Treatment Of Left Ventricular Failure Research Articles

Novel Therapeutic Targets for the Treatment of Right Ventricular Remodeling: Insights from the Pulmonary Artery Banding Model.

Right ventricular (RV) function is the main determinant of the outcome of patients with pulmonary hypertension (PH). RV dysfunction develops gradually and worsens progressively over the course of PH, resulting in RV failure and premature death. Currently, approved therapies for the treatment of left ventricular failure are not established for the RV. Furthermore, the direct effects of specific vasoactive drugs for treatment of pulmonary arterial hypertension (PAH, Group 1 of PH) on RV are not fully investigated. Pulmonary artery banding (PAB) allows to study the pathogenesis of RV failure solely, thereby testing potential therapies independently of pulmonary vascular changes. This review aims to discuss recent studies of the mechanisms of RV remodeling and RV-directed therapies based on the PAB model.

Left Ventricular Failure Produces Profound Lung Remodeling and Pulmonary Hypertension in Mice

Chronic left ventricular failure causes pulmonary congestion with increased lung weight and type 2 pulmonary hypertension. Understanding the molecular mechanisms for type 2 pulmonary hypertension and the development of novel treatments for this condition requires a robust experimental animal model and a good understanding of the nature of the resultant pulmonary remodeling. Here we demonstrate that chronic transverse aortic constriction causes massive pulmonary fibrosis and remodeling, as well as type 2 pulmonary hypertension, in mice. Thus, aortic constriction-induced left ventricular dysfunction and increased left ventricular end-diastolic pressure are associated with a ≤5.3-fold increase in lung wet weight and dry weight, pulmonary hypertension, and right ventricular hypertrophy. Interestingly, the aortic constriction-induced increase in lung weight was not associated with pulmonary edema but resulted from profound pulmonary remodeling with a dramatic increase in the percentage of fully muscularized lung vessels, marked vascular and lung fibrosis, myofibroblast proliferation, and leukocyte infiltration. The aortic constriction-induced left ventricular dysfunction was also associated with right ventricular hypertrophy, increased right ventricular end-diastolic pressure, and right atrial hypertrophy. The massive lung fibrosis, leukocyte infiltration, and pulmonary hypertension in mice after transverse aortic constriction clearly indicate that congestive heart failure also causes severe lung disease. The lung fibrosis and leukocyte infiltration may be important mechanisms in the poor clinical outcome in patients with end-stage heart failure. Thus, the effective treatment of left ventricular failure may require additional efforts to reduce lung fibrosis and the inflammatory response.

Assistance circulatoire en réanimation

Since the late 90s, technological advances have led to an improvement in survival rates in patients receiving long-term circulatory support for terminal heart failure. As a result, there has been an increased interest in all circulatory support techniques. This review outlines the main support devices currently available in France, their respective advantages and disadvantages, and discusses the management of patients who are suffering from severe cardiogenic shock unresponsive to optimal medical treatment. For these patients, circulatory support can be split into two stages : (1) The rapid implementation of support, focusing on the easier-to-implant and less expensive devices, which will allow time (several weeks) for one of the following : myocardial recovery, implementation of a longer-term support solution, and a heart transplant. These devices include intraaortic balloon pump, Impella® system (left ventricular axial pump), and extracorporeal membrane oxygenation (EMCO). (2) After careful consideration of the possibility of either myocardial recovery or a heart transplant, implementation of long-term cardiac support (for several months or even a few years) via an “artificial heart” may allow patients to return home and regain a certain amount of normality to their life. This is an exceptional treatment; artificial hearts are only implanted in specialized centers, providing the necessary multidisciplinary expertise. There are a number of artificial heart models available, including those that provide monoventricular (left) or biventricular support, those implanted directly into the chest (excluding the power supply) (e.g., CardioWest®), and others that are external to the patient, which are connected to the heart via cannulae. New, completely implantable (apart from the power supply), less noisy axial or centrifugal continuous flow pumps are being developed, representing a significant advance in the treatment of left ventricular failure.

