Left Ventricular Pump Dysfunction Research Articles

CARDIOPULMONARY SUPPORT WITH EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO) DURING CATHETER ABLATION OF VENTRICULAR FIBRILLATION: A CASE REPORT

Abstract The clinical case deals with a 46–year–old man, severely obese and suffering from type II diabetes mellitus and arterial hypertension, a smoker. He was admitted to our department for iterative ventricular fibrillation (VF) following a recent acute myocardial infarction with ST–segment elevation treated with percutaneous coronary angioplasty (PTCA) and implantation of drug–eluting stents on the anterior interventricular. Control coronary angiography showed good results of previous PTCA. On the echocardiogram, left ventricular pump function moderately reduced (EF 45%) with district alterations of the kinetics and aneurysmal dilatation of the ascending aorta. During hospitalization, iterative episodes of VF despite maximal antiarrhythmic therapy, promptly treated with DC shock. Continuous telemetry monitoring showed frequent early premature ventricular complex (PVC) triggering VF episodes. A 12–lead Holter ECG was performed to better identify the morphology of these PVC, documenting PVC of morphology compatible with origin from Purkinjie fibres. An electrophysiological study and mapping of the left ventricle were performed with extracorporeal membrane oxygenation (ECMO) support. During mapping of the middle left interventricular septum, VF occurred several times and was promptly treated with DC shock. In this area have been documented Purkinje fibers and low voltage and multifragmented areas; ablation was then performed by delivering radiofrequency in this area until the all potentials were completely eliminated. After ablation, no more ventricular arrhythmias were induced. Cardiac magnetic resonance imaging was performed which showed large areas of late gadolinium enhancement. The patient underwent automatic defibrillator implantation. Ventricular arrhythmias were no longer documented during telemetric monitoring. In this complex case of significant arrhythmic instability in ischemic heart disease with moderate left ventricular pump dysfunction, ECMO assistance allowed us to effectively and safely perform the ablation of the arrhythmic substrate triggering the iterative episodes of VF.

Decreased ATP production and myocardial contractile reserve in metabolic heart disease

Metabolic syndrome is a cluster of obesity-related metabolic abnormalities that lead to metabolic heart disease (MHD) with left ventricular pump dysfunction. Although MHD is thought to be associated with myocardial energetic deficiency, two key questions have not been answered. First, it is not known whether there is a sufficient energy deficit to contribute to pump dysfunction. Second, the basis for the energy deficit is not clear. To address these questions, mice were fed a high fat, high sucrose (HFHS) ‘Western’ diet to recapitulate the MHD phenotype. In isolated beating hearts, we used 31P NMR spectroscopy with magnetization transfer to determine a) the concentrations of high energy phosphates ([ATP], [ADP], [PCr]), b) the free energy of ATP hydrolysis (∆G~ATP), c) the rate of ATP production and d) flux through the creatine kinase (CK) reaction. At the lowest workload, the diastolic pressure-volume relationship was shifted upward in HFHS hearts, indicative of diastolic dysfunction, whereas systolic function was preserved. At this workload, the rate of ATP synthesis was decreased in HFHS hearts, and was associated with decreases in both [PCr] and ∆G~ATP. Higher work demands unmasked the inability of HFHS hearts to increase systolic function and led to a further decrease in ∆G~ATP to a level that is not sufficient to maintain normal function of sarcoplasmic Ca2+-ATPase (SERCA). While [ATP] was preserved at all work demands in HFHS hearts, the progressive increase in [ADP] led to a decrease in ∆G~ATP with increased work demands. Surprisingly, CK flux, CK activity and total creatine were normal in HFHS hearts. These findings differ from dilated cardiomyopathy, in which the energetic deficiency is associated with decreases in CK flux, CK activity and total creatine. Thus, in HFHS-fed mice with MHD there is a distinct metabolic phenotype of the heart characterized by a decrease in ATP production that leads to a functionally-important energetic deficiency and an elevation of [ADP], with preservation of CK flux.

