http://www.jhltonline.org
ORIGINAL CLINICAL SCIENCE
Late-onset right ventricular dysfunction after mechanical support by a continuous-flow left ventricular assist device Chris J. Kapelios, MD,a Christos Charitos, MD,b Elisabeth Kaldara, MD,a Konstantinos Malliaras, MD,a Emmeleia Nana, MD,a Christos Pantsios, MD,a Evangelos Repasos, MD,a Michael Tsamatsoulis, MD,b Savvas Toumanidis, MD,c and John N. Nanas, MD, PhDa From the aDepartment of Cardiology, University of Athens School of Medicine, Athens; bDepartment of Cardiac Surgery, Evangelismos Hospital, Athens; and the cDepartment of Therapeutics, Alexandra Hospital, University of Athens Medical School, Athens, Greece.
KEYWORDS: chronic heart failure; destination therapy; left ventricular assist device; right ventricular failure; right ventricular dysfunction; mechanical support
BACKGROUND: Right heart failure (RHF) is a serious post-operative complication of left ventricular assist device (LVAD) implantation, with significant morbidity and mortality. Many clinical, hemodynamic and laboratory variables have been shown to have prognostic value for appearance of RHF. We sought to investigate the incidence of new-onset right ventricular dysfunction (RVD) complicating the long-term use of LVADs. METHODS: We retrospectively examined all patients supported with a continuous-flow LVAD for 41 year at our center. RESULTS: Twenty patients (mean age 54 ⫾ 10 years, 95% men, 60% with ischemic cardiomyopathy, left ventricular ejection fraction 22 ⫾ 6%, pulmonary capillary wedge pressure 23.5 ⫾ 7.5 mm Hg, brain natriuretic peptide [BNP] 1,566 ⫾ 1,536 pg/ml, serum creatinine 1.6 ⫾ 0.64 mg/dl, furosemide dose 643 ⫾ 410 mg/day) underwent long-term mechanical support as destination therapy support with a continuous-flow LVAD (HeartMate II) at our center. During follow-up (1,219 ⫾ 692 days), 9 patients (45%) manifested symptoms and signs of RVD (increase in right atrial pressure [RAP], BNP and daily furosemide dose compared with the early post-operative period). In these patients, RAP was increased by 6.6 ⫾ 2.6 mm Hg and BNP by 526 ⫾ 477 pg/ml, whereas furosemide dose increased by 145 ⫾ 119 mg. The mean and median times of RVD onset were 2.3 ⫾ 1.5 and 2.1 years, respectively, after LVAD implantation (range 0.4 to 4.8 years). Four of these patients (44.4%) demonstrated further deterioration of RV function and died 73 ⫾ 106 days (median 25 days, range 9 to 231 days) after first manifestation of RVD. Comparisons of baseline variables regarding medical history and clinical status did not demonstrate significant differences between the patients with or without RVD, including parameters related to RV function at the time of implantation. CONCLUSIONS: Late-onset RVD is a complication of LVAD support, which can manifest several months to years from device implantation. This complication has significant adverse implications with regard to patient outcome. Prognostic factors need to be identified to follow and treat high-risk patients more efficiently. J Heart Lung Transplant ]]]];]:]]]–]]] r 2015 International Society for Heart and Lung Transplantation. All rights reserved.
Reprint requests: John N. Nanas, MD, PhD, Third Department of Cardiology, University of Athens School of Medicine, 67 Mikras Asias Street, 11 527 Athens, Greece. Telephone: þ30-210-823-6877. Fax: þ30-210-778-9901. E-mail address: [email protected]
Right ventricular failure (RVF) is a common complication of left ventricular assist device (LVAD) implantation.1 It is usually reported in the early post-operative period and is accompanied by significantly increased peri-operative
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2015.05.024
2
The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]
morbidity and mortality and a compromised survival to and after heart transplantation (HTx).2–6 The pathophysiologic mechanisms underlying the development of RVF after LVAD implantation are complex. The improved cardiac output with LVAD assistance leads to a sudden increase in right ventricular (RV) pre-load. The leftward shift of the interventricular septum distorts RV geometry and diminishes the systolic capacity of the RV.7 Moreover, during cardiopulmonary bypass, complement activation and blood transfusions also increase pulmonary vascular resistance and result in increased RV after load.2 The RV cannot acutely increase its contractility in these conditions of increased pre- and after-load and RV failure ensues. Timely identification of the patients who will postoperatively develop RVF represents a significant therapeutic target. These patients may be given a higher priority for HTx, and the implantation of a right ventricular assist device (RVAD) may be considered earlier. Nevertheless, the potential of late RV dysfunction (RVD) presentation after prolonged LV mechanical support has been neither recognized nor investigated until now. Our study was designed to investigate the incidence of RVD after long-term mechanical support with a continuousflow LVAD.
Methods Devices An implantable, second-generation, continuous-flow HeartMate II LVAD (Thoratec, Pleasanton, CA) was implanted in all patients.
Study sample Over the 7.5-year period from February 2006 through November 2013, 30 patients underwent durable mechanical circulatory support with a HeartMate II LVAD at our tertiary-care university institute. All patients who were supported with an LVAD for a period of 41 year were identified from our database.
blocker; pre-operative dosing of furosemide; and estimated 1-year probability of survival, according to the Seattle Heart Failure Model score.9 With regard to follow-up, the parameters recorded were treatment doses of β-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or mineralocorticoid receptor blockers as well as the frequency of resynchronization therapy.
Laboratory data Plasma hemoglobin, white cell blood count, liver function tests, blood urea, creatinine and uric acid, total serum bilirubin, sodium, cholesterol and brain natriuretic peptide (BNP) levels were recorded and included in the analysis.
Echocardiography measurements The parameters recorded and evaluated were LV end-diastolic and end-systolic diameters, RV mid-regional end-diastolic diameter, severity of mitral and tricuspid valve regurgitation and LV ejection fraction (Simpson’s method).
Hemodynamic measurements A pulmonary artery catheter was used to measure capillary wedge pressure, RV pressure, pulmonary artery pressure (PAP), right atrial pressure (RAP) and cardiac index (CI). Systemic vascular resistance (in dynes/s/cm5) and pulmonary vascular resistance (Wood units) were calculated. RV stroke work index (RVSWI) was calculated using the following formula: RVSWI ¼ (mean PAP – mean RAP) SVI 1,000, where SVI (stroke volume index) equals CI divided by heart rate.
RVF and RVD definitions RVF is defined and classified according to the International Mechanically Assisted Circulatory Support Registry (available online at http://www.ishlt.org/registries/protocol.asp/) as follows: Severe right heart failure (RHF): Need for RV assist device
implantation.
Study design Medical history, clinical, laboratory, echocardiography and hemodynamic data at LVAD implantation from all patients were recorded. The study was approved by our institution’s ethics review board and conformed to the principles outlined in the Declaration of Helsinki.
Medical history and clinical status The parameters recorded and evaluated were: age; gender; body mass index; body surface area (using the Dubois formula)8; etiology of heart failure; time from first heart failure (HF) diagnosis; New York Heart Association functional class; preoperative need for positive inotropic agents or intra-aortic balloon pump support; presence of diabetes mellitus; left bundle branch block and cardiac resynchronization therapy; pre-operative treatment with a β-blocker, an angiotensin-converting enzyme inhibitor/ angiotensin receptor blocker or a mineralocorticoid receptor
Moderate RHF: Inotrope or intravenous or inhaled pulmo-
nary vasodilator (e.g., prostaglandin E or inhaled nitric oxide) for a duration of 41 week at any time after LVAD implantation. Mild RHF: Meeting 2 of the 4 following clinical criteria: CVP 4 18 mm Hg or mean RAP 4 18 mm Hg. CI o 2.3 liters/min/m2 (according to Swan). Ascites or evidence of moderate to worse peripheral edema. Evidence of elevated central venous pressure (CVP) by echocardiography (dilated vena cava, inferior vena cava with collapse), physical examination (signs of increased jugular venous pressure). RVD in our study was defined as the appearance of persistent symptoms and signs of peripheral vascular congestion (elevated CVP, hepatomegaly or congestion-related pain of the right upper quadrant, peripheral edema, ascites, increase in BNP values) necessitating the significant up-titration of diuretics dose (increase of 480 mg or 3-fold the intial dose) or use of positive inotropic agents.
