. METHODS Randomized controlled trials (RCTs) in which researchers evaluated the effect of perioperative use of GDHT on postoperative recovery in comparison with conventional fluid therapy following abdominal surgery in adults (i.e., >16 years) were considered. The effect sizes with 95% CIs were calculated. RESULTS Forty-five eligible RCTs were included. Perioperative GDHT was associated with a significant reduction in short-term mortality (risk ratio [RR] 0.75, 95% CI 0.61-0.91, p = 0.004, I 2 = 0), long-term mortality (RR 0.80, 95% CI 0.64-0.99, p = 0.04, I 2 = 4%), and overall complication rates (RR 0.76, 95% CI 0.68-0.85, p < 0.0001, I 2 = 38%). GDHT also facilitated gastrointestinal function recovery, as demonstrated by shortening the time to first flatus by 0.4 days (95% CI -0.72 to -0.08, p = 0.01, I 2 = 74%) and the time to toleration of oral diet by 0.74 days (95% CI -1.44 to -0.03, p < 0.0001, I 2 = 92%). CONCLUSIONS This systematic review of available evidence suggests that the use of perioperative GDHT may facilitate recovery in patients undergoing major abdominal surgery.
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8.
Effects of Obesity on Cardiovascular Hemodynamics, Cardiac Morphology, and Ventricular Function.
Alpert, MA, Omran, J, Bostick, BP
Current obesity reports. 2016;(4):424-434
Abstract
Obesity produces a variety of hemodynamic alterations that may cause changes in cardiac morphology which predispose to left and right ventricular dysfunction. Various neurohormonal and metabolic alterations commonly associated with obesity may contribute to these abnormalities of cardiac structure and function. These changes in cardiovascular hemodynamics, cardiac morphology, and ventricular function may, in severely obese patients, predispose to heart failure, even in the absence of other forms of heart disease (obesity cardiomyopathy). In normotensive obese patients, cardiac involvement is commonly characterized by elevated cardiac output, low peripheral vascular resistance, and increased left ventricular (LV) end-diastolic pressure. Sleep-disordered breathing may lead to pulmonary arterial hypertension and, in association with left heart failure, may contribute to elevation of right heart pressures. These alterations, in association with various neurohormonal and metabolic abnormalities, may produce LV hypertrophy; impaired LV diastolic function; and less commonly, LV systolic dysfunction. Many of these alterations are reversible with substantial voluntary weight loss.
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9.
Calcium sensitizers: What have we learned over the last 25 years?
Pollesello, P, Papp, Z, Papp, JG
International journal of cardiology. 2016;:543-8
Abstract
The use of inotropes for correcting hemodynamic dysfunction in patients with congestive heart failure has been described over many decades. Drugs such as cardiac glycosides, cathecolamines, phosphodiestherase inhibitors, and calcium sensitizers have been in turn proposed. However, the number of new chemical entities in this therapeutic field has been surprisingly low, and the current selection of drugs is limited. One of the paradigm shifts in the discovery for new inotropes was to focus on 'calcium sensitizers' instead of 'calcium mobilizers'. This was designed to lead to the development of safer inotropes, devoid of the complications that arise due to increased intracellular calcium levels. However, only three such calcium sensitizers have been fully developed over the latest 30 years. Moreover, two of these, levosimendan and pimobendan, have multiple molecular targets and other pharmacologic effects in addition to inotropy, such as peripheral vasodilation. More recently, omecamtiv mecarbil was described, which is believed to have a pure inotropy action that is devoid of pleiotropic effects. When the clinical data of these three calcium sensitizers are compared, it appears that the less pure inotropes have the cutting edge over the purer inotrope, due to additional effects during the treatment of a complex syndrome such as acute congested heart failure. This review aims to answer the question whether calcium sensitization per se is a sufficient strategy for bringing required clinical benefits to patients with heart failure. This review is dedicated to the memory of Heimo Haikala, a true and passionate innovator in this challenging field.
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10.
Ivabradine: A Unique and Intriguing Medication for Treating Cardiovascular Disease.
Nawarskas, JJ, Bowman, BN, Anderson, JR
Cardiology in review. 2015;(4):201-11
Abstract
There has been much research linking elevated resting heart rate to cardiovascular morbidity and mortality. Based on these findings, a lower resting heart rate would be of theoretical benefit in patients with cardiovascular disease. From a pathophysiologic perspective, a lower resting heart rate would be of particular benefit in patients with ischemic heart disease and/or heart failure. Although β-blockers and nondihydropyridine calcium channel blockers are effective at lowering heart rate, they have many other pharmacologic effects that may not be desirable in some patients, such as negative inotropy. Ivabradine is a drug designed to lower heart rate without any other demonstrable pharmacologic effects; in other words, a pure heart rate-lowering drug. It functions by blocking the hyperpolarization-activated cyclic nucleotide gated channels (f-channels) specific for the sinoatrial node and disrupting If ion current flow. This effectively prolongs diastolic depolarization and slows firing in the sinoatrial node, which lowers heart rate. The effects of ivabradine are most pronounced at higher heart rates (use-dependence), which is important in minimizing the development of symptomatic bradycardia. Clinical trials have demonstrated ivabradine to be an effective antianginal drug both alone and in combination with β-blocker therapy, although it has not been shown to produce a demonstrable effect on reducing major adverse cardiovascular events. In patients with heart failure, ivabradine has demonstrated many hemodynamic benefits, but its effect on clinical outcomes have been mixed and dependent on baseline heart rate, ie, the drug may be of benefit with higher baseline heart rates, but detrimental with low baseline heart rates. The adverse effects of ivabradine are not uncommon, but are rarely severe and include visual disturbances, bradycardia, and atrial fibrillation. Although ivabradine is a very interesting new agent, its variable benefits in large-scale clinical trials leave its exact place in therapy still somewhat nebulous. Unanswered questions include which patient populations would benefit most from this drug, and which concomitant medications would produce the best clinical outcomes when used with ivabradine.