Hypertension-induced Congestive Heart Failure

Arterial hypertension used to be the most common cause of congestive left ventricular failure. With the availability and common use of antihypertensive treatment the incidence and prevalence of hypertension-induced left ventricular failure has gradually declined. Today congestive heart failure due to underlying coronary heart disease is by far more common than the hypertension-induced variety. The effect of treatment of left ventricular failure in recent years, in particular with angiotensin converting enzyme inhibitors and carvedilol, has been impressive.

Cardiopulmonary bypass support for treatment of left ventricular failure following coronary artery bypass grafting: the effects on epicardial microflow and graft flow.

The relationship between graft blood flow, epicardial microflow and mean arterial pressure were studied to evaluate the use of repeated cardiopulmonary bypass (CPB) support for intraoperative heart failure following aorto-coronary bypass surgery. Ten patients with unstable angina and suffering from intraoperative heart failure (group A) were compared to 22 patients with stable angina (group B). In group A, during heart failure, the mean arterial pressure fell by 41% (29.9 +/- 6.8 mmHg, p < 0.01), graft flow (GF) by 67% (9.2 +/- 2.6 ml/min, p < 0.01) and epicardial microflow by 64% (19 +/- 4 AU, p < 0.01). After 15-56 min of assisted CPB support, the epicardial microflow and GF were partially restored. There were significant correlations between GF, epicardial microflow and CPB time. In group B, after protamine infusion, the epicardial microflow and GF were significantly greater than group A values (66 +/- 14 AU, p < 0.001 and 29 +/- 9 ml/min, p < 0.001, respectively). It is concluded that the use of temporary assisted CPB support to treat intraoperative heart failure allows the recovery of the myocardium and thereby restores the mean arterial pressure. The recovery of GF and epicardial flow occurred to a lesser extent. CPB support appeared to be suitable for about 60 min, probably because of increasing disturbance to the GF and the epicardial microcirculation.

Cardiomegaly and Vasoactive Hormones in Rats with Chronic Myocardial Infarction: Long-Term Effects of Chlorothiazide

1. The effects of prolonged chlorothiazide treatment of left ventricular failure on cardiac hypertrophy, circulating vasoactive hormones and exchangeable body sodium were examined in rats with chronic myocardial infarction induced by left coronary artery ligation. Chlorothiazide therapy commenced either immediately or 2 weeks after infarction. For 4 weeks, the rats were given either chlorothiazide (50 mg day-1 kg-1) in their drinking water or drinking water alone. 2. Cardiac weight increased in untreated rats with infarction in comparison with sham-operated controls, indicating the presence of chronic left ventricular dysfunction, although exchangeable body sodium, plasma renin activity, plasma vasopressin and plasma osmolality remained unchanged. 3. Chlorothiazide raised haematocrit and plasma renin activity equally in rats with and without infarction, although exchangeable body sodium, plasma vasopressin and plasma osmolality were not changed by the treatment. Plasma atrial natriuretic peptide was 2-fold higher in rats with infarction and this response was not affected by chlorothiazide treatment. Chlorothiazide therapy did not prevent or reverse cardiac hypertrophy. 4. Chronic diuretic therapy in this experimental model of heart failure did not reduce extracellular sodium, plasma vasopressin or the extent of ventricular hypertrophy, possibly because the condition was associated with activation of the renin-angiotensin system.

The Concept of “Direct Mechanical Ventricular Assistance” in the Treatment of Left-Ventricular Failure - Part 2: Results of the New Intrathoracic Implantable Multi-Chamber Pump System (IMPS) in an Animal Study

