Positive Inotropic Drugs Research Articles

First Experimental Evaluation of Cardiac Apex Rotation with an Epicardial Coriolis Force Sensor

Cardiac apex rotation, quantified by sophisticated techniques (radiopaque markers and tagged magnetic resonance), has been shown to provide a sensitive index of left ventricle (LV) dynamics. The authors describe the first experimental assessment of cardiac apex rotation using a gyroscopic sensor based on Coriolis force, epicardially glued on the apex. Dynamics of apex rotation were evaluated in a sheep at baseline, after a positive inotropic drug infusion, and after impairment of cardiac function induced by coronary ligation. To evaluate the efficacy of the sensor to monitor cardiac function, results were compared to contractility variations expressed by the maximum value of the first derivative of LV pressure (LVdP/dtMAX). After inotropic drug infusion, a parallel increasing trend resulted for LVdP/dtMAX, for the maximum value of angular velocity measured by the sensor, and for apex rotation angle derived from velocity signal (+146%, +155%, and +11% from baseline, respectively), whereas a decreasing trend of all three parameters resulted after coronary ligation (-35%, -31%, and -65%). The twist pattern also was altered from baseline. These initial results suggest that the use of an implantable rotation sensor based on Coriolis force can be an efficient and effective tool to assess LV torsional deformation both in normal and failing hearts.

The contractile apparatus as a target for drugs against heart failure: Interaction of levosimendan, a calcium sensitiser, with cardiac troponin c

Cardiac failure is one of the leading causes of mortality in developed countries. As life expectancies of the populations of these countries grow, the number of patients suffering from cardiac insufficiency also increases. Effective treatments are being sought and recently a new class of drugs, the calcium sensitisers, was developed. These drugs cause a positive inotropic effect on cardio-myocytes by interacting directly with the contractile apparatus. Their mechanism of action is not accompanied by an increase in intracellular calcium concentration at therapeutic doses, as seen for the older generation of positive inotropic drugs, and thus does not induce calcium-related deleterious effects such as arrhythmias or apoptosis. Levosimendan is a novel calcium sensitiser which has been discovered by using cardiac troponin C (cTnC) as target protein. This drug has been proved to be a well-tolerated and effective treatment for patients with severe decompensated heart failure. This review describes the basic principles of muscle contraction, the main components of the contractile apparatus and their roles in the heart contraction. The regulatory proteins troponin C (cTnC), troponin I (cTnI), troponin T (cTnT), and tropomyosin (Tm) and their interactions are discussed in details. The concept of calcium sensitisation is thereafter explained and a few examples of calcium sensitisers and their putative mechanisms are discussed. Finally, the binding of levosimendan to cTnC and its mechanism of action are described and the results discussed under the light of the action of this drug in vitro and in vivo.

Cardiac sarcolemmal ion channels and transporters as possible targets for antiarrhythmic and positive inotropic drugs: strategies of the past--perspectives of the future.

In this article we overview the most important antiarrhythmic and positive inotropic mechanisms based on pharmacological modification of an ion channel or a transport protein in the surface membrane of cardiac myocytes. First we briefly characterize the ion currents mediated by these proteins in atrial and ventricular cells. Since the level of expression of ion channels is markedly altered in various types of chronic heart diseases, such as atrial fibrillation or heart failure, cardiac remodelling characteristic of these cases is also discussed. The paper gives evaluation of the currently applied most important antiarrhythmic strategies and some insight into the perspectives of the future by reviewing a few but promising mechanisms and drugs that are currently investigated. Positive inotropic agents and mechanisms are similarly treated, focusing primarily on proarrhythmic risks or potential antiarrhythmic effects of these compounds. Based on the backgrounds and aims above, modification of the followings factors is discussed in details: I(Na), I(Ca), I(Kr), I(Ks), I(Kl), I(to), I(Kur), I(K,Ach), I(K,ATP), I(f), gap-junction channel, Na(+)/K(+) pump, Na(+)/Ca(2+) exchanger, Na(+)/H(+) exchanger, as well as the intracellular concentrations of sodium and calcium ions. In addition to the critical evaluation of each manipulation, the following general conclusions can be drawn. (1) Since large modifications in action potential parameters are usually disadvantageous at long time scale, combination of the various mechanisms, each represented at a moderate degree, appears to be better. (2) Regarding Class III. antiarrhythmic action, selective potassium channel blockers free of reverse rate-dependent properties should be preferred. (3) Partial inhibition of the Na(+)/Ca(2+) exchanger may result-paradoxically in an antiarrhythmic action under specific conditions, in addition to its positive inotropic effect. We believe that investigation of new antiarrhythmic mechanisms, rather than new compounds of the old families, might be most beneficial in order to effectively treat life threatening cardiac arrhythmias in the future.

