The Acorn CorCap Cardiac Support Device (CSD; Acorn Cardiovascular Inc, St. Paul, MN) is a woven polyester jacket that is placed around the heart and designed to reverse the progressive remodeling associated with dilated cardiomyopathy. However, the effects of the Acorn CSD on myofiber stress and ventricular function remain unknown. We tested the hypothesis that the Acorn CSD reduces end-diastolic (ED) myofiber stress.
A previously described weakly coupled biventricular finite element (FE) model and circulatory model based on magnetic resonance images of a dog with dilated cardiomyopathy was used. Virtual applications of the CSD alone (Acorn), CSD with rotated fabric fiber orientation (rotated), CSD with 5% prestretch (tight), and CSD wrapped only around the left ventricle (LV; LV-only) were performed, and the effect on myofiber stress at ED and pump function was calculated.
The Acorn CSD has a large effect on ED myofiber stress in the LV free wall, with reductions of 55%, 79%, 92%, and 40% in the Acorn, rotated, tight, and LV-only cases, respectively. However, there is a tradeoff in which the Acorn CSD reduces stroke volume at LV end-diastolic pressure of 8 mm Hg by 23%, 25%, 30%, and 7%, respectively, in the Acorn, rotated, tight, and LV-only cases.
The Acorn CSD significantly reduces ED myofiber stress. However, CSD wrapped only around the LV was the only case with minimal negative effect on pump function. Findings suggest that LV-only CSD and Acorn fabric orientation should be optimized to allow maximal myofiber stress reduction with minimal reduction in pump function.
To evaluate the impact of long term cardiac resynchronisation therapy (CRT) on left atrial and left ventricular (LV) reverse remodelling and reversal to sinus rhythm (SR) in patients with heart failure with atrial fibrillation (AF).
74 consecutive patients (age 68 (8) years; 67 men) with advanced heart failure and AF (20 persistent and 54 permanent) were implanted with a CRT device.
Main outcome measures
Patients were evaluated clinically (New York Heart Association (NYHA) class, quality of life, six minute walk test) and echocardiographically (LV ejection fraction, LV diameters, and left atrial diameters) before and after six months of CRT. Additionally, restoration of SR was evaluated after six months of CRT.
NYHA class, quality of life score, six minute walk test, and LV ejection fraction had improved significantly after six months of CRT. In addition, left atrial and LV end diastolic and end systolic diameters had decreased from 59 (9) to 55 (9) mm, from 72 (10) to 67 (10) mm, and from 61 (11) to 56 (11) mm, respectively (all p < 0.01). During implantation 18 of 20 (90%) patients with persistent AF were cardioverted to SR. At follow up 13 of 18 (72%) patients had returned to AF and none had spontaneously reverted to SR; thus, only 5 of 74 (7%) were in SR.
Six months of CRT resulted in significant clinical benefit with significant left atrial and LV reverse remodelling. Despite these beneficial effects, 93% of patients had not reverted to SR.
cardiac resynchronisation therapy; atrial fibrillation; heart failure
Autonomic abnormalities exist in heart failure (HF) and contribute to disease progression. Activation of the Carotid sinus baroreflex (CSB) has been shown to reduce sympathetic outflow and augment parasympathetic vagal tone. This study tested the hypothesis that long-term electrical activation of carotid sinus baroreflex improves left ventricular (LV) function and attenuates progressive LV remodeling in dogs with advanced chronic HF.
Methods and Results
Studies were performed in 14 dogs with coronary microembolization-induced HF (LV ejection fraction, EF ~25%). Eight dogs were chronically instrumented for bilateral CSB activation using the Rheos® System (CVRx® Inc., Minneapolis, MN) and 6 were not and served as controls. All dogs were followed for 3 months and none received other background therapy. During follow-up, treatment with CSB increased LV EF 4.0 ± 2.4 % compared to a reduction in control dogs of −2.8 ± 1.0% (p<0.05). Similarly, treatment with CSB decreased LV end-systolic volume −2.5 ± 2.7 ml compared to an increase in control dogs of 6.7 ± 2.9 ml (p<0.05). Compared to control, CSB activation significantly decreased LV end-diastolic pressure and circulating plasma norepinephrine, normalized expression of cardiac β1-adrenergic receptors, β-adrenergic receptor kinase and nitric oxide synthase and reduced interstitial fibrosis and cardiomyocyte hypertrophy.