An assist device was developed which is able to support the pumping function of the heart by direct application of pressure to the left ventricle. The goal of this animal study in pigs was to determine whether it is possible to maintain sufficient blood circulation with the aid of the new system when the heart is fibrillating or its capacity has been greatly reduced. Following sternotomy complete invasive monitoring was installed. The intrathoracic implantable mechanical multi-chamber pump system (IMPS) was placed around the left ventricle. By means of the beta-blocker carazolol, systolic left-ventricular pressure (LVPsys), cardiac output, heart rate, and left-ventricular dp/dtmax (LVdp/dtmax) were gradually lowered and the pump system was tested intermittently. Then the heart was fibrillated and the system was tested again. When cardiac output, LVdp/dtmax, and systolic blood pressure were reduced by approximately 50% IMPS was able to increase LVPsys by 83% (IMPS) on: 96 +/- 9 mmHg vs. IMPS off: 63 +/- 6 mmHg), and the blood pressure in the carotid artery by 86% (IMPS on: 95/40 +/-15 mmHg vs. IMPS off: 69/38 +/- 9 mmHg). The mean cardiac output was 64% (IMPS on: 4.3 L/min vs. IMPS off: 3.9L/min); in most cases a great variability could be observed depending on the preload, the heart rate, and the mode of pressure application. When the heart was fibrillating, IMPS was able to maintain adequate circulatory conditions with LVPsys = 88%, blood pressure in the carotid artery = 85%, and LVdp/dtmax = 57% of the control values measured before fibrillation and beta-blockade. The system presented here is able to support the impaired left ventricle and to replace its pumping function. The advantages of the system are its efficiency and the lack of contact of the circulating blood with foreign surfaces. Whether the system is suited for bridging and recovery support shall be clarified in further studies.

The Concept of “Direct Mechanical Ventricular Assistance” in the Treatment of Left-Ventricular Failure - Part 1: Idea, Development and Construction of an Implantable Multi-Chamber Pump System Partially Surrounding the Heart

In this paper we present a therapeutic concept for the treatment of heart failure due to muscular inability to pump properly. The basic principle of this concept triggered numerous studies, then with the aim of cardiopulmonary resuscitation, back in the 1970s. In general, it dealt with mechanical systems which led to an increase in stroke volume, systolic blood pressure, and cardiac output through the application of pressure directly to the left ventricle. After a critical appraisal of the relevant literature from technical, physical, and medical viewpoints, and our own preliminary studies on animal hearts within the framework of mock circulation experiments, we have conceived a new functional principle for direct mechanical ventricular assistance based on squeezing the left ventricle only. We have begun development of the system which has the advantages of ease of use, high biocompatibility due to lack of contact between blood and system components, the prevention of infection through complete intrathoracic implantation (long-range goal), and the fact that the patient's own heart can be supported by the system without being removed from the circulatory system (support of the residual myocardial function). Technical as well as medical prerequisites are indicated, and the materials selection and construction principles of the control, pressure generation, pressure transduction, and ventricular compression unit are described. It has proved possible to construct a prototype system to be used in animal experiments, which, through pneumatic inflation of a chamber system partially surrounding the left ventricle, should be able to augment or take over the pumping function of the left ventricle.

Enoximone and acute left ventricular failure during weaning from mechanical ventilation after cardiac surgery

To evaluate enoximone, a phosphodiesterase III inhibitor, in the treatment of left ventricular failure during the weaning of patients from mechanical ventilation after heart surgery. Open label, prospective, weaning trial. Cardiothoracic surgical intensive care unit (ICU) in a university hospital. Nine patients were studied after one or more unsuccessful attempts at weaning from mechanical ventilation due to left ventricular dysfunction. For each patient, two respiratory weaning attempts were studied: the first one as a control and the second one with enoximone infused at a rate of 30 micrograms/kg/min for 30 mins, then at a rate of 10 micrograms/kg/min. Hemodynamic measurements were performed at the following interval times: baseline during mechanical ventilation; during spontaneous ventilation with a T-piece for a minimum of 10 mins; during mechanical ventilation after the enoximone infusion for 30 mins; during spontaneous ventilation for a minimum of 10 mins with an enoximone infusion running. During spontaneous ventilation, enoximone increased cardiac index by 34% but mean artery, right atrial, and pulmonary artery occlusion pressures did not change. Despite an increase in venous admixture due to augmented cardiac index and inhibition of hypoxic vasoconstriction, no oxygen debt occurred because oxygen delivery increased. Seven of nine patients were weaned successfully from mechanical ventilation. Because of its positive inotropic and vasodilatory properties, enoximone is helpful for respiratory weaning of patients with left ventricular failure after cardiac surgery.

