Thromboembolic stroke in patients with a HeartMate-II left ventricular assist device - the role of anticoagulation.

BACKGROUND AND PURPOSE: It is unknown what the optimal anticoagulant level is to prevent thromboembolic stroke in patients with left ventricular assist device (LVAD) support. We aimed to evaluate the relation between coagulation status and the occurrence of thromboembolic stroke in HeartMate-II LVAD assisted patients. METHODS: Thirty-eight consecutive patients with a HeartMate-II LVAD were included. Coagulation status was classified according to INR and aPTT ratio at: 1) the moment of first thromboembolic stroke; and 2) during the two weeks preceding the first thromboembolic stroke to assess long-term coagulation status. In patients without stroke, coagulation status was determined just before heart transplant, VAD explantation or death, whichever came first, and at two weeks preceding these surrogate endpoints. Based on coagulation status, patients were divided in two groups: Group I (reference group) was defined as INR below 2 and aPTT ratio below 1.5; Group II (adequate anticoagulation) as INR above 2 or aPTT ratio above 1.5. Logistic regression analysis was performed to assess the odds ratio for developing stroke for patients with adequate anticoagulation compared to the reference Group. RESULTS: Thromboembolic stroke occurred in six (16 %) patients, none within 2 weeks after LVAD implantation. Considering coagulation status at the time of event, patients in coagulation Group II had no decreased risk for thromboembolic stroke (OR 0.78; 95 % CI 0.12-5.0). Results for coagulation status 2 weeks prior of event could not be calculated as all six strokes occurred in Group II. CONCLUSION: In our experience anticoagulation within predefined targets is not associated with a reduced thromboembolic stroke risk in patients with a HeartMate-II LVAD on antiplatelet therapy. However, no firm statement about the effect of either anticoagulant or antiaggregant therapy can be made based on our study. A larger randomized study is needed to support the hypothesis that there may be no additional benefit of coumarin or heparin therapy compared with antiplatelet therapy alone.

Myocardial fibrosis and pro-fibrotic markers in end-stage heart failure patients during continuous-flow left ventricular assist device support.

OBJECTIVES: During support with a left ventricular assist device (LVAD), partial reverse remodelling takes place in which fibrosis plays an important role. In this study, we analysed the histological changes and expression of fibrotic markers in patients with advanced heart failure (HF) during continuous-flow LVAD (cf-LVAD) support. METHODS: In 25 patients, myocardial tissue at the time of LVAD implantation (pre-LVAD) was compared with tissue from the explanted left ventricle (post-LVAD). Interstitial fibrosis and cardiomyocyte size were analysed pre- and post-LVAD. Plasma was obtained from all patients before and during LVAD support. Plasma levels, cardiac mRNA and protein expression of brain natriuretic peptide (BNP), galectin-3 (Gal-3), connective tissue growth factor (CTGF), osteopontin (OPN) and transforming growth factor ß-1 were determined. RESULTS: Fibrosis increased during cf-LVAD unloading (P < 0.05). Cardiomyocytes elongated (P < 0.05), whereas cross-sectional area did not change. BNP, Gal-3, CTGF and OPN were significantly elevated pre-LVAD in comparison with controls. BNP decreased significantly after 1 month of cf-LVAD support (P < 0.001) to near-normal levels. Pro-fibrotic markers remained elevated in comparison with controls. CONCLUSIONS: cf-LVAD support is associated with lengthening of cardiomyocytes, without alterations in diameter size. Remarkably, myocardial fibrosis increased as well as circulating pro-fibrotic markers. Whether the morphological changes are a direct effect of reduced pulsatility during cf-LVAD support or due to HF progression requires further investigation.

Distinct phenotypes of cardiac allograft vasculopathy after heart transplantation: a histopathological study.