In dogs with advanced HF, CSB activation improves global LV function and partially reverses LV remodeling both globally and at cellular and molecular levels.
heart failure; ventricular remodeling; gene expression; baroreflex function
Ventricular remodeling deteriorates myocardial function in congestive heart failure patients. Ventricular restraint therapy using Cardiac Support Device (CSD) is designed to reduce the amount of stress inside the dilated ventricles which in turn halts remodeling. However, as an open mesh surrounding the heart, it is unknown what the mechanical properties of the CSD are in different fiber orientations.
Composite specimens of CorCap™ CSD fabric and silicone were constructed in different fiber orientations and tested on a custom-built biaxial stretcher. Silicone controls were made and stretched to detect parameters of the matrix. CSD coefficients were calculated using the composite and silicone matrix stress-strain data. Stiffness in different fiber orientations was determined.
Silicone specimens exerted a linear behavior with stiffness of 2.57MPa. For the composites with one fiber set aligned with respect to the stretch axes, stiffness in the direction of the aligned fiber set was higher than that in the cross-fiber direction (14.39MPa vs. 5.66MPa), indicating greater compliance in the cross-fiber direction. When the orientation of the fiber sets in the composite were matched to the expected clinical orientation of the implanted CorCap, the stiffness in the circumferential axis (with respect to the heart) was greater than in the longitudinal axis (10.55MPa vs. 9.70MPa).
The mechanical properties of the CorCap demonstrate directionality with greater stiffness circumferentially than longitudinally. Implantation of CorCap clinically should take into account the directionality of the biomechanics to optimize ventricular restraint.
heart failure; mechanical properties; compliance; CorCap; cardiac support device
Adenosine (AD) elicits cardioprotection through A1-receptor (A1R) activation. Therapy with AD A1R agonists, however, is limited by undesirable actions of full agonism such as bradycardia. This study examined the effects of capadenoson (CAP), a partial AD A1R agonist, on left ventricular (LV) function and remodeling in dogs with heart failure (HF).
Methods and Results
12 dogs with microembolization-induced HF were randomized to 12 weeks oral therapy with CAP (7.5 mg Bid, n=6) or to no therapy (Control, n=6). LV end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction (EF), plasma norepinephrine (NE) and n-terminal pro-brain natriuretic peptide (nt-pro BNP) were measured before (PRE) and 1 and 12 weeks after therapy (POST). LV tissue obtained at POST was used to assess volume fraction of interstitial fibrosis (VFIF), SERCA-2a activity, expression of mitochondria uncoupling proteins (UCP) and glucose transporters (GLUT). In controls, EDV and ESV increased and EF decreased significantly from PRE to POST (EF: 30±2 vs. 27±1 %, p<0.05). In CAP-treated dogs, EDV was unchanged; EF increased significantly after one week (36±2 vs. 27±2 %, p<0.05) with a further increase at POST (39±2 %, p<0.05) while ESV decreased. CAP significantly decreased VFIF, normalized SERCA-2a activity and expression of UCP-2 and -3, and GLUT-1 and -2 and significantly decreased NE and nt-pro BNP.
In HF dogs, CAP improves LV function and prevents progressive remodeling. Improvement of LV systolic function occurs early after initiating therapy. The results support development of partial AD A1R agonists for the treatment of chronic HF.
Heart failure; Ventricular remodeling; Protein expression; Adenosine receptors
Heart failure (HF) is a global phenomenon, and the overall incidence and prevalence of the condition are steadily increasing. Medical therapies have proven efficacious, but only a small number of pharmacological options are in development. When patients cease to respond adequately to optimal medical therapy, cardiac resynchronization therapy has been shown to improve symptoms, reduce hospitalizations, promote reverse remodelling, and decrease mortality. However, challenges remain in identifying the ideal recipients for this therapy. The field of mechanical circulatory support has seen immense growth since the early 2000s, and left ventricular assist devices (LVADs) have transitioned over the past decade from large, pulsatile devices to smaller, more-compact, continuous-flow devices. Infections and haematological issues are still important areas that need to be addressed. Whereas LVADs were once approved only for ‘bridge to transplantation’, these devices are now used as destination therapy for critically ill patients with HF, allowing these individuals to return to the community. A host of novel strategies, including cardiac contractility modulation, implantable haemodynamic-monitoring devices, and phrenic and vagus nerve stimulation, are under investigation and might have an impact on the future care of patients with chronic HF.