Acute right ventricular failure—from pathophysiology to new treatments

The right ventricle (RV) provides sustained low-pressure perfusion of the pulmonary vasculature, but is sensitive to changes in loading conditions and intrinsic contractility. Factors that affect right ventricular preload, afterload or left ventricular function can adversely influence the functioning of the RV, causing ischaemia and right ventricular failure (RVF). As RVF progresses, a pronounced tricuspid regurgitation further decreases cardiac output and worsens organ congestion. This can degenerate into an irreversible vicious cycle. The effective diagnosis of RVF is optimally performed by a combination of techniques including echocardiography and catheterisation, which can also be used to monitor treatment efficacy. Treatment of RVF focuses on alleviating congestion, improving right ventricular contractility and right coronary artery perfusion and reducing right ventricular afterload. As part of the treatment, inhaled nitric oxide or prostacyclin effectively reduces afterload by vasodilating the pulmonary vasculature. Traditional positive inotropic drugs enhance contractility by increasing the intracellular calcium concentration and oxygen consumption of cardiac myocytes, while vasopressors such as norepinephrine increase arterial blood pressure, which improves cardiac perfusion but increases afterload. A new treatment, the calcium sensitiser, levosimendan, increases cardiac contractility without increasing myocardial oxygen demand, while preserving myocardial relaxation. Furthermore, it increases coronary perfusion and decreases afterload. Conversely, traditional treatments of circulatory failure, such as mechanical ventilation and volume loading, could be harmful in the case of RVF. This review outlines the pathophysiology, diagnosis and treatment of RVF, illustrated with clinical case studies.

Pharmacokinetics and pharmacodynamics of intravenous inotropic agents.

Positive inotropic drugs have various mechanisms of action. Long-term use of cyclic adenosine monophosphate (cAMP)-dependent drugs has adverse effects on the prognosis of heart failure patients, whereas digoxin has neutral effect on mortality. There are, however, little data on the effects of intravenous inotropic drugs on the outcome of patients. Intravenous inotropic agents are used to treat cardiac emergencies and refractory heart failure. beta-Adrenergic agonists are rapid acting and easy to titrate, with short elimination half-life. However, they increase myocardial oxygen consumption and are thus hazardous during myocardial ischaemia. Furthermore they may promote myocyte apoptosis. Phosphodiesterase (PDE) III inhibiting drugs (amrinone, milrinone and enoximone) increase contractility by reducing the degradation of cAMP. In addition, they reduce both preload and afterload via vasodilation. Short-term use of intravenous milrinone is not associated with increased mortality, and some symptomatic benefit may be obtained when it is used in refractory heart failure. Furthermore, PDE III inhibitors facilitate weaning from the cardiopulmonary bypass machine after cardiac surgery. Levosimendan belongs to a new group of positive inotropic drugs, the calcium sensitisers. It has complex pharmacokinetics and long-lasting haemodynamic effects as a result of its active metabolites. In comparative trials, it has been better tolerated than the most widely used beta-agonist inotropic drug, dobutamine. The pharmacokinetics of the intravenous inotropic drugs might sometimes greatly modify and prolong the response to the therapy, for example because of long-acting active metabolites. These drugs display considerable differences in their pharmacokinetics and pharmacodynamics, and the selection of the most appropriate inotropic drug for each patient should be based on careful consideration of the clinical status of the patient and on the pharmacology of the drug.