Pulmonary Hypertension and Cor Pulmonale*

This article is directed primarily to primary care physicians. The challenge is to suspect, diagnose, and treat pulmonary arterial hypertension when treatment is most effective and before the effects of cor pulmonale become fully manifested. A good history and physical examination should be followed by electrocardiographic and roentgenographic evaluations. Of additional value are arterial blood gas measurements, two-dimensional echocardiography, first-pass radionuclide angiography, and catheterization of the right ventricle. Chronic obstructive pulmonary disease (COPD) is one of the more common etiologies of pulmonary hypertension and cor pulmonale. COPD is most common in the elderly and cor pulmonale is fairly common among those with COPD; therefore, hypoxic pulmonary hypertension and the resultant cor pulmonale occur mostly in older patients. Because early signs are nonspecific, diagnosis and treatment are often delayed until the pulmonary disorder is severe. Thus it is imperative that the primary care physician be cognizant of this serious problem. Standard treatment of left ventricular failure (ie, "congestive heart failure") could have adverse effects in patients with cor pulmonale.

Myocardial Protection: Role of Vasoactive Drugs

A wide array of vasoactive agents is now available to the anesthesiologist for protection from and treatment of perioperative myocardial ischemia. Different anesthetic techniques have varying effects on the cardiovascular system, the coronary circulation, and myocardial contractile function. To recommend the use of vasoactive agents in the prevention or treatment of intraoperative myocardial ischemia based on their actions in unanesthetized patients or experimental models, and without considering the consequences of the anesthetic technique employed, would seem imprudent and may lead to worsening of ischemia. Finally, right ventricular physiology and pathophysiology is significantly different from left ventricular physiology, and thus, it is not surprising that treatment of acute right ventricular failure requires interventions that differ significantly from treatment of left ventricular failure.

First-Line Treatment of Left Ventricular Failure Complicating Acute Myocardial Infarction

A prospective randomised trial compared the immediate haemodynamic effects of intravenous diuretic (frusemide), venodilator (isosorbide dinitrate), arteriolar dilator (hydralazine), and positive inotropic stimulation (prenalterol) as first-line therapy for acute left ventricular (LV) failure following myocardial infarction. Forty-eight patients with transmural myocardial infarction and a pulmonary artery occluded pressure (PAOP) of greater than 20 mm Hg were studied within 18 h of admission to a coronary care unit. Both frusemide (-4 mm Hg; p less than 0.01) and isosorbide dinitrate (-6 mm Hg; p less than 0.01) reduced LV filling pressure without change in cardiac index and heart rate. Although both hydralazine and prenalterol increased cardiac index (p less than 0.01), the reduction in LV filling pressure (-2 mm Hg; p less than 0.05) was less than with frusemide and isosorbide dinitrate, and was associated with an increased heart rate (+8 and +13 beats min-1; p less than 0.01). These data suggest that in acute heart failure following myocardial infarction the four treatment modalities could be ranked in descending order of potential benefit as follows: venodilatation (isosorbide dinitrate)--decrease of LV pressure/work; diuretic therapy (frusemide)--decrease of LV pressure/work offset by a transient pressor effect; arteriolar dilatation (hydralazine)--decrease of LV pressure/work and of PAOP, but offset by tachycardia; and positive inotropic therapy (beta 1-agonist prenalterol)--tachycardia and augmented LV afterload. Combination of the former and latter agents, because of their differing modes of action, should offer haemodynamic advantages over monotherapy and deserves further evaluation.

Neonatal pulmonary hypertension: pathophysiologic-based therapy.