Kapelios et al.
Late-Onset RVD and LVAD Support
3
Table 1 Characteristics of Study Population at the Time of Left Ventricular Assist Device Implantation Variable
Value
Age (years) Male gender Ischemic heart disease Body surface area (m2) New York Heart Association class Left ventricular ejection fraction (%) Pulmonary capillary wedge pressure (mm Hg) Pre-operative need for intra-aortic balloon pump Furosemide dose (mg/day) Serum creatinine (mg/dl) BNP (pg/ml)
53.5 ⫾ 10.4 19 (95) 12 (60) 1.89 ⫾ 0.2 3.85 ⫾ 0.4 21.9 ⫾ 6.2 23.5 ⫾ 7.5 7 (35) 643 ⫾ 410 1.60 ⫾ 0.64 1,566 ⫾ 1,536
Values expressed as mean ⫾ SD or number (%) of observations. BNP, brain natriuretic peptide.
Statistical analysis We used PASW Statistics version 19.0 (SPSS, Inc., Chicago, Illinois) for all statistical analyses. Continuous variables are expressed as mean ⫾ standard deviation and were compared using the unpaired t-test. Categorical variables are expressed as counts and percentages and were compared using the chi-square test. Comparison of withingroup changes between the early post-implant period and long-term follow-up was performed with the paired t-test. All significance tests were 2-tailed, and p o 0.05 was considered statistically significant.
Results A total of 20 patients (67% of all patients) fulfilled the predefined criteria and were included in the analysis. Among the 10 patients excluded, 4 had undergone recent implantation and were followed for o1 year at the time of the analysis and the remaining 6 had died within the first year; 2 in the early post-operative period from septic shock and sudden cardiac death, respectively, 3 from multi-organ dysfunction and 1 from stroke. However, none of the patients excluded from the analysis had presented with Table 2
symptoms or signs of RVD during the available follow-up. Patients’ baseline characteristics, as well as clinical, laboratory, echocardiography and hemodynamic variables, are presented in Table 1. Patients’ age was 53.5 ⫾ 10.4 years, 95% were men and 60% had ischemic cardiomyopathy. During the follow-up period (mean duration 3.4 ⫾ 1.9 years, median duration 2.9 years, range 1.2 to 7.1 years) 9 patients (45%) developed RVD with clinical manifestations of peripheral congestion. Detailed information on the time of incidence of RVD is presented in Table 2. At the time of RVD appearance in these patients, the mean increase of RAP from the early post-operative period was of 6.6 ⫾ 2.6 mm Hg (p ¼ 0.001), whereas in the no-RVD group patients it was 1.2 ⫾ 2.0 mm Hg (p ¼ 0.34) (p ¼ 0.005 for between-group comparison). The respective changes of BNP values and daily furosemide dose in the RVD and noRVD group patients were: 527 ⫾ 477 (p ¼ 0.029) vs 22 ⫾ 115 pg/ml (p ¼ 0.73), p ¼ 0.08 for between-group comparison; and 145 ⫾ 119 (p ¼ 0.035) vs –12 ⫾ 77 mg (p ¼ 0.75), p ¼ 0.047 for between-group comparison, respectively (Figure 1). The mean and median time of RVD onset were 2.3 ⫾ 1.5 and 2.1 years after LVAD implantation (range 0.4 to 4.8 years) (Figure 2). Four of these patients (44.4%) showed further deterioration of RV function, despite the use of high doses of intravenous inotropes and pulmonary vasodilators, and they eventually died 73 ⫾ 106 days (median 25 days; range 9 to 231 days) after the first manifestation of RVD and 2.9 ⫾ 1.8 years after the initiation of LVAD support overall. The mode of patients’ death was isolated RVF in 2 patients and RVF complicated by septic shock/multi-organ dysfunction in the other 2. Importantly, the study population consisted of destination therapy (DT) patients, who were ineligible for HTx and could not be assisted with an RVAD. Interestingly, survival in the other 5 patients who were stabilized only with diuretics dose up-titration, without the need for inotropes or vasodilators, was significantly higher (60% vs 0%; log-rank test, p ¼ 0.003). The mode of death in the 2 patients who died in this subgroup was brain cancer and hemorrhagic stroke and occurred 381 and 740 days postRVD appearance, respectively. All comparisons of patients’ characteristics between the 2 groups are shown in Table 3. Univariate comparisons of
Time-dependent Information on RVD and Death Among Patients Presenting With RVD
Patient number
Age at implantation (years)
Gender
1 2 3 4 5 6 7 8 9
62 66 59 51 54 62 62 48 56
M M M M M M M M M
HF etiology
Time from implantation until RVD appearance
Inotropes for RVD
Death from RVD
Time from RVD appearance until death
IDM ICM ICM ICM ICM IDM IDM IDM ICM
813 1,722 128 527 509 1,695 506 753 919
No Yes No Yes No No No Yes Yes
No Yes No Yes No No No Yes Yes
— 231 381 9 — — 740 30 20
ICM, ischemic cardiomyopathy, IDM, idiopathic dilated cardiomyopathy; M, male; RVD, right ventricular dysfunction
4
The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]
Figure 1 Changes in BNP, right atrial pressure and dose of furosemide between early LVAD support and prolonged follow-up in the 2 study groups (p o 0.05 for all changes in the RVF group).
the variables regarding medical history and clinical status did not demonstrate significant differences between the groups of patients with or without RVD after LVAD implantation. Interestingly, body surface area was similar in the 2 groups (1.93 vs 1.84 m2 for the RVD and no RVD groups, respectively, p ¼ 0.33), as were the rates of preoperative support with positive inotropic agents (100% vs 90.9%, p ¼ 0.38) or an intra-aortic balloon pump (44.4% vs 27.3%, p ¼ 0.65). Notably, there was a mild trend for patients presenting with RVD to be of older age (57.8 vs 49.9 years, p ¼ 0.09). Regarding the doses of optimal HF medical therapy during follow-up, patients presenting with RVD tended to receive the recommended medication,
especially ACE inhibitors (p ¼ 0.11) and mineralocorticoid receptor antagonists (p ¼ 0.10), at lower doses than those who did not have RVD, but the difference was not statistically significant (Table 4). Analysis of laboratory parameters revealed a strong trend for patients who developed late-onset RVD during followup to have higher values of serum creatinine before LVAD implantation (1.9 vs 1.4 mg/dl, p ¼ 0.06). Values for liver function tests, bilirubin and BNP did not differ between the 2 study groups. Comparison of the RVD and no-RVD groups with regard to echocardiography and hemodynamic indices did not confer any significant differences. LV and RV dimensions and intracardial filling pressures were similar between the groups. Similarly, severity of valve disease did not differ between the 2 groups in our cohort. However, there was a strong trend for decreased systematic vascular resistance in patients who eventually presented with RVD (1,350 vs 1,750 dynes/s/cm5, p ¼ 0.06).
Discussion
Figure 2 Kaplan–Meier curve of survival free from RVD in the study population.
Our study has demonstrated that RVD can appear as a lateonset complication in patients who undergo long-term mechanical assistance with a continuous-flow LVAD. This complication appeared commonly, affecting 4 of 10 patients who were supported for 41 year in this cohort. Furthermore, the incidence of late-onset RVD seems to have imposed a significant deleterious effect on prognosis of patients, as it was the underlying cause of death in 45% of patients presenting with RVD and in 20% of patients in the study population overall. Characteristically, the mean interval from RVD manifestation until time of death was approximately 2 months, implying that RVD constitutes a
Kapelios et al.