Cardiac resynchronization therapy, when added to optimal medical therapy, increases longevity in symptomatic congestive heart failure patients with left ventricular ejection fractions (LVEF) ≤0.35 and QRS durations >120 ms. Cardiac resynchronization therapy is also associated with electrical and mechanical reverse remodeling. We examined whether reverse remodeling predicts increased survival rates in non-trial settings.
Recipients of cardiac resynchronization therapy and defibrillators (n=112; 78 men; mean age, 69 ± 11 yr) underwent repeat echocardiography and electrocardiography at least 90 days after device implantation. Forty patients had mechanical responses of at least 0.05 improvement in absolute LVEF; 56 had electrical responses (any narrowing of biventricular-paced QRS duration compared with the electrocardiogram immediately after therapy). During a mean follow-up period of 3.1 ± 1.7 years, 55 patients died. The average death rate per 100 person-years was lower among mechanical responders than nonresponders (9.2% vs 23.9%; P=0.009); the unadjusted hazard ratio was 0.39 (95% confidence interval [CI], 0.19–0.79).
In a multivariate model adjusted for age, sex, baseline LVEF, and QRS duration, mechanical responders had 60% better survival than nonresponders (hazard ratio=0.40; 95% CI, 0.21–0.79; P=0.008). No difference in survival was observed in electrical response. In our association of absolute change in LVEF over the observed range with death (using restricted cubic splines), we observed a linear relationship with survival.
In patients given cardiac resynchronization therapy, mechanical but not electrical remodeling was associated with better survival rates, suggesting that mechanical remodeling underlies this therapy's mechanism of conferring a survival benefit.
Cardiac resynchronization therapy/methods; combined modality therapy; heart conduction system/physiopathology; heart failure/mortality/physiopathology/therapy; predictive value of tests; survival analysis; ventricular dysfunction, left/mortality/prevention & control/therapy; ventricular remodeling
β-Blockers are standard therapy for patients with heart failure (HF). This study compared the effects of chronic monotherapy with 2 different β1-selective adrenoceptor blockers, namely atenolol and metoprolol succinate, on left ventricular (LV) function and remodeling in dogs with coronary microembolization-induced HF [LV ejection fraction (EF) 30–40%].
Twenty HF dogs were randomized to 3 months of therapy with atenolol (50 mg once daily, n = 6), metoprolol succinate (100 mg, once daily, n = 7) or to no therapy (control, n = 7). LV EF and volumes were measured before initiating therapy and after 3 months of therapy. The change (Δ) in EF and volumes between measurements before and after therapy was calculated and compared among study groups.
In controls, EF decreased and end-systolic volume increased. Atenolol prevented the decrease in EF and the increase in ESV. In contrast, metoprolol succinate significantly increased EF and decreased end-systolic volume. ΔEF was significantly higher and Δend-systolic volume significantly lower in metoprolol succinate-treated dogs compared to atenolol-treated dogs (EF: 6.0 ± 0.86% vs. 0.8 ± 0.85%, p < 0.05; end-systolic volume: −4.3 ± 0.81 ml vs. −1 ± 0.52 ml, p <0.05).
In HF dogs, chronic therapy with atenolol does not elicit the same LV function and remodeling benefits as those achieved with metoprolol succinate.
Heart failure; Myocyte hypertrophy; Ventricular remodeling; Gene expression
Purpose. To provide an ovine model of ventricular remodeling and reverse remodeling by creating congestive heart failure (CHF) and then treating it by implanting a left ventricular assist device (LVAD).
Methods. We induced volume-overload heart failure in 2 sheep; 20 weeks later, we implanted an LVAD and assessed recovery 11 weeks thereafter. We examined changes in histologic and hemodynamic data and levels of cellular markers of CHF.
Results. After CHF induction, we found increases in LV end-diastolic pressure, LV systolic and diastolic dimensions, wall thickness, left atrial diameter, and atrial natriuretic protein (ANP) and endothelin-1 (ET-1) levels; β-adrenergic receptor (BAR) and dystrophin expression decreased markedly. Biopsies confirmed LV remodeling. After LVAD support, LV systolic and diastolic dimensions, wall thickness, and mass, and ANP and ET-1 levels decreased. Histopathologic and hemodynamic markers improved, and BAR and dystrophin expression normalized.
Conclusions. We describe a successful sheep model for ventricular and reverse remodeling.