Inhibition of class I histone deacetylase activity represses matrix metalloproteinase-2 and -9 expression and preserves LV function postmyocardial infarction.

Left ventricular (LV) remodeling, after myocardial infarction (MI), can result in LV dilation and LV pump dysfunction. Post-MI induction of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated as causing deleterious effects on LV and extracellular matrix remodeling in the MI region and within the initially unaffected remote zone. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We assessed the efficacy of both class I/IIb- and class I-selective HDAC inhibitors on MMP-2 and MMP-9 abundance and determined if treatment resulted in the attenuation of adverse LV and extracellular matrix remodeling and improved LV pump function post-MI. MI was surgically induced in MMP-9 promoter reporter mice and randomized for treatment with a class I/IIb HDAC inhibitor for 7 days post-MI. After MI, LV dilation, LV pump dysfunction, and activation of the MMP-9 gene promoter were significantly attenuated in mice treated with either the class I/IIb HDAC inhibitor tichostatin A or suberanilohydroxamic acid (voronistat) compared with MI-only mice. Immunohistological staining and zymographic levels of MMP-2 and MMP-9 were reduced with either tichostatin A or suberanilohydroxamic acid treatment. Class I HDAC activity was dramatically increased post-MI. Treatment with the selective class I HDAC inhibitor PD-106 reduced post-MI levels of both MMP-2 and MMP-9 and attenuated LV dilation and LV pump dysfunction post-MI, similar to class I/IIb HDAC inhibition. Taken together, these unique findings demonstrate that selective inhibition of class I HDACs may provide a novel therapeutic means to attenuate adverse LV remodeling post-MI.

Reply to “Letter to the editor: ‘Cyclosporin A in left ventricular remodeling after myocardial infarction’”

Reply to “Letter to the editor: ‘Cyclosporin A in left ventricular remodeling after myocardial infarction’”

Invited Commentary

Invited Commentary

Prevention of Myofilament Dysfunction by β-Blocker Therapy in Postinfarct Remodeling

Myofilament contractility of individual cardiomyocytes is depressed in remote noninfarcted myocardium and contributes to global left ventricular pump dysfunction after myocardial infarction (MI). Here, we investigated whether beta-blocker therapy could restore myofilament contractility. In pigs with a MI induced by ligation of the left circumflex coronary artery, beta-blocker therapy (bisoprolol, MI+beta) was initiated on the first day after MI. Remote left ventricular subendocardial biopsies were taken 3 weeks after sham or MI surgery. Isometric force was measured in single permeabilized cardiomyocytes. Maximal force (F(max)) was lower, whereas Ca(2+) sensitivity was higher in untreated MI compared with sham (both P<0.05). The difference in Ca(2+) sensitivity was abolished by treatment of cells with the beta-adrenergic kinase, protein kinase A. beta-blocker therapy partially reversed F(max) and Ca(2+) sensitivity to sham values and significantly reduced passive force. Despite the lower myofilament Ca(2+) sensitivity in MI+beta compared with untreated myocardium, the protein kinase A induced reduction in Ca(2+) sensitivity was largest in cardiomyocytes from myocardium treated with beta-blockers. Phosphorylation of beta-adrenergic target proteins (myosin binding protein C and troponin I) did not differ among groups, whereas myosin light chain 2 phosphorylation was reduced in MI, which coincided with increased expression of protein phosphatase 1. beta-blockade fully restored the latter alterations and significantly reduced expression of protein phosphatase 2a. beta-blockade reversed myofilament dysfunction and enhanced myofilament responsiveness to protein kinase A in remote myocardium after MI. These effects likely contribute to the beneficial effects of beta-blockade on global left ventricular function after MI.