INTRODUCTION: Long-term survival after heart transplantation (HTx) is hampered by cardiac allograft vasculopathy (CAV). Better understanding of the pathophysiological mechanisms of CAV might have considerable consequences for therapeutic approaches in the future. The aim of the present study was to investigate the histological phenotypes of CAV in relation with clinical patient characteristics. METHODS AND RESULTS: Coronary cross-sections from 51 HTx patients were obtained at autopsy. CAV was observed in 42 patients (82%). Three histological CAV phenotypes were identified (H-CAV 1-3). No CAV (H-CAV 0) is as seen in normal coronary arteries; intimal thickening consisting of a layer of longitudinal oriented smooth muscle cells. In H-CAV 1 to 3 a second intimal layer is formed, on top of the longitudinal oriented smooth muscle cell layer, with predominantly mononuclear inflammatory infiltrate in loose connective tissue (H-CAV 1), smooth muscle cells in different orientation (H-CAV 2), or a fibrotic intimal lesion (H-CAV 3). H-CAV type was significantly related with time after transplantation, age at transplantation, the amount of atherosclerotic disease and the occurrence of infection. In addition, morphometric analysis revealed that higher H-CAV types have a relatively larger intimal area, that is compensated for by expansive arterial remodeling of the artery. CONCLUSION: CAV in an ongoing process that can be classified into three different phenotypes; inflammatory lesions, lesions rich of smooth muscle cells and fibrotic lesions. Our results suggest that these phenotypes are related to time after transplantation, age at transplantation, the amount of atherosclerotic disease and the occurrence of infection.

Noninvasive arterial blood pressure waveforms in patients with continuous-flow left ventricular assist devices.

Arterial blood pressure and echocardiography may provide useful physiological information regarding cardiac support in patients with continuous-flow left ventricular assist devices (cf-LVADs). We investigated the accuracy and characteristics of noninvasive blood pressure during cf-LVAD support. Noninvasive arterial pressure waveforms were recorded with Nexfin (BMEYE, Amsterdam, The Netherlands). First, these measurements were validated simultaneously with invasive arterial pressures in 29 intensive care unit patients. Next, the association between blood pressure responses and measures derived by echocardiography, including left ventricular end-diastolic dimensions (LVEDDs), left ventricular end-systolic dimensions (LVESDs), and left ventricular shortening fraction (LVSF) were determined during pump speed change procedures in 30 outpatients. Noninvasive arterial blood pressure waveforms by the Nexfin monitor slightly underestimated invasive measures during cf-LVAD support. Differences between noninvasive and invasive measures (mean ± SD) of systolic, diastolic, mean, and pulse pressures were -7.6 ± 5.8, -7.0 ± 5.2, -6.9 ± 5.1, and -0.6 ± 4.5 mm Hg, respectively (all <10%). These blood pressure responses did not correlate with LVEDD, LVESD, or LVSF, while LVSF correlated weakly with both pulse pressure (r = 0.24; p = 0.005) and (dP(art)/dt)max (r = 0.25; p = 0.004). The dicrotic notch in the pressure waveform was a better predictor of aortic valve opening (area under the curve [AUC] = 0.87) than pulse pressure (AUC = 0.64) and (dP(art)/dt)max (AUC = 0.61). Patients with partial support rather than full support at 9,000 rpm had a significant change in systolic pressure, pulse pressure, and (dP(art)/dt)max during ramp studies, while echocardiographic measures did not change. Blood pressure measurements by Nexfin were reliable and may thereby act as a compliment to the assessment of the cf-LVAD patient.

Two young women with soft tissue tumours of the heart.

Primary cardiac sarcomas often strike young, healthy patients and tend to have a dismal prognosis. Because of limited experience, the heterogeneous nature of cardiac sarcomas and different treatment results of patients with malignant primary tumours of the heart, the role of heart transplantation should be weighed on a case-by-case basis.

[An artificial heart: bridge to transplantation or permanent?]. / Een steunhart: tot transplantatie of voor altijd?

An artificial heart is a continuous-flow pump device with a constant output, which usually supports the left ventricle. Over the past five years, survival rates with an artificial heart have increased dramatically, but with an annual mortality of 10% per year compared with 6% for heart transplantation the artificial heart is mainly a 'bridge to transplantation' or an alternative for those patients who are not suitable for heart transplant, 'destination therapy'. It is anticipated that the number and severity of complications will decrease as a result of technological progress. The artificial heart could then become a long-term treatment option providing a good quality of life and thus become equivalent to a heart transplant.

Exercise hemodynamics during extended continuous flow left ventricular assist device support: the response of systemic cardiovascular parameters and pump performance.