Late-Onset RVD and LVAD Support
5
Table 3 Comparison of Baseline Demographic, Clinical, Echocardiographic and Hemodynamic Variables Between Patients Who Presented With and Without RVD During Follow-up Characteristic
RVD group (N ¼ 9)
No RVD group (N ¼ 11)
p
Age (years) Male gender Time from first diagnosis (months) Ischemic cardiomyopathy Body mass index (kg/m2) Body surface area (m2) New York Heart Association class Pre-operative need for inotropes Pre-operative need for IABP Left bundle branch block Cardiac resynchronization therapy Diabetes mellitus Pre-operative receipt of: β-blocker ACE inhibitor/ARB Aldosterone antagonist Pre-operative furosemide dose (mg/day) Seattle Heart Failure Model estimated 1-year survival probability Plasma hemoglobin (g/dl) White cell blood count Aspartate aminotransferase (U/liter) Alanine aminotransferase (U/liter) Total bilirubin (mg/dl) Serum urea (mg/dl) Serum creatinine (mg/dl) Uric acid (mg/dl) Serum sodium (mEq/liter) BNP (pg/ml) Left ventricular end-diastolic diameter (mm) Left ventricular end-systolic diameter (mm) Left ventricular ejection fraction (%) Mid-regional right ventricular end-diastolic diameter (mm) Moderate to severe mitral valve regurgitation Moderate to severe tricuspid valve regurgitation Right atrial pressure (mm Hg) Right ventricular pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Pulmonary capillary wedge pressure (mm Hg) Cardiac index (liters/min/m2) Systematic vascular resistance (dynes/s/cm5) Pulmonary vascular resistance (Wood units) Right ventricular stroke work index RAP/PCWP
57.8 ⫾ 5.9 9 (100) 85.2 ⫾ 43.3 5 (55.6) 27.7 ⫾ 5.3 1.93 ⫾ 0.2 3.9 ⫾ 0.3 9 (100) 4 (44.4) 7 (77.8) 1 (11.1) 4 (44.4)
49.9 ⫾ 12.1 10 (90.9) 103.8 ⫾ 81.8 7 (63.6) 25.3 ⫾ 4.7 1.84 ⫾ 0.2 3.8 ⫾ 0.4 10 (90.9) 3 (27.3) 6 (54.5) 5 (45.5) 4 (36.4)
0.09 0.38 0.55 0.73 0.30 0.33 0.68 0.38 0.65 0.30 0.11 0.73
2 (22.2) 0 (0) 6 (66.6) 635 ⫾ 409 22.6 ⫾ 18.7 11.7 ⫾ 1.4 8,457 ⫾ 3,077 38 ⫾ 25 48 ⫾ 47 1.1 ⫾ 0.3 87 ⫾ 31 1.9 ⫾ 0.8 8.6 ⫾ 2.1 136 ⫾ 3 1,819 ⫾ 1,492 73 ⫾ 7.1 61.6 ⫾ 9.3 22.8 ⫾ 7.2 36.9 ⫾ 5.6 1 (11.1) 1 (11.1) 7.1 ⫾ 4.4 49.7 ⫾ 11.0 31.6 ⫾ 5.3 21.6 ⫾ 4.2 2.0 ⫾ 0.7 1,350 ⫾ 318 2.7 ⫾ 1.1 711 ⫾ 387 0.33 ⫾ 0.21
5 (45.5) 2 (18.2) 9 (81.8) 650 ⫾ 432 38.4 ⫾ 32.8 12.4 ⫾ 1.6 7,981 ⫾1,920 48 ⫾ 42 63 ⫾ 46 1.3 ⫾ 0.8 72 ⫾ 24 1.4 ⫾ 0.3 7.6 ⫾ 2.8 137 ⫾ 5 1,359 ⫾ 1,611 71.9 ⫾ 7.1 61.5 ⫾ 7.5 21.2 ⫾ 5.6 37.0 ⫾ 3.3 2 (18.2) 0 (0) 8.5 ⫾ 5.7 58.6 ⫾ 19.4 36.6 ⫾ 10.5 25.1 ⫾ 9.4 1.8 ⫾ 0.5 1,750 ⫾ 535 3.5 ⫾ 2.1 787 ⫾ 340 0.30 ⫾ 0.15
0.30 0.20 0.46 0.94 0.22 0.31 0.69 0.48 0.52 0.48 0.23 0.06 0.49 0.69 0.52 0.74 0.98 0.58 0.98 0.68 0.28 0.57 0.23 0.20 0.31 0.49 0.06 0.36 0.65 0.74
Values expressed as mean ⫾ SD or number (%) of observations. Bold values are statistically significant. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BNP, brain natriuretic peptide; IABP, intra-aortic balloon pump; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; RVD, right ventricular dysfunction.
cumbersome clinical condition for which available therapeutic options are limited (RVAD, heart transplantation) or ineffective. Importantly, the only tested variables that showed a trend toward having prognostic value for the identification of patients at increased risk for developing long-term RVD were pre-operative values of serum creatinine and systematic vascular resistance. In addition, older age also seemed to correlate weakly with increased incidence of RVF during follow-up. Finally, although statistical significance was not reached, possibly due to the small sample size, patients who finally developed RVD
could tolerate lower doses of recommended HF medication (β-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or mineralocorticoid receptor blockers) during follow-up and less often required resynchronization therapy. This observation is novel and conceivably important as it could generate further investigation into the potential salutary, anti-remodeling effects of neurohormonal blockade, even in end-stage HF patients under mechanical circulatory support. Moreover, further research is warranted regarding the correlation between resynchronization therapy and long-term preservation of RV function.
The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]
6
Table 4 Comparison of Doses of Optimal HF Pharmacologic and Resynchronization Therapy for Heart Failure Among Patients Who Presented With and Without RVD During Follow-up Treatment
RVD group (N ¼ 9)
No RVD group (N ¼ 11)
p
Cardiac resynchronization therapy Post-operative dose β-blocker ACE inhibitor/ARB Mineralocorticoid receptor antagonist
1 (11.1)
5 (45.5)
0.11
29 ⫾ 26 7⫾8 16 ⫾ 17
55 ⫾ 51 15 ⫾ 11 30 ⫾ 16
0.11 0.12 0.11
Values expressed as mean ⫾ SD or number (%) of observations. Doses estimated based on the equivalence of doses with referral medication carvedilol (β-blocker), enalapril (angiotensin-converting enzyme [ACE] inhibitor/angitensin receptor blocker [ARB]) and epleronone (mineralocorticoid receptor antagonist). Doses reflect the time-point before right ventricular dysfunction (RVD) appearance for the RVD group or latest follow-up for the no-RVD group.