Medical and device therapies that reduce heart failure morbidity and mortality also lead to decreased left ventricular (LV) volume and mass, and a more normal elliptical shape of the ventricle. These are due to changes in myocyte size, structure and organization that have been referred to collectively as “reverse remodeling.” Moreover, there are subsets of patients whose hearts have undergone reverse remodeling either spontaneously, or following medical or device therapies, and whose clinical course is associated with freedom from future heart failure events. This phenomenon has been referred to as “myocardial recovery.” Despite the frequent interchangeable use of the terms myocardial recovery and reverse remodeling to describe the reversal of various aspects of the heart failure phenotype following medical and device therapy, the literature suggests that there are important differences between these two phenomenon, and that myocardial recovery and reverse remodeling are not synonymous. In the following review, we will discuss the biology of cardiac remodeling, cardiac reverse remodeling and myocardial recovery, with the intent of providing a conceptual framework for understanding myocardial recovery.
heart failure; left ventricular remodeling; reverse remodeling; myocardial recovery; myocardial remission
To investigate properties of multiple bioelectric impedance signals recorded during congestive heart failure (CHF) by utilizing various electrode configurations of an implanted cardiac resynchronization therapy (CRT) system.
Monitoring of CHF has relied mainly on right-heart sensors.
Fifteen normal dogs underwent implantation of CRT systems using standard leads. An additional left atrial (LA) pressure lead-sensor was implanted in 5 dogs. Continuous rapid right ventricular (RV) pacing was applied over several weeks. Left ventricular (LV) catheterization and echocardiography were performed biweekly. Six steady-state impedance signals, utilizing intrathorcaic and intracardiac vectors, were measured via ring (r), coil (c), and device Can electrodes.
All animals developed CHF after 2–4 weeks of pacing. Impedance diminished gradually during CHF induction, but at varying rates for different vectors. Impedance during CHF decreased significantly in all measured vectors: LVr-Can, −17%; LVr-RVr, −15%; LVr-RAr, −11%; RVr-Can, −12%; RVc-Can, −7%; RAr-Can, −5%. The LVr-Can vector reflected both the fastest and largest change in impedance in comparison to vectors employing only right-heart electrodes, and was highly reflective of changes in LV end-diastolic volume and LA pressure.
Impedance, acquired via different lead-electrodes, have variable responses to CHF. Impedance vectors employing a LV lead are highly responsive to physiologic changes during CHF. Measuring multiple impedance signals could be useful for optimizing ambulatory monitoring in heart failure patients.
cardiac resynchronization therapy; hemodynamic monitoring; pulmonary edema
Various electrophysiological procedures and device implantation has been shown to improve morbidity and mortality in patients with atrial fibrillation (AF) and patients with heart failure (HF). Non-invasive cardiac imaging is used extensively in the pre-procedural patient selection and for procedural guidance. In this review, we will discuss the application of pre-procedural cardiac imaging in patients with AF prior to pulmonary vein and left atrial ablation as well as insertion of left atrial occluder device. We also discuss the role of non-invasive cardiac imaging in the selection of appropriate HF patients for device therapy as well as their use in guiding implantation of biventricular pacemaker for cardiac resynchronization therapy by assessing left ventricular ejection fraction, coronary venous anatomy, mechanical dyssynchrony and myocardial scar. We describe new research associated with pre-procedural imaging in these patient cohorts.
Computed tomography; magnetic resonance imaging; echocardiography; atrial fibrillation; ablation; left atrium; pulmonary veins; heart failure; left ventricular ejection fraction; cardiac resynchronization therapy; dyssynchrony; Preprocedural imaging
Cardiac resynchronization therapy (CRT) is an important device-based, non-pharmacological approach that has shown, in large randomized trials, to improve left ventricular (LV) function and reduce both morbidity and mortality rates in selected patients affected by advanced heart failure (HF): New York Heart Association (NYHA) functional class III–IV, reduced LV systolic function with an ejection fraction (EF) ≤35%, QRS duration ≥120 ms, on optimal medical therapy, and who were in sinus rhythm. For the first time, the latest ESC and AHA/ACC/HRS Guidelines have considered atrial fibrillation (AF) patients, who constitute an important subgroup of HF patients, as eligible to receive CRT. Nevertheless, these Guidelines did not include a strategy for defining differentiated approaches according to AF duration or burden. In this review, the authors explain in which way AF may interfere with adequate CRT delivery, how to manage different AF burden, and finally present a brief overview on the effects of CRT in AF patients.