Morbidity and mortality in patients with advanced heart failure receiving outpatient continuous infusion of positive inotropic drugs

Morbidity and mortality in patients with advanced heart failure receiving outpatient continuous infusion of positive inotropic drugs

Extended application of an LC–MS/MS method for the analysis of vesnarinone and its metabolites in human urine and dialysate fluid

Vesnarinone, a positive inotropic drug developed for congestive heart failure, and its metabolites (OPC-8230, OPC-18136, OPC-18137) were analyzed in human dialysate and urine (plus an additional metabolite: OPC-18692 in urine) samples using a modification to a previously published LC–MS/MS assay for the analysis of human plasma and urine samples. OPC-8192, a structural analogue of vesnarinone, was used as the internal standard. The analytes of interest were extracted from human dialysate or urine by a solid phase extraction method using a pre-conditioned C-18 extraction column. The analytes were then resolved by a 7 min gradient elution on a reverse phase high performance liquid chromatographic column. Vesnarinone and metabolites were detected on a PE/Sciex API III+Biomolecular Mass analyzer in MS/MS mode using a Turbo IonSpray interface. The linear range of quantitation in dialysate was 2.00–100.00 ng/ml for vesnarinone and 0.50–25.00 ng/ml for each metabolite. In urine, the linear range was of 0.50–25.00 μg/ml for vesnarinone and 0.10–5.00 μg/ml for the metabolites. This method was used to support the analysis of urine and dialysate samples from renally impaired patients who are on vesnarinone treatment.

Management of pulmonary hypertension: physiological and pharmacological considerations for anesthesiologists.

For decades the pulmonary circulation was not considered as important as the systemic (“greater”) circulation. However, pulmonary hypertension can arise because of many diseases of the heart and lung. Therefore, increasing efforts in research have been undertaken leading to a profound increase in un

Perioperative considerations in the patient with a left ventricular assist device.

Perioperative considerations in the patient with a left ventricular assist device.

Incidence and risk calculation of inotropic support in patients undergoing cardiac surgery with cardiopulmonary bypass using an automated anaesthesia record-keeping system

This retrospective study analysed the effects of preoperative and intraoperative factors on the occurrence of inotropic support after cardiopulmonary bypass (CPB). The data sets of 1471 adult patients having received elective cardiac surgery with CPB were recorded using an online anaesthesia record-keeping system. Patients were judged to have required inotropic drug support if they had received one or a combination of the positive inotropic drugs, epinephrine, dobutamine and enoximone. The effects of age, height, weight, body mass index, gender, chronic heart failure, documented preoperative myocardial infarction, left main coronary artery disease, preoperative history of hypertension, chronic renal failure, diabetes mellitus, chronic obstructive pulmonary disease (COPD), preoperative medical treatment, type of surgical procedure, duration of CPB, duration of aortic clamping and reperfusion time were analysed by logistic regression for predictive power of the need for positive inotropic drugs. Of the patients, 32.4% received positive inotropic drugs in the operating theatre after weaning from CPB. The overall 30-day mortality was 2.2%. Of non-survivors, 81.8% received inotropes compared with 18.2% of survivors (P < 0.01). The numbers of previous myocardial infarctions (odds ratio (OR), 2.01), congestive heart failures New York Heart Association class > 2 (OR, 1.85), COPD (OR, 1.85) and age > 65 yr (OR, 1.62), aortic cross clamping time of > 90 min (OR, 2.32) and coronary artery bypass surgery (OR, 0.43) all represented influential factors within the logistic regression model. The knowledge of these risk factors should be useful in increasing the anaesthetist's vigilance in those patients most at risk for inotropic support and in providing for more timely therapeutic intervention and optimizing anaesthesia management.