Many studies have been performed over the years to identify potential clinical or paraclinical indices that could reliably predict the subgroup of heart failure patients who will manifest RVF early post-LVAD implantation.10–15 However, the incidence of late-onset RVD after durable, circulatory support has not yet been reported and investigated. The lack of relevant published data is probably due to the limited number of patients who have been supported by continuous-flow LVADs for 41 year. Indicatively, in the era of pulsatile-flow LVADs (2006 to 2009), due to their innate defects regarding durability, only 100 patients received support with a first-generation LVAD as DT and only 29 continued to be supported 18 months after implantation.16 It was only in January 2010 that the U.S. Food and Drug Administration granted approval for the first durable, continuous-flow LVAD for DT, thus enabling prolonged circulatory support. Consequently, the patients for whom long-term data are presently available are derived from this subgroup of patients, which constitutes a small portion of the total population of LVAD patients.17 In the USA and in many other countries, patients on LVAD support have higher priority status for HTx; patients who remain alive with a bridge-to-transplantation (BTT) indication will be transplanted eventually and cannot, for this reason, contribute to the study of late-onset comorbidities and complications. On the other hand, in an environment of very limited availability of donor organs, as in our country, patients with an initial BTT indication will inevitably require longterm support, due to the lack of available grafts, irrespective of initial indication. Accordingly, we are able to have longer term follow-up of continuous-flow LVAD patients. The pathophysiologic mechanisms that underlie the development of RVD after long-term mechanical support with an LVAD are poorly understood. Some older reviews,2 which did not systematically study the issue, attributed RVF to the annular dilation of the RV due to chronic leftward displacement of the interventricular septum, which in turn leads to reduced coaptation of the tricuspid valve and gradually increased regurgitation with subsequent further RV pre-load increases. Nevertheless, another possibly unrecognized contributing mechanism involves RV dyssynchrony.18 Chronic RV dyssynchrony induced by the nonpulsatile mode of LV unloading and the leftward shift of the interventricular septum could, in the long-term, contribute significantly to impairment of RV function and the appearance of RVD, independently of the fact that LVAD
support confers significant amelioration of RV hemodynamics.19 Irrespective of the underlying mechanism, knowing whether or not a patient will develop RVD post-LVAD implantation could enable an evidenced-based approach for strategy assessment (BTT or candidacy, DT) and timely implementation of alternative therapeutic options (biventricular mechanical support, HTx). In particular, patients with severe RV dysfunction, which is predicted to persist during LVAD support,20 or are at increased risk for developing post-implant RVF or RVD must be considered ineligible for LVAD implantation with the indication of DT, as this would constitute hazardous use of expensive and limited health resources, such as mechanical support. In the setting of BTT, for patients with a higher risk of developing RVF, and considering complications and morbidities associated with long-term biventricular support, widely available and inexpensive, short-term BTT modalities, such as the intra-aortic balloon pump,21–23 may be considered as the initial approach.
Study limitations Due to the single-center nature of this study and the small number of patients included, generalization of the results should be applied with caution before confirmation is available from larger population analyses. However, this does not diminish the significance of our finding that lateonset RVD not only exists but represents an epidemiologically important condition that complicates the course of prolonged circulatory support with a continuous-flow LVAD. Although the data were collected prospectively, our study is limited by its retrospective design. Despite a detailed analysis of baseline characteristics, our study was mainly descriptive. Therefore, we cannot exclude the possible contribution of some of other, unidentified variables to RVD. Larger studies with more patients are warranted to clarify the prognostic significance of various entities and variables. Moreover, many indices regarding the peri- and post-operative course of patients, which could have prognostic significance for the incidence of late-onset RVD, were not available and were not included in the analysis. In conclusion, RVD represents a late complication of mechanical circulatory support with continuous-flow
Kapelios et al.
Late-Onset RVD and LVAD Support
LVADs. RVD can manifest not only in the immediate postoperative period but also several months to years after device implantation. It seems probable that the typically utilized clinical and paraclinical markers are insufficient for accurate prediction of late-onset RVD. Timely recognition of the patients who will present this complication in the long term, although difficult at present, would be an invaluable tool for improving outcomes in LVAD patients.
Disclosure statement The authors have no conflicts of interest to disclose.
References 1. Dang NC, Topkara VK, Mercando M, et al. Right heart failure after left ventricular assist device implantation in patients with chronic congestive heart failure. J Heart Lung Transplant 2006;25:1-6. 2. Romano MA, Cowger J, Aaronson KD, et al. Diagnosis and management of right-sided heart failure in subjects supported with left ventricular assist devices. Curr Treat Options Cardiovasc Med 2010;12:420-30. 3. Deng MC, Edwards LB, Hertz MI, et al. Mechanical circulatory support device database of the International Society for Heart and Lung Transplantation: third annual report—2005. J Heart Lung Transplant 2005;24:1182-7. 4. Kavarana MN, Pessin-Minsley MS, Urtecho J, et al. Right ventricular dysfunction and organ failure in left ventricular assist device recipients: a continuing problem. Ann Thorac Surg 2002;73:745-50. 5. Morgan JA, John R, Lee BJ, et al. Is severe right ventricular failure in left ventricular assist device recipients a risk factor for unsuccessful bridging to transplant and post-transplant mortality? Ann Thorac Surg 2004;77:859-63. 6. Ochiai Y, McCarthy PM, Smedira NG, et al. Predictors of severe right ventricular failure after implantable left ventricular assist device insertion: analysis of 245 patients. Circulation 2002;106(suppl 1): 198-202. 7. Santamore WP, Austin EH III, Gray L Jr. Overcoming right ventricular failure with left ventricular assist devices. J Heart Lung Transplant 1997;16:1122-8. 8. DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 1916;17:863-71. 9. Levy WC, Mozaffarian D, Linker DT, et al. The Seattle Heart Failure Model: prediction of survival in heart failure. Circulation 2006;113: 1424-33.
7 10. Kormos RL, Teuteberg JJ, Pagani FD, et al. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010;139:1316-24. 11. Matthews JC, Koelling TM, Pagani FD, et al. The right ventricular failure risk score a pre-operative tool for assessing the risk of right ventricular failure in left ventricular assist device candidates. J Am Coll Cardiol 2008;51:2163-72. 12. Fitzpatrick JR III, Frederick JR, Hsu VM, et al. Risk score derived from pre-operative data analysis predicts the need for biventricular mechanical circulatory support. J Heart Lung Transplant 2008;27: 1286-92. 13. Puwanant S, Hamilton KK, Klodell CT, et al. Tricuspid annular motion as a predictor of severe right ventricular failure after left ventricular assist device implantation. J Heart Lung Transplant 2008;27:1102-7. 14. Raina A, Rammohan HRS, Gertz ZM, et al. Postoperative right ventricular failure after left ventricular assist device placement is predicted by preoperative echocardiographic structural, hemodynamic, and functional parameters. J Card Fail 2013;19:16-24. 15. Shiga T, Kinugawa K, Imamura T, et al. Combination evaluation of preoperative risk indices predicts requirement of biventricular assist device. Circ J 2012;76:2785-91. 16. Kirklin JK, Naftel DC, Kormos RL, et al. Second INTERMACS annual report: more than 1,000 primary left ventricular assist device implants. J Heart Lung Transplant 2010;29:1-10. 17. Kirklin JK, Naftel DC, Kormos RL, et al. Fifth INTERMACS annual report: risk factor analysis from more than 6,000 mechanical circulatory support patients. J Heart Lung Transplant 2013;32:141-56. 18. Felix SE, Martina JR, Kirkels JH, et al. Continuous-flow left ventricular assist device support in patients with advanced heart failure: points of interest for the daily management. Eur J Heart Fail 2012;14:351-6. 19. Pauwaa S, Bhat G, Tatooles AJ, et al. How effective are continuous flow left ventricular assist devices in lowering high pulmonary artery pressures in heart transplant candidates? Cardiol J 2012;19:153-8. 20. Palardy M, Nohria A, Rivero J, et al. Right ventricular dysfunction during intensive pharmacologic unloading persists after mechanical unloading. J Card Fail 2010;16:218-24. 21. Umakanthan R, Hoff SJ, Solenkova N, et al. Benefits of ambulatory axillary intra-aortic balloon pump for circulatory support as bridge to heart transplant. J Thorac Cardiovasc Surg 2012;143:1193-7. 22. Estep JD, Cordero-Reyes AM, Bhimaraj A, et al. Percutaneous placement of an intra-aortic balloon pump in the left axillary/subclavian position provides safe, ambulatory long-term support as bridge to heart transplantation. J Am Coll Cardiol 2013;1:382-8. 23. Kapelios CJ, Terrovitis JV, Siskas P, et al. Counterpulsation: a concept with a remarkable past, an established present and challenging future. Int J Cardiol 2014;172:318-25.