Atrial fibrillation; Heart failure; Resynchronization; Defibrillators; Ablation
Left ventricular assist devices (LVAD) are currently used to either “bridge” patients with terminal congestive heart failure (CHF) until cardiac transplantation is possible or optionally for patients with contraindications for transplantation (“destination therapy”). Mechanical support is associated with a marked decrease of cardiac dilation and hypertrophy as well as numerous cellular and molecular changes (“reverse cardiac remodeling”), which can be accompanied by improved cardiac function (“bridge to recovery”) in a relatively small subset of patients with heart transplantation no longer necessary even after removal of the device (“weaning”). In the recent past, novel pharmacological strategies have been developed and are combined with mechanical support, which has increased the percentage of patients with improved clinical status and cardiac performance. Gene expression profiles have demonstrated that individuals who recover after LVAD show different gene expression compared to individuals who do not respond to unloading. This methodology holds promise for the future to develop read out frames to identify individuals who can recover after support. Aside from describing the morphological changes associated with “reverse cardiac remodeling”, this review will focus on signal transduction, transcriptional regulation, apoptosis, cell stress proteins, matrix remodeling, inflammatory mediators and aspects of neurohormonal activation in the failing human heart before and after ventricular unloading.
Congestive heart failure (CHF); ventricular unloading; left ventricular assist device (LVAD); reverse cardiac remodeling; morphology; weaning.
The consequences of aggressive therapy following a myocardial infarction (MI) on ventricular remodeling are not well established. Thus, the objective of this study was to analyze the prevalence, clinical characteristics, and predictors of left ventricular remodeling in the era of modern medical therapy.
Clinical characteristics and echocardiographic data were analyzed in 66 consecutive patients with anterior infarction at admission and at 6-month follow-up. Ventricular remodeling was defined as an increase of 10% in ventricular end-systolic or end-diastolic diameter.
In our study, 58% of patients presented with ventricular remodeling. Patients with remodeling possessed higher total plasma creatine kinase (CPK), MB-fraction (CPK-MB), heart rate, heart failure, shortness of breath, and reperfusion therapy than patients without remodeling. In contrast, patients with remodeling had a smaller ejection fraction, E-Wave deceleration time (EDT), and early (E′ Wave) and late (A′ Wave) diastolic mitral annulus velocity (average of septal and lateral walls), but a higher E/E′ than patients without remodeling. Patients with remodeling used more diuretics, digoxin, oral anticoagulants and aldosterone antagonists than patients without remodeling. In the multivariate analyses, only E′ Wave was an independent predictor of ventricular remodeling. Each 1 unit increase in the E′ Wave was associated with a 59% increased odds of ventricular remodeling.
In patients with anterior MI, despite contemporary treatment, ventricular remodeling is still a common event. In addition, diastolic function can have an important role as a predictor of remodeling in this scenario.
predictors; remodeling; ventricular dilation
Atrial fibrillation (AF) is commonly associated with congestive heart failure (CHF). The autonomic nervous system is involved in the pathogenesis of both AF and CHF. We examined the role of autonomic remodeling in contributing to AF substrate in CHF.
Methods and Results
Electrophysiological mapping was performed in the pulmonary veins (PVs) and left atrium (LA) in 38 rapid-ventricular paced dogs (CHF group) and 39 controls under the following conditions: vagal stimulation, isoproterenol infusion, β-adrenergic blockade, acetylcholinesterase (AChE) inhibition (physostigmine), parasympathetic blockade, and double autonomic blockade. Explanted atria were examined for nerve density/distribution, muscarinic receptor (MR) and beta-adrenergic receptor (βAR) densities, and AChE activity.
In CHF dogs, there was an increase in nerve bundle size, parasympathetic fibers/bundle, and density of sympathetic fibrils and cardiac ganglia, all preferentially in the posterior LA/PVs. Sympathetic hyperinnervation was accompanied by increases in β1AR density and in sympathetic effect on ERPs and activation direction. β-adrenergic blockade slowed AF dominant frequency. Parasympathetic remodeling was more complex, resulting in increased AChE activity, unchanged MR density, unchanged parasympathetic effect on activation direction, and decreased effect of vagal stimulation on ERP (restored by AChE inhibition). Parasympathetic blockade markedly decreased AF duration.
