Alterations in Ca2+ cycling proteins and G alpha q signaling after left ventricular assist device support in failing human hearts

OBJECTIVE: Left ventricular assist device support mechanically unloads the failing ventricle with resultant improvement in cardiac geometry and function in patients with end-stage heart failure. Activation of the G alpha q signaling pathway, including protein kinase C, appears to be involved in the progression of heart failure. Similarly down-regulation of Ca2+ cycling proteins may contribute to contractile depression in this clinical syndrome. Thus we examined whether protein kinase C activation and decreased Ca2+ cycling protein levels could be reversed by left ventricular assist device support. METHODS: Left ventricular myocardial specimens were obtained from seven patients during placement of left ventricular assist device and heart transplantation. We examined changes in protein levels of G alpha q, phospholipase C beta 1, regulators of G protein signaling (RGS), sarcoplasmic reticulum Ca2+ ATPase, phospholamban and translocation of protein kinase C isoforms (alpha, beta 1, and beta 2). RESULTS: The paired pre- and post-left ventricular assist device samples revealed that RGS2, a selective inhibitor of G alpha q, was decreased (P < 0.01), while the status of G alpha q, phospholipase C beta 1, RGS3 and RGS4 were unchanged after left ventricular assist device implantation. Translocation of protein kinase C isoforms remained unchanged. Left ventricular assist device support increased sarcoplasmic reticulum Ca2+ ATPase protein level (P < 0.01), while phospholamban abundance was unchanged. CONCLUSIONS: We conclude that altered protein expression and stoichiometry of the major cardiomyocyte Ca2+ cycling proteins rather than reduced phospholipase C beta 1 activation may contribute to improved mechanical function produced by left ventricular assist device support in human heart failure.     

Altered exercise pulmonary function after left ventricular assist device implantation

The use of LVADs as a bridge to heart transplantation is increasing steadily as more surgical centers add this effective strategy for end-stage heart failure patients. Fundamental exercise physiology in the presence of LVADs has been described previously, and data is available that supports the safety and efficacy of exercise in this population. Variants to the expected exercise response that may be secondary to LVAD implantation, such as the pulmonary restrictive pattern that developed in the patient described in this case study, may occur. Clinicians should consider assessment and monitoring of pulmonary function in this patient population, especially in patients with exercise-induced dyspnea and perhaps patients with pre-existing pulmonary limitation.     

Improved survival rates support left ventricular assist device implantation early after myocardial infarction

OBJECTIVES

Implantation of left ventricular assist devices (LVADs) early after acute myocardial infarction (MI) has traditionally been thought to be associated with high mortality rates due to technical limitations and severe end-organ dysfunction. At some experienced centers, doctors have refrained from earlier operation after MI to allow for a period of hemodynamic and end-organ stabilization.

METHODS

We retrospectively investigated the effect of preoperative MI on the survival rates of 25 patients who received a Thermocardiosystems Incorporated LVAD either <2 weeks (Early) (n = 15) or >2 weeks (Late) (n = 10) after MI. Outcome variables included perioperative right ventricular assistance (and right-sided circulatory failure), hemodynamic indexes, percent transplanted or explanted, and mortality.

RESULTS

No statistically significant differences were demonstrated between demographic, perioperative or hemodynamic variables between the Early and Late groups. Patients in the Early group demonstrated a lower rate of perioperative mechanical right ventricular assistance, but had a higher rate of perioperative inhaled nitric oxide use. In addition, 67% of patients in the Early group survived to transplantation and 7% to explantation, findings comparable to those in the Late group (60% and 0% respectively).

CONCLUSIONS

This clinical experience suggests that patients may have comparable outcomes whether implanted early or late after acute MI. These data therefore support the early identification and timely application of this modality in post-MI LVAD candidates, as this strategy may also reveal a subgroup of patients for whom post-MI temporary LVAD insertion may allow for full ventricular recovery.     

Myocardial creatine kinase expression after left ventricular assist device support

OBJECTIVES: We examined whether unloading of the left ventricle with a ventricular assist device (LVAD) can result in normalization of the creatine kinase (CK) abnormalities in the failing human heart. BACKGROUND: Left ventricular failure is associated with a decrease of myocardial total CK activity and a fetal shift in CK isoform expression that results in an increase in the cytosolic brain type homodimeric-creatine kinase (CK-B) subunit and decreases of the cytosolic muscle-creatine kinase (CK-M) and CK-mitochondrial (CK-Mt) isoforms. The mechanisms of this abnormality are not known. METHODS: Total CK activity and CK protein isoform expression (Western blotting) were examined in 11 patients with end-stage cardiomyopathy. In 7 patients, myocardial tissue was also obtained after 4.1 +/- 1.1 months of left ventricular assist device (LVAD) support. RESULTS: Left ventricular unloading produced by LVAD implantation resulted in a 270% +/- 114% increase in total CK activity (p < 0.01) that was associated with a 69% +/- 18% increase in CK-M protein expression (p < 0.01) and a 121% +/- 69% increase in CK-Mt protein expression (p < 0.01), but no significant change in CK-B expression. CONCLUSIONS: Systolic and diastolic unloading provided by the LVAD resulted in increases of total CK activity as well as CK-Mt and CK-M protein expression. The failure of CK-B expression to decrease suggests that abnormalities other than increased loading are responsible for the increase in CK-B expression in the failing heart.     