ORIGINAL CLINICAL SCIENCE
Late-onset right ventricular dysfunction after mechanical support by a continuous-flow left ventricular assist device Chris J. Kapelios, MD,a Christos Charitos, MD,b Elisabeth Kaldara, MD,a Konstantinos Malliaras, MD,a Emmeleia Nana, MD,a Christos Pantsios, MD,a Evangelos Repasos, MD,a Michael Tsamatsoulis, MD,b Savvas Toumanidis, MD,c and John N. Nanas, MD, PhDa From the aDepartment of Cardiology, University of Athens School of Medicine, Athens; bDepartment of Cardiac Surgery, Evangelismos Hospital, Athens; and the cDepartment of Therapeutics, Alexandra Hospital, University of Athens Medical School, Athens, Greece.
KEYWORDS: chronic heart failure; destination therapy; left ventricular assist device; right ventricular failure; right ventricular dysfunction; mechanical support
BACKGROUND: Right heart failure (RHF) is a serious post-operative complication of left ventricular assist device (LVAD) implantation, with significant morbidity and mortality. Many clinical, hemodynamic and laboratory variables have been shown to have prognostic value for appearance of RHF. We sought to investigate the incidence of new-onset right ventricular dysfunction (RVD) complicating the long-term use of LVADs. METHODS: We retrospectively examined all patients supported with a continuous-flow LVAD for 41 year at our center. RESULTS: Twenty patients (mean age 54 ⫾ 10 years, 95% men, 60% with ischemic cardiomyopathy, left ventricular ejection fraction 22 ⫾ 6%, pulmonary capillary wedge pressure 23.5 ⫾ 7.5 mm Hg, brain natriuretic peptide [BNP] 1,566 ⫾ 1,536 pg/ml, serum creatinine 1.6 ⫾ 0.64 mg/dl, furosemide dose 643 ⫾ 410 mg/day) underwent long-term mechanical support as destination therapy support with a continuous-flow LVAD (HeartMate II) at our center. During follow-up (1,219 ⫾ 692 days), 9 patients (45%) manifested symptoms and signs of RVD (increase in right atrial pressure [RAP], BNP and daily furosemide dose compared with the early post-operative period). In these patients, RAP was increased by 6.6 ⫾ 2.6 mm Hg and BNP by 526 ⫾ 477 pg/ml, whereas furosemide dose increased by 145 ⫾ 119 mg. The mean and median times of RVD onset were 2.3 ⫾ 1.5 and 2.1 years, respectively, after LVAD implantation (range 0.4 to 4.8 years). Four of these patients (44.4%) demonstrated further deterioration of RV function and died 73 ⫾ 106 days (median 25 days, range 9 to 231 days) after first manifestation of RVD. Comparisons of baseline variables regarding medical history and clinical status did not demonstrate significant differences between the patients with or without RVD, including parameters related to RV function at the time of implantation. CONCLUSIONS: Late-onset RVD is a complication of LVAD support, which can manifest several months to years from device implantation. This complication has significant adverse implications with regard to patient outcome. Prognostic factors need to be identified to follow and treat high-risk patients more efficiently. J Heart Lung Transplant ]]]];]:]]]–]]] r 2015 International Society for Heart and Lung Transplantation. All rights reserved.
Reprint requests: John N. Nanas, MD, PhD, Third Department of Cardiology, University of Athens School of Medicine, 67 Mikras Asias Street, 11 527 Athens, Greece. Telephone: þ30-210-823-6877. Fax: þ30-210-778-9901. E-mail address: [email protected]
Right ventricular failure (RVF) is a common complication of left ventricular assist device (LVAD) implantation.1 It is usually reported in the early post-operative period and is accompanied by significantly increased peri-operative
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2015.05.024
2
The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]
morbidity and mortality and a compromised survival to and after heart transplantation (HTx).2–6 The pathophysiologic mechanisms underlying the development of RVF after LVAD implantation are complex. The improved cardiac output with LVAD assistance leads to a sudden increase in right ventricular (RV) pre-load. The leftward shift of the interventricular septum distorts RV geometry and diminishes the systolic capacity of the RV.7 Moreover, during cardiopulmonary bypass, complement activation and blood transfusions also increase pulmonary vascular resistance and result in increased RV after load.2 The RV cannot acutely increase its contractility in these conditions of increased pre- and after-load and RV failure ensues. Timely identification of the patients who will postoperatively develop RVF represents a significant therapeutic target. These patients may be given a higher priority for HTx, and the implantation of a right ventricular assist device (RVAD) may be considered earlier. Nevertheless, the potential of late RV dysfunction (RVD) presentation after prolonged LV mechanical support has been neither recognized nor investigated until now. Our study was designed to investigate the incidence of RVD after long-term mechanical support with a continuousflow LVAD.
Methods Devices An implantable, second-generation, continuous-flow HeartMate II LVAD (Thoratec, Pleasanton, CA) was implanted in all patients.
Study sample Over the 7.5-year period from February 2006 through November 2013, 30 patients underwent durable mechanical circulatory support with a HeartMate II LVAD at our tertiary-care university institute. All patients who were supported with an LVAD for a period of 41 year were identified from our database.
blocker; pre-operative dosing of furosemide; and estimated 1-year probability of survival, according to the Seattle Heart Failure Model score.9 With regard to follow-up, the parameters recorded were treatment doses of β-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or mineralocorticoid receptor blockers as well as the frequency of resynchronization therapy.
Laboratory data Plasma hemoglobin, white cell blood count, liver function tests, blood urea, creatinine and uric acid, total serum bilirubin, sodium, cholesterol and brain natriuretic peptide (BNP) levels were recorded and included in the analysis.
Echocardiography measurements The parameters recorded and evaluated were LV end-diastolic and end-systolic diameters, RV mid-regional end-diastolic diameter, severity of mitral and tricuspid valve regurgitation and LV ejection fraction (Simpson’s method).
Hemodynamic measurements A pulmonary artery catheter was used to measure capillary wedge pressure, RV pressure, pulmonary artery pressure (PAP), right atrial pressure (RAP) and cardiac index (CI). Systemic vascular resistance (in dynes/s/cm5) and pulmonary vascular resistance (Wood units) were calculated. RV stroke work index (RVSWI) was calculated using the following formula: RVSWI ¼ (mean PAP – mean RAP) SVI 1,000, where SVI (stroke volume index) equals CI divided by heart rate.
RVF and RVD definitions RVF is defined and classified according to the International Mechanically Assisted Circulatory Support Registry (available online at http://www.ishlt.org/registries/protocol.asp/) as follows: Severe right heart failure (RHF): Need for RV assist device
implantation.
Study design Medical history, clinical, laboratory, echocardiography and hemodynamic data at LVAD implantation from all patients were recorded. The study was approved by our institution’s ethics review board and conformed to the principles outlined in the Declaration of Helsinki.
Medical history and clinical status The parameters recorded and evaluated were: age; gender; body mass index; body surface area (using the Dubois formula)8; etiology of heart failure; time from first heart failure (HF) diagnosis; New York Heart Association functional class; preoperative need for positive inotropic agents or intra-aortic balloon pump support; presence of diabetes mellitus; left bundle branch block and cardiac resynchronization therapy; pre-operative treatment with a β-blocker, an angiotensin-converting enzyme inhibitor/ angiotensin receptor blocker or a mineralocorticoid receptor
Moderate RHF: Inotrope or intravenous or inhaled pulmo-
nary vasodilator (e.g., prostaglandin E or inhaled nitric oxide) for a duration of 41 week at any time after LVAD implantation. Mild RHF: Meeting 2 of the 4 following clinical criteria: CVP 4 18 mm Hg or mean RAP 4 18 mm Hg. CI o 2.3 liters/min/m2 (according to Swan). Ascites or evidence of moderate to worse peripheral edema. Evidence of elevated central venous pressure (CVP) by echocardiography (dilated vena cava, inferior vena cava with collapse), physical examination (signs of increased jugular venous pressure). RVD in our study was defined as the appearance of persistent symptoms and signs of peripheral vascular congestion (elevated CVP, hepatomegaly or congestion-related pain of the right upper quadrant, peripheral edema, ascites, increase in BNP values) necessitating the significant up-titration of diuretics dose (increase of 480 mg or 3-fold the intial dose) or use of positive inotropic agents.