What is wrong with positive inotropic drugs? Lessons from basic science and clinical trials

Chronic mechanical overload modifies myocardial performance to adapt muscle economy to new environmental conditions. Improved thermodynamic status is achieved by reexpression of the foetal programme, which slows the maximum shortening velocity and impairs the adrenergic system. This is followed by the most characteristic structural change in chronic mechanical overload - the development of a permanent negative inotropic state. Consequently, the prescription of inotropic drugs in chronic heart failure (CHF) goes against the physiological processes of adaptation. The situation in clinical practice is confused by the fact that several inotropic drugs have additional vasodilatory effects. However, large clinical trials have shown that, except for digitalis, inotropes have an overall deleterious effect on long-term survival in CHF. The Digitalis Investigation Group (DIG) trial concluded that digoxin has no influence on all-cause or cardiovascular mortality, but that it reduces risk of hospitalization for CHF. It is proposed that the beneficial effects of digitalis are due to its sympatholytic effects. Given that several other classes of drugs have clearly been shown to reduce mortality, there is decreasing support for long-term use of digoxin in CHF. This class of drugs should now be considered most suitable for short-term use in acute episodes of decompensated heart failure.

What is wrong with positive inotropic drugs? Lessons from basic science and clinical trials

What is wrong with positive inotropic drugs? Lessons from basic science and clinical trials

What is wrong with positive inotropic drugs? Lessons from basic science and clinical trials

What is wrong with positive inotropic drugs? Lessons from basic science and clinical trials

Positive Inotropic Drug Infusions for Patients With Heart Failure: Current Controversies and Best Practice

Positive Inotropic Drug Infusions for Patients With Heart Failure: Current Controversies and Best Practice

Positive inotropic drug infusions for patients with heart failure: current controversies and best practice.

Patients who experience severe symptoms of heart failure and repeated hospitalizations for exacerbations may benefit from positive inotropic drug infusion therapy such as dobutamine or milrinone. This article provides an overview of inotropic drug delivery in the home including current controversies and best practices to ensure safe home care policies and practice.

New concepts in diastolic dysfunction and diastolic heart failure: Part II: causal mechanisms and treatment.

As described in Part I of this 2-part article,1 diastolic heart failure is common and causes significant alterations in prognosis. In Part II, experimental studies that have provided insight into the mechanisms that cause diastolic heart failure will be described.2–19⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ In addition, current treatment strategies and the design of future clinical trials of diastolic heart failure will be discussed. The development of truly effective therapy for diastolic heart failure depends on gaining a clear understanding of the basic mechanisms that alter diastolic function and the ability to efficiently target these mechanisms to correct these abnormalities in diastolic function. Conceptually, the mechanisms that cause abnormalities in diastolic function that lead to the development of diastolic heart failure can be divided into factors intrinsic to the myocardium itself (myocardial) and factors that are extrinsic to the myocardium (extramyocardial; Table 1). Myocardial factors can be divided into structures and processes within the cardiac muscle cell (cardiomyocyte), within the extracellular matrix (ECM) that surrounds the cardiac muscle cell, and that activate the autocrine or paracrine production of neurohormones. Each of these mechanisms are active in the major pathological processes that result in diastolic dysfunction and heart failure. Myocardial and extramyocardial mechanisms, cellular and extracellular mechanisms, and neurohumoral activation each play a role in the development of diastolic heart failure caused by ischemia, pressure-overload hypertrophy, and restrictive and hypertrophic cardiomyopathy. View this table: Table 1105290. Diastolic Heart Failure: Mechanisms ### Cardiomyocyte Diastolic dysfunction can be caused by mechanisms that are intrinsic to the cardiac muscle cells themselves. These include changes in calcium homeostasis caused by (1) abnormalities in the sarcolemmal channels responsible for short- and long-term extrusion of calcium from the cytosol, such as the sodium calcium exchanger and the calcium pump; (2) …

Effect of carvedilol on survival in severe chronic heart failure

Background Beta-blocking agents reduce the risk of hospitalization and death in patients with mild-to-moderate heart failure, but little is known about their effects in severe heart failure. Methods We evaluated 2289 patients who had symptoms of heart failure at rest or on minimal exertion, who were clinically euvolemic, and who had an ejection fraction of less than 25 percent. In a double-blind fashion, we randomly assigned 1133 patients to placebo and 1156 patients to treatment with carvedilol for a mean period of 10.4 months, during which standard therapy for heart failure was continued. Patients who required intensive care, had marked fluid retention, or were receiving intravenous vasodilators or positive inotropic drugs were excluded. Results There were 190 deaths in the placebo group and 130 deaths in the carvedilol group. This difference reflected a 35 percent decrease in the risk of death with carvedilol (95 percent confidence interval, 19 to 48 percent; P=0.0014, adjusted for interim analyses). A...