L-type Ca2+ channel density and regulation are altered in failing human ventricular myocytes and recover after support with mechanical assist devices

Ca2+ influx through the L-type calcium channel (LTCC) induces Ca2+ release from the sarcoplasmic reticulum (SR) and maintains SR Ca2+ loading. Alterations in LTCC properties, their contribution to the blunted adrenergic responsiveness in failing hearts and their recovery after support with LV assist devices (LVAD) were studied. L-type Ca2+ current (I(Ca,L)) was measured under basal conditions and in the presence of isoproterenol (ISO), dibutyryl-cAMP (db-cAMP), Bay K 8644 (BayK), Okadaic acid (OA, a phosphatase inhibitor), and phosphatase 2A (PP2A) in nonfailing (NF), failing (F), and LVAD-supported human left ventricular myocytes (HVMs). Basal I(Ca,L) density was not different in the 3 groups but I(Ca,L) was activated at more negative voltages in F- and LVAD- versus NF-HVMs (V(0.5): -7.18+/-1.4 and -7.0+/-0.9 versus 0.46+/-1.1 mV). Both ISO and db-cAMP increased I(Ca,L) in NF- and LVAD- significantly more than in F-HVMs (NF >LVAD> F: ISO: 90+/-15% versus 77+/-19% versus 24+/-12%; db-cAMP: 235%>172%>90%). ISO caused a significant leftward shift of the I(Ca,L) activation curve in NF- and LVAD- but not in F-HVMs. After ISO and db-cAMP, the I(Ca,L) activation was not significantly different between groups. BayK also increased I(Ca,L) more in NF- (81+/-30%) and LVAD- (70+/-15%) than in F- (51+/-8%) HVMs. OA increased I(Ca, L) by 85.6% in NF-HVMs but had no effect in F-HVMs, while PP2A decreased I(Ca, L) in F-HVMs by 35% but had no effect in NF-HVMs. These results suggest that the density of LTCC is reduced in F-HVMs but basal I(Ca,L) density is maintained by increasing in LTCC phosphorylation.     

Apoptosis, Bcl-2, and proliferating cell nuclear antigen in the failing human heart: observations made after implantation of left ventricular assist device

BACKGROUND: Heart failure is characterized by progressive left ventricular remodeling, a complex process that results from cell growth and cell death. The quantitative contribution of apoptotic cells toward left ventricular remodeling has varied widely in tissue removed from cardiomyopathic hearts. Apoptosis has been responsive to angiotensin-converting enzyme inhibition in experimental heart failure, but the dynamics and responsiveness to chronic left ventricular unloading have not been studied. METHODS AND RESULTS: We studied 8 patients with severe heart failure before and after chronic left ventricular unloading with a left ventricular assist device (LVAD). Tissue from the left ventricular apex removed at the time of LVAD implantation was examined for apoptosis using the technique of terminal deoxynucleotidyl transferase deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) in 10 patients. These same hearts explanted at the time of cardiac transplantation were then examined for apoptosis after patients had been on the LVAD for 99 +/- 20 (SEM) days. An additional 10 patients with equally severe heart failure who underwent heart transplantation without the use of an LVAD served as controls. Eight hearts obtained at autopsy approximately 6 hours after death from patients who died of non-cardiovascular disease causes served as non-heart failure controls. Additionally, 6 hearts were examined by immunohistochemistry for the antiapoptotic protein, Bcl-2, and for the repair and/or proliferation marker, proliferating cell nuclear antigen (PCNA), before and after LVAD. Apoptosis was not detected in the tissue sections from the hearts of 8 patients at the time of LVAD implantation. Only 1 of these patients had limited apoptosis (< 1 apoptotic cell/1,000 myocytes) after LVAD insertion. Three of 10 patients with severe heart failure who did not receive an LVAD but underwent transplantation showed limited apoptosis (< 1 apoptotic cell/1,000 myocytes). Likewise, none of the control hearts from patients who died of noncardiovascular disease manifested apoptosis. Six of 6 patients overexpressed Bcl-2 at the time of LVAD insertion. In all these patients, Bcl-2 returned to negligible levels after chronic unloading of the heart. Likewise, PCNA was abundantly expressed in 5 of 6 failing hearts at the time of LVAD implantation and was reduced in 4 of 5 hearts after chronic unloading by LVAD. CONCLUSION: Apoptosis is a rare or inconsistent finding in the failing human heart. Overexpression of such indicators of cellular stress and DNA replication and/or repair as Bcl-2 and PNCA in heart failure may be altered by optimizing left ventricular loading conditions by such mechanical devices as the LVAD.     