Kapelios et al.
Late-Onset RVD and LVAD Support
3
Table 1 Characteristics of Study Population at the Time of Left Ventricular Assist Device Implantation Variable
Value
Age (years) Male gender Ischemic heart disease Body surface area (m2) New York Heart Association class Left ventricular ejection fraction (%) Pulmonary capillary wedge pressure (mm Hg) Pre-operative need for intra-aortic balloon pump Furosemide dose (mg/day) Serum creatinine (mg/dl) BNP (pg/ml)
53.5 ⫾ 10.4 19 (95) 12 (60) 1.89 ⫾ 0.2 3.85 ⫾ 0.4 21.9 ⫾ 6.2 23.5 ⫾ 7.5 7 (35) 643 ⫾ 410 1.60 ⫾ 0.64 1,566 ⫾ 1,536
Values expressed as mean ⫾ SD or number (%) of observations. BNP, brain natriuretic peptide.
Statistical analysis We used PASW Statistics version 19.0 (SPSS, Inc., Chicago, Illinois) for all statistical analyses. Continuous variables are expressed as mean ⫾ standard deviation and were compared using the unpaired t-test. Categorical variables are expressed as counts and percentages and were compared using the chi-square test. Comparison of withingroup changes between the early post-implant period and long-term follow-up was performed with the paired t-test. All significance tests were 2-tailed, and p o 0.05 was considered statistically significant.
Results A total of 20 patients (67% of all patients) fulfilled the predefined criteria and were included in the analysis. Among the 10 patients excluded, 4 had undergone recent implantation and were followed for o1 year at the time of the analysis and the remaining 6 had died within the first year; 2 in the early post-operative period from septic shock and sudden cardiac death, respectively, 3 from multi-organ dysfunction and 1 from stroke. However, none of the patients excluded from the analysis had presented with Table 2
symptoms or signs of RVD during the available follow-up. Patients’ baseline characteristics, as well as clinical, laboratory, echocardiography and hemodynamic variables, are presented in Table 1. Patients’ age was 53.5 ⫾ 10.4 years, 95% were men and 60% had ischemic cardiomyopathy. During the follow-up period (mean duration 3.4 ⫾ 1.9 years, median duration 2.9 years, range 1.2 to 7.1 years) 9 patients (45%) developed RVD with clinical manifestations of peripheral congestion. Detailed information on the time of incidence of RVD is presented in Table 2. At the time of RVD appearance in these patients, the mean increase of RAP from the early post-operative period was of 6.6 ⫾ 2.6 mm Hg (p ¼ 0.001), whereas in the no-RVD group patients it was 1.2 ⫾ 2.0 mm Hg (p ¼ 0.34) (p ¼ 0.005 for between-group comparison). The respective changes of BNP values and daily furosemide dose in the RVD and noRVD group patients were: 527 ⫾ 477 (p ¼ 0.029) vs 22 ⫾ 115 pg/ml (p ¼ 0.73), p ¼ 0.08 for between-group comparison; and 145 ⫾ 119 (p ¼ 0.035) vs –12 ⫾ 77 mg (p ¼ 0.75), p ¼ 0.047 for between-group comparison, respectively (Figure 1). The mean and median time of RVD onset were 2.3 ⫾ 1.5 and 2.1 years after LVAD implantation (range 0.4 to 4.8 years) (Figure 2). Four of these patients (44.4%) showed further deterioration of RV function, despite the use of high doses of intravenous inotropes and pulmonary vasodilators, and they eventually died 73 ⫾ 106 days (median 25 days; range 9 to 231 days) after the first manifestation of RVD and 2.9 ⫾ 1.8 years after the initiation of LVAD support overall. The mode of patients’ death was isolated RVF in 2 patients and RVF complicated by septic shock/multi-organ dysfunction in the other 2. Importantly, the study population consisted of destination therapy (DT) patients, who were ineligible for HTx and could not be assisted with an RVAD. Interestingly, survival in the other 5 patients who were stabilized only with diuretics dose up-titration, without the need for inotropes or vasodilators, was significantly higher (60% vs 0%; log-rank test, p ¼ 0.003). The mode of death in the 2 patients who died in this subgroup was brain cancer and hemorrhagic stroke and occurred 381 and 740 days postRVD appearance, respectively. All comparisons of patients’ characteristics between the 2 groups are shown in Table 3. Univariate comparisons of
Time-dependent Information on RVD and Death Among Patients Presenting With RVD
Patient number
Age at implantation (years)
Gender
1 2 3 4 5 6 7 8 9
62 66 59 51 54 62 62 48 56
M M M M M M M M M
HF etiology
Time from implantation until RVD appearance
Inotropes for RVD
Death from RVD
Time from RVD appearance until death
IDM ICM ICM ICM ICM IDM IDM IDM ICM
813 1,722 128 527 509 1,695 506 753 919
No Yes No Yes No No No Yes Yes
No Yes No Yes No No No Yes Yes
— 231 381 9 — — 740 30 20
ICM, ischemic cardiomyopathy, IDM, idiopathic dilated cardiomyopathy; M, male; RVD, right ventricular dysfunction
4
The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]
Figure 1 Changes in BNP, right atrial pressure and dose of furosemide between early LVAD support and prolonged follow-up in the 2 study groups (p o 0.05 for all changes in the RVF group).
the variables regarding medical history and clinical status did not demonstrate significant differences between the groups of patients with or without RVD after LVAD implantation. Interestingly, body surface area was similar in the 2 groups (1.93 vs 1.84 m2 for the RVD and no RVD groups, respectively, p ¼ 0.33), as were the rates of preoperative support with positive inotropic agents (100% vs 90.9%, p ¼ 0.38) or an intra-aortic balloon pump (44.4% vs 27.3%, p ¼ 0.65). Notably, there was a mild trend for patients presenting with RVD to be of older age (57.8 vs 49.9 years, p ¼ 0.09). Regarding the doses of optimal HF medical therapy during follow-up, patients presenting with RVD tended to receive the recommended medication,
especially ACE inhibitors (p ¼ 0.11) and mineralocorticoid receptor antagonists (p ¼ 0.10), at lower doses than those who did not have RVD, but the difference was not statistically significant (Table 4). Analysis of laboratory parameters revealed a strong trend for patients who developed late-onset RVD during followup to have higher values of serum creatinine before LVAD implantation (1.9 vs 1.4 mg/dl, p ¼ 0.06). Values for liver function tests, bilirubin and BNP did not differ between the 2 study groups. Comparison of the RVD and no-RVD groups with regard to echocardiography and hemodynamic indices did not confer any significant differences. LV and RV dimensions and intracardial filling pressures were similar between the groups. Similarly, severity of valve disease did not differ between the 2 groups in our cohort. However, there was a strong trend for decreased systematic vascular resistance in patients who eventually presented with RVD (1,350 vs 1,750 dynes/s/cm5, p ¼ 0.06).
Discussion
Figure 2 Kaplan–Meier curve of survival free from RVD in the study population.
Our study has demonstrated that RVD can appear as a lateonset complication in patients who undergo long-term mechanical assistance with a continuous-flow LVAD. This complication appeared commonly, affecting 4 of 10 patients who were supported for 41 year in this cohort. Furthermore, the incidence of late-onset RVD seems to have imposed a significant deleterious effect on prognosis of patients, as it was the underlying cause of death in 45% of patients presenting with RVD and in 20% of patients in the study population overall. Characteristically, the mean interval from RVD manifestation until time of death was approximately 2 months, implying that RVD constitutes a
Kapelios et al.