Anesthetic management of a patient with hypertrophic obstructive cardiomyopathy after percutaneous transluminal septal myocardial ablation: Early postinterventional period and anesthetic considerations

IN PATIENTS with hypertrophic cardiomyopathy, positive inotropic drugs, decreasing venous return, or systemic vascular resistance worsens the obstruction of the left ventricular outflow tract, 1 Thompson RC Liberthson RR Lowenstein E Perioperative anesthetic risk of noncardiac surgery in hypertrophic obstructive cardiomyopathy. JAMA. 1985; 254: 2419-2421 Crossref PubMed Scopus (77) Google Scholar , 2 Wigle ED Rakowski H Kimball BP et al. Hypertrophic cardiomyopathy. Clinical spectrum and treatment. Circulation. 1995; 92: 1680-1692 Crossref PubMed Scopus (698) Google Scholar and serious problems might occur during general anesthesia. Percutaneous transluminal septal myocardial ablation (PTSMA), in which septal branches of the left anterior descending coronary artery are occluded with ethanol, has been performed as catheter treatment for hypertrophic obstructive cardiomyopathy (HOCM). 3 Sigwart U Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy. Lancet. 1995; 346: 211-214 Abstract PubMed Google Scholar , 4 Faber L Seggewiss H Gleichmann U Percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: Results with respect to intraprocedural myocardial contrast echocardiography. Circulation. 1998; 98: 2415-2421 Crossref PubMed Scopus (308) Google Scholar , 5 Knight C Kurbaan AS Seggewiss H et al. Nonsurgical septal reduction for hypertrophic obstructive cardiomyopathy: Outcome in the first series of patients. Circulation. 1997; 95: 2075-2081 Crossref PubMed Scopus (281) Google Scholar There is no report, however, on the effects of general anesthesia in patients with this procedure. A case of general anesthesia in a patient with HOCM, who underwent PTSMA 1 week before surgery, is reported.

Positive inotropic drug infusions for the patient with heart failure

Positive inotropic drug infusions for the patient with heart failure

Pathophysiology of chronic heart failure

Heart failure is a changing paradigm. The hemodynamic model, which served our needs well from the 1950s through the early 1980s, has now been largely abandoned, except for the management of decompensated patients in the hospital. The pathophysiology is exceedingly complex and involves structural changes, such as loss of myofilaments, apoptosis and disorganization of the cytoskeleton, as well as disturbances in Ca 2+ homeostasis, alteration in receptor density, signal transduction, and collagen synthesis. A more contemporary working hypothesis is that heart failure is a progressive disorder of left ventricular remodeling, usually resulting from an index event, that culminates in a clinical syndrome characterized by impaired cardiac function and circulatory congestion. This change in the framework of our understanding of the pathophysiology of heart failure is predicated on the results of numerous clinical trials conducted during the past 20 years. New therapies are now evolving that are designed to inhibit neuroendocrine and cytokine activation, whereas drugs specifically designed to heighten cardiac contractility and “unload” the left ventricle have proven to be unhelpful in long-term management of patients with chronic heart failure. However, the hemodynamic model is still relevant for patients in the hospital with decompensated heart failure, where positive inotropic drugs and vasodilators are still widely used. The modern treatment of chronic heart failure is now largely based on the neurohormonal hypothesis, which states that neuroendocrine activation is important in the progression of heart failure and that inhibition of neurohormones is likely to have long-term benefit with regard to morbidity and mortality. Thus, the evolution of treatment for chronic heart failure as a result of clinical trials has provided much enlightenment for our understanding of the fundamental biology of the disorder, a reversal of the usual flow of information from basic science to clinical investigation.