In this heart failure model autonomic and electrophysiologic remodeling occurs involving the posterior left atrium and pulmonary veins. Despite synaptic compensation, parasympathetic hyperinnervation contributes significantly to AF maintenance. Parasympathetic and/or sympathetic signaling may be possible therapeutic targets for AF in CHF.
atrial fibrillation; autonomic nervous system; heart failure
Assisted circulation by extracorporeal and extracardiac bypass techniques must be based on the requirements of the heart and of the total body, though these may differ. The cardiac problem in cardiogenic shock is more likely to be a biventricular problem demanding decompression of both sides. Extra pulmonary oxygenation should be avoided because of complexity in long-term use. Principles of assisted circulation may be applied in an extra-thoracic temporary manner or as an intracorporeal long-term device without removal of the heart. We have compared a number of extracorporeal mechanical bypass techniques (left ventricular bypass, left atrial bypass, right atrial plus left ventrical bypass, and right atrial plus left atrial bypass) in dogs at different flow rates with control groups (nitroprusside, metabolic substrates, and no therapy) for survival during and after 4-hour treatment periods in a standard severe myocardial infarction preparation with biventricular failure. The left ventricle was cannulated in a retrograde manner. Right atrial bypass was mixed with oxygenated left ventricular blood before return without oxygenation.
Results in 50 dogs revealed that without treatment 20% survived; left ventricular plus right atrial bypass provided 100% survival during the 4-hour treatment, whereas left ventricular bypass and nitroprusside were intermediate with approximately 70% survival. Respiration and acid-base balance were not significantly altered by right atrial bypass, which provided adequate decompression of the right ventricle. Flow rates of 50% of control levels were adequate to provide normal or increased peripheral circulation as well as decompression of both ventricles and maintenance of sinus or nodal rhythm. Left atrial or left ventricular bypass alone was unable to support the heart or circulation in severe failure. Hemodynamics, including total body perfusion, atrial pressures, and dP/dt were improved significantly only by left ventricular plus right atrial bypass, even though reduced rates of flow were used. Similar findings were seen in lactic acid, CPK, and oxygen consumption. The addition of metabolic substrates currently does not improve survival though they appear to act as metabolic modulators.
We conclude that the principle of a low flow left ventricular plus right atrial bypass without an oxygenator offers a technique for long- or short-term assistance.
This study investigates alterations in myocardial microvasculature, fibrosis and hypertrophy before and after mechanical unloading of the failing human heart.
Recent studies demonstrated the pathophysiologic importance and significant mechanistic links between microvasculature, fibrosis and hypertrophy during the cardiac remodeling process. The effect of left ventricular assist device (LVAD) unloading on cardiac endothelium and microvasculature is unknown and its influence on fibrosis and hypertrophy regression to the point of atrophy is controversial.
Hemodynamic data and left ventricular tissue were collected from patients with chronic heart failure at LVAD implant and explant (n=15), and from normal donors (n=8). New advances in digital microscopy provided a unique opportunity for comprehensive whole-field, endocardium-to-epicardium evaluation for microvascular density, fibrosis, cardiomyocyte size and glycogen content. Ultrastructural assessment was done with electron microscopy.
Hemodynamic data revealed significant pressure unloading with LVAD. This was accompanied by a 33% increase in microvascular density (p=0.001) and a 36% decrease in microvascular lumen area (p=0.028). In agreement with these findings we also identified immunohistochemical ultrastructural evidence of endothelial cell activation. In addition, LVAD unloading significantly increased interstitial and total collagen content without any associated structural, ultrastructural or metabolic cardiomyocyte changes suggestive of hypertrophy regression to the point of atrophy and degeneration.
LVAD unloading resulted in increased microvascular density accompanied by increased fibrosis and no evidence of cardiomyocyte atrophy. These new insights into the effects of LVAD unloading on microvasculature and associated key remodeling features may guide future studies of unloading-induced reverse remodeling of the failing human heart.
heart failure; remodeling; left ventricular assist device; unloading; microvasculature
Heart failure (HF) is a global epidemic that continues to cause significant morbidity and mortality despite advances in medical therapy. Ventricular assist device technology has emerged as a therapeutic option to bridge patients with end-stage HF to heart transplantation or as an alternative to transplantation in selected patients. In some patients, mechanical unloading induced by ventricular assist devices leads to improvement of myocardial function and a possibility of device removal. The implementation of this advanced technology requires multiple pharmacological interventions, both in the perioperative and long-term periods, in order to minimize potential complications and improve patient outcomes. We herein review the latest available evidence supporting the use of specific pharmacological interventions and current practices in the care of these patients: anticoagulation, bleeding management, pump thrombosis, infections, arrhythmias, right ventricular failure, hypertension, desensitization protocols, among others. Areas of uncertainty and ground for future research are also highlighted.