Exercise After Myocardial Infarction Improves Contractility and Decreases Myofilament Ca 2+ Sensitivity

See related article, pages 1079–1088 While myocardial infarction (MI) is the major cause of heart failure, there are conflicting data over the roles of abnormal calcium handling and myofilament function. The acute injury leads to the activation of neurohormones and cytokines, subsequent myocardial remodelling, further decline in heart function, and finally overt heart failure. Depressed myocyte contractility in the remodelled myocardium can largely be explained by Ca2+ handling abnormalities.1 Abnormalities in myofilament function are less well understood. A seminal study in pigs demonstrated that impaired pump function three weeks after MI can also be attributed to decreased maximal isometric tension in skinned cardiomyocytes in areas remote from the ischemic border zone.2 Somewhat paradoxically, the impairment occurred in the context of increased Ca2+ sensitivity of the myofilaments. The authors attributed the increased Ca2+ sensitivity following MI to reduced protein kinase A-mediated troponin I (TnI) phosphorylation.2 Increased myofilament Ca2+ sensitivity has also been reported for end-stage human heart failure, apparently largely because of a reduction of TnI phosphorylation.3 One of the most effective and least expensive therapies for cardiovascular disease is exercise. Clinical studies generally show a benefit of exercise training and a reduction of cardiac mortality after MI by 26%.4 The question remains of how soon to start exercising, especially after a large MI. In several clinical5 and animal6,7 studies, there were detrimental consequences when exercise began immediately after an MI. In the current issue of Circulation Research , de Waard et al8 present remarkable data addressing the question of exercise training early post MI. After a large MI, mice were subjected to 8 weeks of “voluntary” exercise training. Exercise had no detrimental effects on mortality and minimal effects on myocardial hypertrophy and left ventricular remodelling. Furthermore, there …

Early Exercise Training Normalizes Myofilament Function and Attenuates Left Ventricular Pump Dysfunction in Mice With a Large Myocardial Infarction

The extent and mechanism of the cardiac benefit of early exercise training following myocardial infarction (MI) is incompletely understood, but may involve blunting of abnormalities in Ca(2+)-handling and myofilament function. Consequently, we investigated the effects of 8-weeks of voluntary exercise, started early after a large MI, on left ventricular (LV) remodeling and dysfunction in the mouse. Exercise had no effect on survival, MI size or LV dimensions, but improved LV fractional shortening from 8+/-1 to 12+/-1%, and LVdP/dt(P30) from 5295+/-207 to 5794+/-207 mm Hg/s (both P<0.05), and reduced pulmonary congestion. These global effects of exercise were associated with normalization of the MI-induced increase in myofilament Ca(2+)-sensitivity (DeltapCa(50)=0.037). This effect of exercise was PKA-mediated and likely because of improved beta(1)-adrenergic signaling, as suggested by the increased beta(1)-adrenoceptor protein (48%) and cAMP levels (36%; all P<0.05). Exercise prevented the MI-induced decreased maximum force generating capacity of skinned cardiomyocytes (F(max) increased from 14.3+/-0.7 to 18.3+/-0.8 kN/m(2) P<0.05), which was associated with enhanced shortening of unloaded intact cardiomyocytes (from 4.1+/-0.3 to 7.0+/-0.6%; P<0.05). Furthermore, exercise reduced diastolic Ca(2+)-concentrations (by approximately 30%, P<0.05) despite the unchanged SERCA2a and PLB expression and PLB phosphorylation status. Importantly, exercise had no effect on Ca(2+)-transient amplitude, indicating that the improved LV and cardiomyocyte shortening were principally because of improved myofilament function. In conclusion, early exercise in mice after a large MI has no effect on LV remodeling, but attenuates global LV dysfunction. The latter can be explained by the exercise-induced improvement of myofilament function.

Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic β-adrenoreceptor activation