Late-Onset RVD and LVAD Support
5
Table 3 Comparison of Baseline Demographic, Clinical, Echocardiographic and Hemodynamic Variables Between Patients Who Presented With and Without RVD During Follow-up Characteristic
RVD group (N ¼ 9)
No RVD group (N ¼ 11)
p
Age (years) Male gender Time from first diagnosis (months) Ischemic cardiomyopathy Body mass index (kg/m2) Body surface area (m2) New York Heart Association class Pre-operative need for inotropes Pre-operative need for IABP Left bundle branch block Cardiac resynchronization therapy Diabetes mellitus Pre-operative receipt of: β-blocker ACE inhibitor/ARB Aldosterone antagonist Pre-operative furosemide dose (mg/day) Seattle Heart Failure Model estimated 1-year survival probability Plasma hemoglobin (g/dl) White cell blood count Aspartate aminotransferase (U/liter) Alanine aminotransferase (U/liter) Total bilirubin (mg/dl) Serum urea (mg/dl) Serum creatinine (mg/dl) Uric acid (mg/dl) Serum sodium (mEq/liter) BNP (pg/ml) Left ventricular end-diastolic diameter (mm) Left ventricular end-systolic diameter (mm) Left ventricular ejection fraction (%) Mid-regional right ventricular end-diastolic diameter (mm) Moderate to severe mitral valve regurgitation Moderate to severe tricuspid valve regurgitation Right atrial pressure (mm Hg) Right ventricular pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Pulmonary capillary wedge pressure (mm Hg) Cardiac index (liters/min/m2) Systematic vascular resistance (dynes/s/cm5) Pulmonary vascular resistance (Wood units) Right ventricular stroke work index RAP/PCWP
57.8 ⫾ 5.9 9 (100) 85.2 ⫾ 43.3 5 (55.6) 27.7 ⫾ 5.3 1.93 ⫾ 0.2 3.9 ⫾ 0.3 9 (100) 4 (44.4) 7 (77.8) 1 (11.1) 4 (44.4)
49.9 ⫾ 12.1 10 (90.9) 103.8 ⫾ 81.8 7 (63.6) 25.3 ⫾ 4.7 1.84 ⫾ 0.2 3.8 ⫾ 0.4 10 (90.9) 3 (27.3) 6 (54.5) 5 (45.5) 4 (36.4)
0.09 0.38 0.55 0.73 0.30 0.33 0.68 0.38 0.65 0.30 0.11 0.73
2 (22.2) 0 (0) 6 (66.6) 635 ⫾ 409 22.6 ⫾ 18.7 11.7 ⫾ 1.4 8,457 ⫾ 3,077 38 ⫾ 25 48 ⫾ 47 1.1 ⫾ 0.3 87 ⫾ 31 1.9 ⫾ 0.8 8.6 ⫾ 2.1 136 ⫾ 3 1,819 ⫾ 1,492 73 ⫾ 7.1 61.6 ⫾ 9.3 22.8 ⫾ 7.2 36.9 ⫾ 5.6 1 (11.1) 1 (11.1) 7.1 ⫾ 4.4 49.7 ⫾ 11.0 31.6 ⫾ 5.3 21.6 ⫾ 4.2 2.0 ⫾ 0.7 1,350 ⫾ 318 2.7 ⫾ 1.1 711 ⫾ 387 0.33 ⫾ 0.21
5 (45.5) 2 (18.2) 9 (81.8) 650 ⫾ 432 38.4 ⫾ 32.8 12.4 ⫾ 1.6 7,981 ⫾1,920 48 ⫾ 42 63 ⫾ 46 1.3 ⫾ 0.8 72 ⫾ 24 1.4 ⫾ 0.3 7.6 ⫾ 2.8 137 ⫾ 5 1,359 ⫾ 1,611 71.9 ⫾ 7.1 61.5 ⫾ 7.5 21.2 ⫾ 5.6 37.0 ⫾ 3.3 2 (18.2) 0 (0) 8.5 ⫾ 5.7 58.6 ⫾ 19.4 36.6 ⫾ 10.5 25.1 ⫾ 9.4 1.8 ⫾ 0.5 1,750 ⫾ 535 3.5 ⫾ 2.1 787 ⫾ 340 0.30 ⫾ 0.15
0.30 0.20 0.46 0.94 0.22 0.31 0.69 0.48 0.52 0.48 0.23 0.06 0.49 0.69 0.52 0.74 0.98 0.58 0.98 0.68 0.28 0.57 0.23 0.20 0.31 0.49 0.06 0.36 0.65 0.74
Values expressed as mean ⫾ SD or number (%) of observations. Bold values are statistically significant. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BNP, brain natriuretic peptide; IABP, intra-aortic balloon pump; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; RVD, right ventricular dysfunction.
cumbersome clinical condition for which available therapeutic options are limited (RVAD, heart transplantation) or ineffective. Importantly, the only tested variables that showed a trend toward having prognostic value for the identification of patients at increased risk for developing long-term RVD were pre-operative values of serum creatinine and systematic vascular resistance. In addition, older age also seemed to correlate weakly with increased incidence of RVF during follow-up. Finally, although statistical significance was not reached, possibly due to the small sample size, patients who finally developed RVD
could tolerate lower doses of recommended HF medication (β-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or mineralocorticoid receptor blockers) during follow-up and less often required resynchronization therapy. This observation is novel and conceivably important as it could generate further investigation into the potential salutary, anti-remodeling effects of neurohormonal blockade, even in end-stage HF patients under mechanical circulatory support. Moreover, further research is warranted regarding the correlation between resynchronization therapy and long-term preservation of RV function.
The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]
6
Table 4 Comparison of Doses of Optimal HF Pharmacologic and Resynchronization Therapy for Heart Failure Among Patients Who Presented With and Without RVD During Follow-up Treatment
RVD group (N ¼ 9)
No RVD group (N ¼ 11)
p
Cardiac resynchronization therapy Post-operative dose β-blocker ACE inhibitor/ARB Mineralocorticoid receptor antagonist
1 (11.1)
5 (45.5)
0.11
29 ⫾ 26 7⫾8 16 ⫾ 17
55 ⫾ 51 15 ⫾ 11 30 ⫾ 16
0.11 0.12 0.11
Values expressed as mean ⫾ SD or number (%) of observations. Doses estimated based on the equivalence of doses with referral medication carvedilol (β-blocker), enalapril (angiotensin-converting enzyme [ACE] inhibitor/angitensin receptor blocker [ARB]) and epleronone (mineralocorticoid receptor antagonist). Doses reflect the time-point before right ventricular dysfunction (RVD) appearance for the RVD group or latest follow-up for the no-RVD group.