Ventricular assist device; Chronic mechanical circulatory support; Pharmacology; Anticoagulation; Bleeding; Infection; Right ventricular failure; HLA sensitization; Arrhythmias; Harefield protocol
Clinical and experimental evidence has recently accumulated about the importance of alterations of Na+ channel (NaCh) function and slow myocardial conduction for arrhythmias in infarcted and failing hearts (HF). The present study evaluated the molecular mechanisms of local alterations in the expression of NaCh subunits which underlie Na+ current (INa) density decrease in HF. HF was induced in 5 dogs by sequential coronary microembolization and developed approximately 3 months after the last embolization (left ventricle, LV, ejection fraction = 27±7%). 5 normal dogs served as a control group. Ventricular cardiomyocytes (VCs) were isolated enzymatically from LV mid-myocardium and INa was measured by whole-cell patch-clamp. The mRNA encoding the cardiac-specific sodium channel (NaCh) α-subunit Nav1.5, and one of its auxiliary subunits β1 (NaChβ1), was analyzed by competitive RT-PCR. Protein levels of Nav1.5, NaChβ1 and NaChβ2 were evaluated by Western blotting. The maximum density of INa/Cm was decreased in HF (n=5) compared to control hearts (32.3±2.6 vs. 50.8±6.5 pA/pF, mean±SEM, n=5, P<0.05). The steady-state inactivation and activation of INa remained unchanged in HF compared to control hearts. The levels of mRNA encoding Nav1.5, and NaChβ1 were unaltered in failing hearts. However, Nav1.5 protein expression was reduced about 30% in HF, while NaChβ1 and NaChβ2 protein were unchanged. We conclude that experimental HF in dogs results in post-transcriptional changes in cardiac NaCh α-subunit expression.
heart failure; sodium channel; β-subunits; patch clamp; RT-PCR; Western blot
This review examines the use of cardiac resynchronisation therapy (CRT) for chronic, severe, systolic heart failure. Left ventricular (LV) remodelling is the final common pathway of systolic heart failure and portends a poor prognosis. It is characterised by progressive LV dilatation, deterioration of ventricular contractile function and distortion of LV cavity shape. The LV remodelling process is triggered by prolonged pressure or volume overload, loss of contracting myocytes from myocardial infarction, genetic abnormalities of contractile proteins or exposure to cardiotoxic agents. Current therapeutic strategies for systolic heart failure aim to slow or halt the remodelling process. “Reverse remodelling” is a relatively new concept, where progressive LV dilatation and deterioration in contractile function are not simply arrested, but partially reversed. Cardiac resynchronisation therapy is a novel and effective treatment for systolic heart failure, and is associated with reverse remodelling of the LV.
heart failure; resynchronisation; ventricular remodelling; echocardiography
Chronic congestive heart failure (CHF) was induced in dogs by the construction of an aorto-caval fistula below the level of the renal arteries. Aorto-caval fistula dogs showed signs of CHF which included ascites, hind limb edema, and pulmonary congestion. Ventricular catheterization indicated a significantly higher left ventricular end diastolic pressure and lower maximum velocity of left ventricular pressure development/left ventricular end diastolic pressure in CHF dogs when compared to sham-operated controls. Heart weight/body weight ratios were significantly higher in CHF dogs. Electrophysiological recordings from medullated left atrial type B receptors from the cervical vagus indicated a depressed sensitivity of these receptors in CHF dogs when compared to sham-operated control dogs. For any given change in left atrial pressure, the discharge of left atrial receptors was significantly reduced in CHF dogs compared with sham-operated controls. The mechanism for this depressed sensitivity was investigated. Sonomicrometry of the left atrial appendage indicated a decreased compliance of the left atrial appendage in the dogs with chronic CHF. In addition, microscope examination of the complex unencapsulated receptor endings taken from the left atrial endocardium indicated a marked alteration in receptor morphology. A loss of the end arborization was the most typical finding. It is concluded that chronic CHF brought about by an aorto-caval fistula results in a depressed left atrial stretch receptor response and that both decreased left atrial compliance and structural alterations in the receptor endings may account for this depressed sensitivity.
Myostatin inhibits myoblast differentiation/proliferation and may play a role in heart failure (HF) and reverse remodelling after left ventricular assist device (LVAD) support. This study sought to characterize myostatin expression and activation in advanced HF before and after LVAD support.