There is no direct evidence to indicate that pump dysfunction in a dilated chamber reflects the impact of chamber dilatation rather than the degree of intrinsic systolic failure resulting from myocardial damage. In the present study, we explored the relative roles of intrinsic myocardial systolic dysfunction and chamber dilatation as mediators of left ventricular (LV) pump dysfunction. Administration of isoproterenol, a beta-adrenoreceptor agonist, for 3 mo to rats (0.1 mg.kg(-1).day(-1)) resulted in LV pump dysfunction as evidenced by a reduced LV endocardial fractional shortening (echocardiography) and a decrease in the slope of the LV systolic pressure-volume relation (isolated heart preparations). Although chronic beta-adrenoreceptor activation induced cardiomyocyte damage (deoxynucleotidyl transferase-mediated dUTP nick-end labeling) as well as beta(1)- and beta(2)-adrenoreceptor inotropic downregulation (attenuated contractile responses to dobutamine and salbutamol), these changes failed to translate into alterations in intrinsic myocardial contractility. Indeed, LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress-strain relation (isolated heart preparations) were unchanged. A normal intrinsic myocardial systolic function, despite the presence of cardiomyocyte damage and beta-adrenoreceptor inotropic downregulation, was ascribed to marked increases in myocardial norepinephrine release, to upregulation of alpha-adrenoreceptor-mediated contractile effects as determined by phenylephrine responsiveness, and to compensatory LV hypertrophy. LV pump failure was attributed to LV dilatation, as evidenced by increased LV internal dimensions (echocardiography), and a right shift and increased volume intercept of the LV diastolic pressure-volume relation. In conclusion, chronic sympathetic stimulation, despite reducing beta-adrenoreceptor-mediated inotropic responses and promoting myocyte apoptosis, may nevertheless induce pump dysfunction primarily through LV dilatation, rather than intrinsic myocardial systolic failure.

Mechanical Device–Based Methods of Managing and Treating Heart Failure

Despite advances in pharmacological treatments aimed at neurohormonal blockade for heart failure in the setting of left ventricular pump dysfunction, there is still a growing number of patients with advanced symptoms who suffer significant morbidity and mortality. Mechanical stresses and chronic neurohormonal activation conspire to propagate maladaptive ventricular remodeling responsible for the insidious nature of this disease. Recent studies suggest that further pharmacological neurohormonal blockade may not be safe or effective, which has driven development of devices for this patient population. Furthermore, such devices may target fundamental pathophysiological abnormalities that are largely hemodynamic and mechanical in nature that are not addressed by available pharmacological agents. The profound reverse remodeling routinely associated with left ventricular assist device use, reviewed in detail, further validates device-based approaches and should inspire research to find ways to make this recovery more complete and permanent. Accordingly, this review focuses on the multitude of mechanical device-based approaches currently being investigated to manage and treat this population. From devices for monitoring patient status to anticipate congestive heart failure exacerbations and preemptively adjust therapy to devices to support preterminal patients with end-stage disease, it is recognized that these device-based approaches will assume an increasingly important role in treating the growing number of patients with advanced heart failure.

Beta-adrenergic activation initiates chamber dilatation in concentric hypertrophy.

It is uncertain whether chronic beta-adrenoreceptor (beta-AR)-activation in hypertension could initiate the progression from compensated left ventricular (LV) hypertrophy to pump dysfunction. It is also uncertain if this effect is through adverse LV remodeling (chamber dilatation with wall thinning and pump dysfunction) or intrinsic myocardial contractile dysfunction. We evaluated the effect of 5 months of isoprenaline (0.02 mg x kg(-1) x d(-1)) on hemodynamics, LV wall thickness, cavity size, and interstitial characteristics in spontaneously hypertensive rats (SHR) with compensated LV hypertrophy. In the absence of myocyte necrosis, changes in volume preload, pressure afterload, and heart rate or decreases in baseline systolic myocardial elastance (load independent measure of intrinsic myocardial contractility), ISO produced a right shift in LV diastolic pressure-volume (P-V) relations (chamber dilatation), a decrease in LV wall thickness despite a further increase in LV weight in SHR, LV pump dysfunction (right shift in LV systolic P-V relations), and deleterious interstitial remodeling (increments in total and noncrosslinked myocardial collagen concentrations). The isoprenaline-induced LV geometric, chamber performance, and interstitial changes were similar to alterations noted during decompensation in older SHR. In summary, in the absence of tissue necrosis and baseline intrinsic myocardial contractile dysfunction, chronic beta-AR activation induces interstitial and chamber remodeling and, hence, pump dysfunction. These data suggest that chronic sympathetic activation initiates the progression from compensated concentric LV hypertrophy in hypertension to cardiac dysfunction primarily through deleterious cardiac remodeling rather than intrinsic myocardial contractile dysfunction.

Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective.

A milestone in the progression of congestive heart failure (CHF) is myocardial remodeling. Left ventricular (LV) remodeling during the progression of CHF is accompanied by changes in the structure of the myocardial extracellular matrix. Recent clinical and experimental studies have noted that increased release of tumor necrosis factor alpha (TNF-alpha) can contribute to LV myocardial remodeling. Experimental studies have noted that the induction of TNF-alpha can result in LV dilation and proceed to LV pump dysfunction. The biological effects of TNF-alpha are mediated through TNF receptors that are present on all nucleated cells in the heart. TNF receptor activation can induce a number of cellular and molecular events which contribute to LV remodeling in CHF, and include changes in myocyte size and viability and alterations in myocardial structure/composition. In vitro studies have demonstrated that TNF receptor activation can cause the induction of a proteolytic system. This proteolytic system, the matrix metalloproteinases (MMPs), is upregulated in models of LV dysfunction and possesses the capacity to degrade a wide variety of extracellular matrix components. Therefore, one pathway by which TNF-alpha can influence LV myocardial remodeling is through the induction of a specific portfolio of MMP species. Future basic and clinical studies which directly alter TNF receptor activity and measure myocardial MMP species and the relation to LV remodeling will provide new insight into this disease process and future therapeutic modalities.

Relationship between external load and isolated myocyte contractile function with CHF in pigs.

Past studies have demonstrated that the negative relationship between afterload and contractile performance of papillary muscles is shifted downward and to the left with the development of hypertrophy. However, it remained unclear whether a similar load-contractility relationship could be constructed for isolated myocytes, particularly with the development of congestive heart failure (CHF). Accordingly, the effect of incrementally increased external loads on the contractile performance of left ventricular (LV) myocytes isolated from pigs in the normal state (n = 5) and after the development of chronic supraventricular tachycardia (SVT)-induced CHF (SVT-CHF; 240 beats/min, 3 wk; n = 5) was examined. This study used precalibrated microspheres to impose a quantifiable load on isolated myocytes, and myocyte contractility was assessed by videomicroscopy. Steady-state unloaded extent of shortening was 5.4 +/- 0.2 microns in control myocytes (n = 80) and was significantly reduced in the myocytes with the development of SVT-CHF (4.4 +/- 0.2 microns, n = 93; P < 0.05). Inverse relationships between relative resistive load and myocyte contractile function were observed at both normal and CHF states (r2 > 0.85). For myocyte velocity of shortening, the slope of this relationship was significantly reduced in the SVT-CHF state compared with controls (-46.3 x 10(-6) and -34.6 x 10(-6) microns3.microN-1.s-1, respectively; P < 0.05). At higher relative resistive loads (> 0.18 x 10(-6) microN/microns2), the reduction in myocyte shortening extent under an equivalent relative resistive load was significantly greater in the SVT-CHF myocytes compared with controls (62.8 +/- 3.9 vs. 45.6 +/- 4.7%, respectively, P < 0.05). The present study demonstrated for the first time that a load-dependent relationship can be derived for intact isolated LV myocytes in both normal and CHF states. The defect in the capacity of SVT-CHF myocytes to respond to an increased relative resistive load is a likely contributory mechanism for the LV pump dysfunction that occurs in this model of CHF.

Tumor necrosis factor-? and tumor necrosis factor receptors in human heart failure

The basic mechanisms that are responsible for the development and progression of congestive heart failure are not known. Although clinicians have traditionally viewed heart failure as a hemodynamic disorder related to left ventricular pump dysfunction, one of the more recent concepts that has emerged is that the development and progression of heart failure is attributable, at least in part, to the overexpression of biologically active molecules that can contribute both to patient symptomatology as well as to disease progression. In this regard, one of the more recent interesting and intriguing observations in clinical heart failure research is the finding that a proinflammatory cytokine, termed tumor necrosis factor-α (TNF-α), is expressed in patients with heart failure. Accordingly, the focus of the present brief review is to summarize recent clinical and experimental observations that implicate the elaboration of TNF-α and TNF receptors in the progression of human heart failure.