AbstractRational management of pulmonary artery hypertension (PAH) in the newborn infant must be based on an understanding of underlying causes. When a specific diagnosis can be made, empirical treatment gives way to specific therapy. For every pathophysiologic abnormality potentially resulting in PAH, clinical entities can be identified and key therapeutic interactions can be considered.1. Pulmonary Venous Hypertension: PAH is secondary to obstruction of blood flow through the left heart. If based on anatomic abnormality (mitral or left atrial), surgical relief of obstruction is required. If PAH is the result or functional abnormality of the left ventricle (transient left ventricular ischemia), medical treatment of left ventricular failure is most important.2. Functional Obstruction of Pulmonary Vascular Bed: Hyperviscosity of blood (polycythemia ‐ HCT &gt; 65) results in increased pulmonary vascular resistance. Treatment consists of reduction of red blood cell volume.3. Pulmonary Vascular Constriction: Hypoxemia with or without pulmonary parenchymal disease (primary or secondary persistent fetal circulation [PFC] syndrome). Therapy is directed at improvement of oxygenation and dilatation of pulmonary arteriolar bed (e.g. O2 hyperventilation and/or pulmonary vasodilator therapy).4. Decreased Pulmonary Vascular Bed: If primary pulmonary hypoplasia is present, no treatment is available. If secondary form (diaphragmatic hernia), surgical repair and pulmonary vasodilatation of contralateral lung is indicated. Extracorporeal membrane oxygenation (ECMO) can be used in severe cases.5. Increased pulmonary blood flow: Causes in the neonate include complex heart disease without pulmonary stenosis; and peripheral A—V fistula. Treatment: Surgical limitation of pulmonary blood flow may be required.Even when PAH is the result of combined etiologies, a prompt well‐organized clinical management plan can follow from understanding of pathologic principles.

Isosorbide 5-mononitrate in the treatment of left ventricular failure following acute myocardial infarction.

Eleven patients with acute left ventricular failure following acute myocardial infarction (mean pulmonary capillary wedge pressure [PCW]>20 20 mmHg) were entered into an open, haemodynamic study of oral isosorbide-5-mononitrate (ISMN). Left ventricular failure was resistant to intravenous diuretic therapy. No patient received concurrent cardioactive drugs nor further diuretic therapy during the study period. Haemodynamic data were acquired via a flow-directed thermodilution catheter placed in the pulmonary artery. Baseline data were acquired prior to the intravenous administration of an ISMN challenge. Thereafter, oral ISMN (20 mg, 8 hourly) was administered over 48 h.

Management of Acute Myocardial Infarction

This article presents plans of therapy based on current knowledge of pathophysiologic mechanisms, taking into consideration the rapid changes in availability of new drugs (or new experiences with old drugs) and new therapeutic interventions. Persistence of ischemic pain in the acute phase, or its recurrence during early convalescence, is a signal of a high-risk state for additional coronary events, and aggressive measures are required to prevent them. The indications, and the role of invasive hemodynamic monitoring in the treatment of left ventricular failure and/or hypotension, are discussed.

Isosorbide Mononitrate in the Treatment of Left Ventricular Failure Following Acute Myocardial Infarction

Isosorbide Mononitrate in the Treatment of Left Ventricular Failure Following Acute Myocardial Infarction

Intravenous use of amrinone for the treatment of the failing heart

Amrinone, a new nonadrenergic, nonglycosidic agent with combined positive inotropic and vasodilating properties, was approved recently for parenteral use in the treatment of left ventricular failure. Its mechanism of action is mediated primarily by selective phosphodiesterase fraction III inhibition, although at high doses alterations of calcium transport may occur. Acute hemodynamic changes produced by amrinone include augmentation of cardiac output and decreases in pulmonary capillary wedge pressure, right atrial pressure and systemic vascular resistance. Heart rate and blood pressure remain unaltered. Myocardial oxygen consumption declines concomitantly with the decrease in systolic wall tension. The efficacy of amrinone is comparable to that of dobutamine and dopamine. Synergistic interactions with catecholamines and vasodilators are described. Adverse effects are minimal, with dosage limited predominantly by decreases in filling pressures.

Hydralazine in the management of left ventricular failure

This study was designed to compare the short and long-term effects of hydralazine when used as a vasodilator in the treatment of left ventricular failure. The hemodynamic changes after the acute intravenous and long-term oral administration of hydralazine were compared in a group of 16 patients with left ventricular failure (14 patients with congestive cardiomyopathy and two with hypertensive heart failure). After 20 mg of hydralazine, administered intravenously there was a 56 percent increase in stroke volume ( P < 0.001) and a 27 percent decrease in left ventricular filling pressure ( P < 0.001) but no significant change in heart rate despite a 16 percent decrease in mean arterial pressure ( P < 0.001). Seven of the patients then took hydralazine, 200 to 300 orally/day for 4 to 6 weeks. They were restudied during therapy with the drug and again 48 to 72 hours after stopping it. After the period of oral treatment there was a 71 percent increase in stroke volume ( P < 0.001) and a 25 percent decrease in left ventricular filling pressure ( P < 0.05). Forty-eight to 72 hours after discontinuation of drug administration, left ventricular filling pressure had returned to the control value (−3 percent, P < 0.05), but the stroke volume was still slightly elevated (14 percent, P < 0.05). The results show that oral administration of hydralazine can produce sustained benefit with changes similar to those induced by intravenous administration. The second control study after discontinuation of hydralazine therapy confirmed that these changes had been induced by and were dependent on the drug.