Ventricular arrhythmias during left ventricular assist device support

Left ventricular assist devices (LVADs) have been used effectively as a "bridge" to cardiac transplantation and as destination therapy in patients with advanced heart failure. Ventricular arrhythmias (VAs) have been reported to occur in LVAD-supported patients, although their incidence, risk factors, and clinical significance have not been characterized. In this study, 111 patients who received LVAD support as a bridge to cardiac transplantation at the University of Pittsburgh Medical Center from January 1987 to June 2001 were evaluated. Clinically significant VA was defined as ventricular fibrillation, sustained ventricular tachycardia, or nonsustained ventricular tachycardia with symptoms requiring antiarrhythmic therapy. Patients were grouped on the basis of the presence or absence of VAs. VAs occurred in 24 patients (22%) during device support. Ischemic heart disease was the cause of heart failure in 71% of patients (17 of 24) in the VA group and 45% of patients (39 of 87) in the group without VAs (p <0.05). The mortality rate was significantly higher (p <0.001) during LVAD support in the group with VAs (33%) compared with the group without VAs (18%). In the group with VAs, the early (1 week) occurrence (9%). In conclusion, although clinically significant VAs occur in patients with heart failure receiving LVAD support, the overall incidence is low. VAs are more frequent in patients with ischemic heart failure, and their occurrence is associated with greater mortality. The occurrence of VAs early after LVAD implantation, in particular, predicts a higher mortality rate.     

Mid-term survival after continuous-flow left ventricular assist device versus heart transplantation

There is a paucity of data about mid-term outcome of patients with advanced heart failure (HF) treated with left ventricular assist device (LVAD) in Europe, where donor shortage and their aging limit the availability and the probability of success of heart transplantation (HTx). The aim of this study is to compare Italian single-centre mid-term outcome in prospective patients treated with LVAD vs. HTx. We evaluated 213 consecutive patients with advanced HF who underwent continuous-flow LVAD implant or HTx from 1/2006 to 2/2012, with complete follow-up at 1 year (3/2013). We compared outcome in patients who received a LVAD (n = 49) with those who underwent HTx (n = 164) and in matched groups of 39 LVAD and 39 HTx patients. Patients that were treated with LVAD had a worse risk profile in comparison with HTx patients. Kaplan–Meier survival curves estimated a one-year survival of 75.5 % in LVAD vs. 82.3 % in HTx patients, a difference that was non-statistically significant [hazard ratio (HR) 1.46; 95 % confidence interval (CI) 0.74–2.86; p = 0.27 for LVAD vs. HTx]. After group matching 1-year survival was similar between LVAD (76.9 %) and HTx (79.5 %; HR 1.15; 95 % CI 0.44–2.98; p = 0.78). Concordant data was observed at 2-year follow-up. Patients treated with LVAD as bridge-to-transplant indication (n = 22) showed a non significant better outcome compared with HTx with a 95.5 and 90.9 % survival, at 1- and 2-year follow-up, respectively. Despite worse preoperative conditions, survival is not significantly lower after LVAD than after HTx at 2-year follow-up. Given the scarce number of donors for HTx, LVAD therapy represents a valid option, potentially affecting the current allocation strategy of heart donors also in Europe.     

Partial support with a centrifugal left ventricular assist device reduces myocardial oxygen consumption in chronic, ischemic heart failure