Many studies have been performed over the years to identify potential clinical or paraclinical indices that could reliably predict the subgroup of heart failure patients who will manifest RVF early post-LVAD implantation.10–15 However, the incidence of late-onset RVD after durable, circulatory support has not yet been reported and investigated. The lack of relevant published data is probably due to the limited number of patients who have been supported by continuous-flow LVADs for 41 year. Indicatively, in the era of pulsatile-flow LVADs (2006 to 2009), due to their innate defects regarding durability, only 100 patients received support with a first-generation LVAD as DT and only 29 continued to be supported 18 months after implantation.16 It was only in January 2010 that the U.S. Food and Drug Administration granted approval for the first durable, continuous-flow LVAD for DT, thus enabling prolonged circulatory support. Consequently, the patients for whom long-term data are presently available are derived from this subgroup of patients, which constitutes a small portion of the total population of LVAD patients.17 In the USA and in many other countries, patients on LVAD support have higher priority status for HTx; patients who remain alive with a bridge-to-transplantation (BTT) indication will be transplanted eventually and cannot, for this reason, contribute to the study of late-onset comorbidities and complications. On the other hand, in an environment of very limited availability of donor organs, as in our country, patients with an initial BTT indication will inevitably require longterm support, due to the lack of available grafts, irrespective of initial indication. Accordingly, we are able to have longer term follow-up of continuous-flow LVAD patients. The pathophysiologic mechanisms that underlie the development of RVD after long-term mechanical support with an LVAD are poorly understood. Some older reviews,2 which did not systematically study the issue, attributed RVF to the annular dilation of the RV due to chronic leftward displacement of the interventricular septum, which in turn leads to reduced coaptation of the tricuspid valve and gradually increased regurgitation with subsequent further RV pre-load increases. Nevertheless, another possibly unrecognized contributing mechanism involves RV dyssynchrony.18 Chronic RV dyssynchrony induced by the nonpulsatile mode of LV unloading and the leftward shift of the interventricular septum could, in the long-term, contribute significantly to impairment of RV function and the appearance of RVD, independently of the fact that LVAD
support confers significant amelioration of RV hemodynamics.19 Irrespective of the underlying mechanism, knowing whether or not a patient will develop RVD post-LVAD implantation could enable an evidenced-based approach for strategy assessment (BTT or candidacy, DT) and timely implementation of alternative therapeutic options (biventricular mechanical support, HTx). In particular, patients with severe RV dysfunction, which is predicted to persist during LVAD support,20 or are at increased risk for developing post-implant RVF or RVD must be considered ineligible for LVAD implantation with the indication of DT, as this would constitute hazardous use of expensive and limited health resources, such as mechanical support. In the setting of BTT, for patients with a higher risk of developing RVF, and considering complications and morbidities associated with long-term biventricular support, widely available and inexpensive, short-term BTT modalities, such as the intra-aortic balloon pump,21–23 may be considered as the initial approach.
Study limitations Due to the single-center nature of this study and the small number of patients included, generalization of the results should be applied with caution before confirmation is available from larger population analyses. However, this does not diminish the significance of our finding that lateonset RVD not only exists but represents an epidemiologically important condition that complicates the course of prolonged circulatory support with a continuous-flow LVAD. Although the data were collected prospectively, our study is limited by its retrospective design. Despite a detailed analysis of baseline characteristics, our study was mainly descriptive. Therefore, we cannot exclude the possible contribution of some of other, unidentified variables to RVD. Larger studies with more patients are warranted to clarify the prognostic significance of various entities and variables. Moreover, many indices regarding the peri- and post-operative course of patients, which could have prognostic significance for the incidence of late-onset RVD, were not available and were not included in the analysis. In conclusion, RVD represents a late complication of mechanical circulatory support with continuous-flow
Kapelios et al.
Late-Onset RVD and LVAD Support
LVADs. RVD can manifest not only in the immediate postoperative period but also several months to years after device implantation. It seems probable that the typically utilized clinical and paraclinical markers are insufficient for accurate prediction of late-onset RVD. Timely recognition of the patients who will present this complication in the long term, although difficult at present, would be an invaluable tool for improving outcomes in LVAD patients.
Disclosure statement The authors have no conflicts of interest to disclose.
References 1. Dang NC, Topkara VK, Mercando M, et al. Right heart failure after left ventricular assist device implantation in patients with chronic congestive heart failure. J Heart Lung Transplant 2006;25:1-6. 2. Romano MA, Cowger J, Aaronson KD, et al. Diagnosis and management of right-sided heart failure in subjects supported with left ventricular assist devices. Curr Treat Options Cardiovasc Med 2010;12:420-30. 3. Deng MC, Edwards LB, Hertz MI, et al. Mechanical circulatory support device database of the International Society for Heart and Lung Transplantation: third annual report—2005. J Heart Lung Transplant 2005;24:1182-7. 4. Kavarana MN, Pessin-Minsley MS, Urtecho J, et al. Right ventricular dysfunction and organ failure in left ventricular assist device recipients: a continuing problem. Ann Thorac Surg 2002;73:745-50. 5. Morgan JA, John R, Lee BJ, et al. Is severe right ventricular failure in left ventricular assist device recipients a risk factor for unsuccessful bridging to transplant and post-transplant mortality? Ann Thorac Surg 2004;77:859-63. 6. Ochiai Y, McCarthy PM, Smedira NG, et al. Predictors of severe right ventricular failure after implantable left ventricular assist device insertion: analysis of 245 patients. Circulation 2002;106(suppl 1): 198-202. 7. Santamore WP, Austin EH III, Gray L Jr. Overcoming right ventricular failure with left ventricular assist devices. J Heart Lung Transplant 1997;16:1122-8. 8. DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 1916;17:863-71. 9. Levy WC, Mozaffarian D, Linker DT, et al. The Seattle Heart Failure Model: prediction of survival in heart failure. Circulation 2006;113: 1424-33.
7 10. Kormos RL, Teuteberg JJ, Pagani FD, et al. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010;139:1316-24. 11. Matthews JC, Koelling TM, Pagani FD, et al. The right ventricular failure risk score a pre-operative tool for assessing the risk of right ventricular failure in left ventricular assist device candidates. J Am Coll Cardiol 2008;51:2163-72. 12. Fitzpatrick JR III, Frederick JR, Hsu VM, et al. Risk score derived from pre-operative data analysis predicts the need for biventricular mechanical circulatory support. J Heart Lung Transplant 2008;27: 1286-92. 13. Puwanant S, Hamilton KK, Klodell CT, et al. Tricuspid annular motion as a predictor of severe right ventricular failure after left ventricular assist device implantation. J Heart Lung Transplant 2008;27:1102-7. 14. Raina A, Rammohan HRS, Gertz ZM, et al. Postoperative right ventricular failure after left ventricular assist device placement is predicted by preoperative echocardiographic structural, hemodynamic, and functional parameters. J Card Fail 2013;19:16-24. 15. Shiga T, Kinugawa K, Imamura T, et al. Combination evaluation of preoperative risk indices predicts requirement of biventricular assist device. Circ J 2012;76:2785-91. 16. Kirklin JK, Naftel DC, Kormos RL, et al. Second INTERMACS annual report: more than 1,000 primary left ventricular assist device implants. J Heart Lung Transplant 2010;29:1-10. 17. Kirklin JK, Naftel DC, Kormos RL, et al. Fifth INTERMACS annual report: risk factor analysis from more than 6,000 mechanical circulatory support patients. J Heart Lung Transplant 2013;32:141-56. 18. Felix SE, Martina JR, Kirkels JH, et al. Continuous-flow left ventricular assist device support in patients with advanced heart failure: points of interest for the daily management. Eur J Heart Fail 2012;14:351-6. 19. Pauwaa S, Bhat G, Tatooles AJ, et al. How effective are continuous flow left ventricular assist devices in lowering high pulmonary artery pressures in heart transplant candidates? Cardiol J 2012;19:153-8. 20. Palardy M, Nohria A, Rivero J, et al. Right ventricular dysfunction during intensive pharmacologic unloading persists after mechanical unloading. J Card Fail 2010;16:218-24. 21. Umakanthan R, Hoff SJ, Solenkova N, et al. Benefits of ambulatory axillary intra-aortic balloon pump for circulatory support as bridge to heart transplant. J Thorac Cardiovasc Surg 2012;143:1193-7. 22. Estep JD, Cordero-Reyes AM, Bhimaraj A, et al. Percutaneous placement of an intra-aortic balloon pump in the left axillary/subclavian position provides safe, ambulatory long-term support as bridge to heart transplantation. J Am Coll Cardiol 2013;1:382-8. 23. Kapelios CJ, Terrovitis JV, Siskas P, et al. Counterpulsation: a concept with a remarkable past, an established present and challenging future. Int J Cardiol 2014;172:318-25.