Orally administered isosorbide dinitrate in patients with and without left ventricular failure due to acute myocardial infarction

The oral effectiveness of 10 mg followed by 20 mg of isosorbide dinitrate in 21 patients with acute mycardial infarction was studied over a period of 13 hours. The patients were grouped according to initial left ventricular filling pressure: group I, pressure less than 20 mm Hg, and group II, pressure more than 20 mm Hg. Patients in group II had left ventricular failure. In both groups isosorbide dinitrate resulted in a significant decrease in pulmonary arterial pressure. The left ventricular filling pressure decreased in group I from 13.6 +/- 4.0 to 7.1 +/- 2.6 mm Hg (mean +/- 1 standard deviation) and in group II from 26.9 +/- 4.6 to 19.0 +/- 3.6 mm Hg (P less than 0.001). Cardiac output decreased in group I from 5.1 +/- 1.0 to 4.5 +/- 0.9 liters/min, whereas in group II it increased significantly from 3.5 +/- 0.8 to 4.1 to 0.9 liters/min (P less than 0.001). In both groups, peripheral arterial blood pressure decreased (P less than 0.60). Heart rate remained constant. Whether cardiac output increased or decreased was found to be dependent on the initial left ventricular filling pressure. In patients with an initially high value (above 20 mm Hg), the increase in cardiac output is probably due to the reduction of afterload. An additional factor may be the decrease in left ventricular filling pressure, which leads to an improved blood supply in the affected mural segments as a result of the decrease in the extravascular component of the coronary resistance. Significant changes in cardiac output and left ventricular filling pressure were achieved 3 to 5 hours after oral administration of isosorbide dinitrate. Clinical signs of failure were less pronounced. Isosorbide dinitrate is, therefore, a therapeutic agent in the treatment of left ventricular failure due to acute myocardial infarction.

Experimental myocardial infarction. VI. Efficacy and toxicity of digitalis in acute and healing phase in intact conscious dogs.

Use of digitalis in myocardial infarction is controversial. To determine the efficacy and toxic threshold, serial infusions of 3 mug/kg per min of acetyl-strophanthidin were given to six intact conscious dogs 24 hr before and 1 hr, 2 days, and 7 days after myocardial infarction induced by inflation of a balloon cuff implanted on the left anterior descending coronary artery. Within 1 hr after myocardial infarction, heart rate increased by 28%. Left ventricular end-diastolic pressure increased from 7 to 20 mm Hg, and stroke volume decreased by 25%. At this time acetylstrophanthidin caused no beneficial hemodynamic change, 1 wk later, the heart rate and left ventricular end-diastolic pressure had declined toward normal but remained elevated. At this time, acetylstrophanthidin lowered left ventricular end-diastolic pressure by 25%, and increased the stroke volume and cardiac output by 25% and 21% respectively, without any change in heart rate or aortic pressure. Tolerance to acetylstrophanthidin, defined as appearance of ventricular tachycardia, declined the 1st hr after myocardial infarction by 24% (P<0.05) from the control level of 43 +/-4 mug/kg (SEM), but subsequently returned to control.Thus, immediately after myocardial infarction, tolerance to acetylstrophanthidin was reduced, and left ventricular failure was not ameliorated. 1 wk later in the healing phase of myocardial infarction, tolerance to acetylstrophanthidin returned to normal and left ventricular performance was improved by this drug. The study suggests a limited therapeutic role for digitalis in the treatment of left ventricular failure in the acute phase immediately after myocardial infarction, but beneficial effects may occur in the healing phase 1 wk later.