BACKGROUND: Left ventricular assist devices (LVAD) are increasingly used for heart failure (CHF); however, the level of optimal support has not been elucidated. We hypothesize that partial LVAD support in an ovine model of microinfarction-induced CHF significantly reduces left ventricular myocardial oxygen consumption (LVVO2). METHODS AND RESULTS: Microembolization of the circumflex coronary artery was used to induce CHF in 5 sheep (ejection fraction 28 +/- 2%). Four months later, animals underwent implantation of a centrifugal LVAD. LVAD flow was incrementally increased from 0% (baseline) to 25%, 50%, and 75% support of the LV. LVVO2 and stroke work (SW) were calculated at each increment. At baseline, LVVO2 (microL/100 g LV/beat) measured 43.2 +/- 3.4. LVVO2 decreased to 26.5 +/- 8.2,* 20.3 +/- 8.9,* and 12.6 +/- 6.3* at 25%, 50%, and 75% support (*P < .05). SW (mm Hg/mL) measured 1933.0 +/- 275.7 at baseline and decreased to 1588.0 +/- 204.1, 1181.0 +/- 157.2,* and 764.5 +/- 171.7* at 25%, 50%, and 75% support. Cardiac output, heart rate, and left main coronary artery blood flow were unaffected with partial support. CONCLUSION: Complete support with a centrifugal LVAD is not necessary for achieving significant reductions in LVVO2 . Partial support of as little as 25% significantly reduces LVVO2 in CHF through comparatively minor reductions in cardiac work. This is the first study to examine partial LVAD support in a CHF model.     

Late sequelae of left ventricular assist device infection presenting after heart transplant

The long‐term use of left ventricular assist devices (LVADs) is becoming more common among the end‐stage heart failure population. At the time of heart transplantation, most of the LVAD is removed, but some of its components might be retained. Retained LVAD prosthetic material can lead to serious infection post heart transplant. We report 4 such cases. Our goal is to highlight the importance of complete prosthetic material removal at the time of cardiac transplant to prevent late‐onset infection, especially in patients with preceding infection, but also in patients without evidence of LVAD infection prior to orthotopic heart transplantation.     

Optimal timing of same-admission orthotopic heart transplantation after left ventricular assist device implantation

AIM To investigate the impact of timing of same-admission orthotopic heart transplant(OHT) after left ventricular assist device(LVAD) implantation on in-hospital mortality and post-transplant length of stay.METHODS Using data from the Nationwide Inpatient Sample from 1998 to 2011, we identified patients 18 years of age or older who underwent implantation of a LVAD and for whom the procedure date was available. We calculated in-hospital mortality for those patients who underwent OHT during the same admission as a function of time from LVAD to OHT, adjusting for age, sex, race, household income, and number of comorbid diagnoses. Finally, we analyzed the effect of time to OHT after LVAD implantation on the length of hospital stay post-transplant.RESULTS Two thousand and two hundred patients underwent implantation of a LVAD in this cohort. One hundred and sixty-four(7.5%) patients also underwent OHT duringthe same admission, which occurred on average 32 d(IQR 7.75-66 d) after LVAD implantation. Of patients who underwent OHT, patients who underwent transplantation within 7 d of LVAD implantation("early") experienced increased in-hospital mortality(26.8% vs 12.2%, P = 0.0483) compared to patients who underwent transplant after 8 d("late"). There was no statistically significant difference in age, sex, race, household income, or number of comorbid diagnoses between the early and late groups. Post-transplant length of stay after LVAD implantation was also not significantly different between patients who underwent early vs late OHT. CONCLUSION In this cohort of patients who received LVADs, the rate of in-hospital mortality after OHT was lower for patients who underwent late OHT(at least 8 d after LVAD implantation) compared to patients who underwent early OHT. Delayed timing of OHT after LVAD implantation did not correlate with longer hospital stays post-transplant.     

Remission of chronic anthracycline-induced heart failure with support from a continuous-flow left ventricular assist device

We report the case of a patient who had chronic anthracycline-induced cardiomyopathy that was reversed after treatment with a left ventricular assist device. A 29-year-old woman had undergone anthracycline-based chemotherapy as a teenager in 1991 and 1992 and received a diagnosis of dilated cardiomyopathy 10 years later. Optimal medical therapy had initially controlled the symptoms of heart failure. However, in June 2006, the symptoms worsened to New York Heart Association functional class IV status. We implanted a continuous-flow left ventricular assist device as a bridge to cardiac transplantation; of note, a left ventricular core biopsy at that time showed no replacement fibrosis. The patient's clinical status improved thereafter, enabling left ventricular assist device ex-plantation after 17 months. To our knowledge, this is the first report of the use of left ventricular assist device support to reverse chronic anthracycline-induced heart failure.     

Remission of chronic, advanced heart failure after left ventricular unloading with an implantable left ventricular assist device

We describe the case of a 35-year-old man with severe, dilated idiopathic cardiomyopathy who was placed on the waiting list for cardiac transplantation. While awaiting transplantation, his heart failure decompensated to such a degree that left ventricular assist device support was necessary. He did well on device support until a pump-pocket infection (methicillin-resistant coagulase-negative staphylococci) developed at 10 months. At that time, echocardiograms showed normal heart size and an ejection fraction of 0.45 to 0.49 without pump support. The pump was, therefore, explanted emergently. The patient has remained clinically stable with preserved ventricular function nearly 13 years after the explantation procedure.