Determinants of circulatory response to intravenous hydralazine in congestive heart failure

To determine whether the circulatory response to hydralazine in heart failure is influenced by initial hemodynamic status or left ventricular (LV) chamber size, 28 patients with chronic LV dysfunction were studied. Hemodynamic measurements and echocardiographic LV end-diastolic dimension were correlated with the response to 20 mg of intravenous hydralazine and to a dose titrated in each patient to reduce systemic resistance by ≥ 20%. Hydralazine, 20 mg, decreased systemic resistance from 23 ± 8 to 18 ± 8 U(p < 0.01) and increased the cardiac index from 2.0 ± 0.5 to 2.5 ± 0.6 liters/min/m 2 (p < 0.01) and the stroke work index from 21 ± 11 to 24 ± 9 g · m/m 2 (p < 0.05). Titrating the dose to decrease systemic resistance by ≥ 20% increased the cardiac index further to 2.7 ± 0.6 liters/min/m 2 and the stroke work index to32 ± 9 g · m/m 2. The change in systemic resistance produced by 20 mg of hydralazine correlated only with initial systemic resistance (r = 0.53), suggesting that vascular response to hydralazine is a direct function of initial vascular resistance. The percentage change in stroke work index produced by 20 mg of hydralazine correlated directly with indexes of LV preloadend-diastolic wall stress (r = 0.69) and pulmonary wedge pressure (r = 0.43) and inversely with stroke work index (r = −0.49), an index of ventricular work. Similar but less close correlations were observed when the dose of hydralazine was titrated. The hemodynamic response to hydralazine did not correlate with LV end-diastolic dimension or right atrial pressure. Thus, vascular response to moderate doses of hydralazine is related to initial systemic vascular resistance. LV pump response is related to the level of initial LV pump dysfunction but not to LV chamber size or right atrial pressure.

Hemodynamic evaluation of exercise-induced ST-segment depression and elevation in ischemic heart disease. Left ventricular cineangiography during exercise.

In order to elucidate the hemodynamic significance of exercise-induced ST-segment shifts in ischemic heart disease, left ventricular cineangiography was carried out in 41 patients at rest and during supine bicycle ergometer exercise. These patients were divided into 2 groups, that is, a normal coronary artery group (6 patients), having neither significant coronary artery stenosis nor exercise-induced ST-segment shifts, and a diseased group (35 patients) having significant coronary artery stenosis (inner-diameter stenosis greater than or equal to 75%). The latter was further divided into 3 subgroups according to exercise-induced ST-segment shifts: ST-unchanged group (17 patients), ST-depression group (11 patients) and ST-elevation group (7 patients). In the normal coronary artery and ST-unchanged groups, exercise produced an increase in left ventricular end-diastolic volume index (LVEDVI), a decrease in left ventricular end-systolic volume index (LVESVI) and increases in stroke index and ejection fraction. In the ST-depression group, the appearance or aggravation of left ventricular wall motion abnormality was induced at the site of coronary artery stenosis by exercise in 9 patients. Both LVEDVI and LVESVI increased, stroke index remained unchanged, and ejection fraction decreased during exercise. In the ST-elevation group, ST-segment elevation was induced in leads with abnormal Q waves. In 2 patients, exercise induced aggravation of wall motion abnormality at the infarctional segment. LVESVI increased, but LVEDVI showed little increase, and stroke index and ejection fraction tended to decrease during exercise. In the ST-depression group, exercise-induced left ventricular pump dysfunction was due to lowered contractility (increased LVESVI) caused by transient myocardial ischemia. In the ST-elevation group, exercise-induced pump dysfunction was mainly due to lowered contractility, and in some of them, the findings suggested that transient myocardial ischemia at or around the region of infarction might be the cause of pump dysfunction. In addition, a poor compensatory effect of the Frank-Starling mechanism seemed to play a role in the onset of such dysfunction in this group.