Methods and results
Left ventricular tissue pairs were collected at LVAD implantation (core) and at cardiac transplantation/LVAD explantation in patients with advanced ischaemic (ICM—ischaemic cardiomyopathy) and non-ischaemic (DCM—dilated cardiomyopathy) HF. Normal cardiac tissue (control) was obtained from hearts not placed for transplantation. Serum was collected independently from patients with stable DCM HF and from healthy controls. Full-length and cleaved propeptide myostatin levels were quantified by western blot analysis. Dilated cardiomyopathy propeptide levels at core were significantly higher than control and significantly increased after LVAD support. Ischaemic cardiomyopathy propeptide levels were higher than control, but did not change after LVAD support. No changes in full-length levels were seen. Serum myostatin levels were significantly higher in DCM HF patients than in healthy controls.
This is the first clinical evidence that myostatin activation is increased in HF. Myostatin may affect cardiac hypertrophy and may mediate regression of cellular hypertrophy after mechanical unloading.
Protein; Myocyte regulation; Dilated cardiomyopathy; Mechanical circulation
Fibroblasts are important in the atrial fibrillation (AF) substrate resulting from congestive heart failure (CHF). We previously noted changes in in vivo indices of fibroblast function in a CHF dog model, but could not detect changes in isolated cells. This study assessed CHF-induced changes in the phenotype of fibroblasts freshly isolated from control versus CHF dogs, and examined effects of cell culture on these differences.
Left-atrial fibroblasts were isolated from control and CHF dogs (ventricular tachypacing 240 bpm×2 weeks). Freshly-isolated fibroblasts were compared to fibroblasts in primary culture. Extracellular-matrix (ECM) gene-expression was assessed by qPCR, protein by Western blot, fibroblast morphology with immunocytochemistry, and K+-current with patch-clamp. Freshly-isolated CHF fibroblasts had increased expression-levels of collagen-1 (10-fold), collagen-3 (5-fold), and fibronectin-1 (3-fold) vs. control, along with increased cell diameter (13.4±0.4 µm vs control 8.4±0.3 µm) and cell spreading (shape factor 0.81±0.02 vs. control 0.87±0.02), consistent with an activated phenotype. Freshly-isolated control fibroblasts displayed robust tetraethylammonium (TEA)-sensitive K+-currents that were strongly downregulated in CHF. The TEA-sensitive K+-current differences between control and CHF fibroblasts were attenuated after 2-day culture and eliminated after 7 days. Similarly, cell-culture eliminated the ECM protein-expression and shape differences between control and CHF fibroblasts.
Freshly-isolated CHF and control atrial fibroblasts display distinct ECM-gene and morphological differences consistent with in vivo pathology. Culture for as little as 48 hours activates fibroblasts and obscures the effects of CHF. These results demonstrate potentially-important atrial-fibroblast phenotype changes in CHF and emphasize the need for caution in relating properties of cultured fibroblasts to in vivo systems.
The CorCap Cardiac Support Device (Acorn Cardiovascular, Inc.) is the first device that specifically addresses ventricular remodeling in heart failure by reducing wall stress. We previously reported outcomes from the Acorn randomized trial to a common closing date (22.9 months of follow up). This report summarizes results of extended follow up to 5 years.
107 patients were enrolled in the No-Mitral Valve Repair/Replacement stratum including 57 in the CorCap treatment group and 50 in the control (optimal medical therapy alone) group. Patients were assessed every year until completing 5 years of follow up, for survival, adverse events, major cardiac procedures, New York Heart Association (NYHA) functional status and echocardiograms, which were read at a core laboratory.
Overall survival rates were similar between the treatment and control groups demonstrating no late adverse effect on mortality. The treatment group had significant reductions in left ventricular end diastolic volume (p = 0.029) as well as a small increase in sphericity index. More patients in the treatment group improved by at least one NYHA functional class (p= 0.0005). There was no difference in rates of adverse events. In a subgroup of patients with an intermediate left ventricular end diastolic dimension, there was a significant reduction in the Kaplan Meier estimate of the freedom from the composite endpoint of death and major cardiac procedures (p= 0.04).
These cumulative data demonstrate the sustained reverse remodeling of the left ventricle and the long term safety and efficacy of the CorCap Cardiac Support Device as an adjunctive therapy for patients with heart failure who remain symptomatic despite optimal medical therapy.