Patients on continuous flow left ventricular assist devices (cf-LVADs) are able to return to an active lifestyle and perform all sorts of physical activities. This study aims to evaluate exercise hemodynamics in patients with a HeartMate II cf-LVAD (HM II). Thirty (30) patients underwent a bicycle exercise test. Along with exercise capacity, systemic cardiovascular responses and pump performance were evaluated at 6 and 12 months after HM II implantation. From rest to maximum exercise, heart rate increased from 87 ± 14 to 140 ± 32 beats/minute (bpm) (P<0.01), while systolic arterial blood pressure increased from 93 ± 12 to 116 ± 21 mm Hg (P<0.01). Total cardiac output (TCO) increased from 4.1 ± 1.1 to 8.5 ± 2.8 L/min (P<0.01) while pump flow increased less, from 5.1 ± 0.7 to 6.4 ± 0.6 L/min (P<0.01). Systemic vascular resistance (SVR) decreased from 1776 ± 750 to 1013 ± 83 dynes.s/cm(5) (P<0.001) and showed the strongest correlation with TCO (r= -0.72; P<0.01). Exercise capacity was affected by older age, while blood pressure increased significantly in men compared with women. Exercise capacity remained consistent at 6 and 12 months after HM II implantation, 51% ± 13% and 52% ± 13% of predicted VO2 max for normal subjects corrected for age and gender. In conclusion, pump flow of the HM II may contribute partially to TCO during exercise, while SVR was the strongest determinant of TCO.

Single-centre experience of 85 patients with a continuous-flow left ventricular assist device: clinical practice and outcome after extended support.

OBJECTIVES: We evaluated our single-centre clinical experience with the HeartMate II (HM II) left ventricular assist device (LVAD) as a bridge to transplantation (BTT) in end-stage heart failure (HF) patients. METHODS: Survival rates, echocardiographic parameters, laboratory values and adverse events of 85 consecutive patients supported with a HM II were evaluated. RESULTS: Overall, mean age was 45 ± 13 years, 62 (73%) were male and non-ischaemic dilatated cardiomyopathy was present in 60 (71%) patients. The median duration of mechanical support was 387 days (IQR 150-600), with a range of 1-1835 days. The 6-month, 1-, 2-, 3- and 4-year survival rates during HM II LVAD support were 85, 81, 76, 76 and 68%, respectively. Echocardiographic parameters demonstrated effective left ventricular unloading, while laboratory results reflected adequate organ perfusion. However, HM II support was associated with adverse events, such as infections in 42 patients (49%; 0.67 events/patient-year), cardiac arrhythmia in 44 (52%; 0.86 events/patient-year), bleeding complications in 32 (38%; 0.43 events/patient-year) and neurological dysfunction in 17 (20%; 0.19 events/patient-year). CONCLUSIONS: In view of the increasing shortage of donor hearts, HM II LVAD support may be considered a life-saving treatment in end-stage HF patients, with good survival. However, it is still associated with some serious adverse events, of which neurological complications are the most critical.

Pump flow estimation from pressure head and power uptake for the HeartAssist5, HeartMate II, and HeartWare VADs.

The use of long-term mechanical circulatory support (MCS) for heart failure by means of implanted continuous-flow left ventricular assist devices (cf-LVADs) will increase, either to enable recovery or to provide a destination therapy. The effectiveness and user-friendliness of MCS will depend on the development of near-physiologic control strategies for which accurate estimation of pump flow is essential. To provide means for the assessment of pump flow, this study presents pump models, estimating pump flow (Q(lvad)) from pump speed (n) and pressure difference across the LVAD (Δp(lvad)) or power uptake (P). The models are evaluated for the axial-flow LVADs HeartAssist5 (HA5) and HeartMate II (HMII), and for a centrifugal pump, the HeartWare (HW). For all three pumps, models estimating Q(lvad) from Δp(lvad) only is capable of describing pump behavior under static conditions. For the axial pumps, flow estimation from power uptake alone was not accurate. When assuming an increase in pump flow with increasing power uptake, low pump flows are overestimated in these pumps. Only for the HW, pump flow increased linearly with power uptake, resulting in a power-based pump model that estimates static pump flow accurately. The addition of pressure head measurements improved accuracy in the axial cf-LVAD estimation models.

Analysis of aortic valve commissural fusion after support with continuous-flow left ventricular assist device.

OBJECTIVES: Continuous-flow left ventricular assist devices (cf-LVADs) may induce commissural fusion of the aortic valve leaflets. Factors associated with this occurrence of commissural fusion are unknown. The aim of this study was to examine histological characteristics of cf-LVAD-induced commissural fusion in relation to clinical variables. METHODS: Gross and histopathological examinations were performed on 19 hearts from patients supported by either HeartMate II (n = 17) or HeartWare (n = 2) cf-LVADs and related to clinical characteristics (14 heart transplantation, 5 autopsy). RESULTS: Eleven of the 19 (58%) aortic valves showed fusion of single or multiple commissures (total fusion length 11 mm [4-20] (median [interquartile range]) per valve), some leading to noticeable nodular displacements or considerable lumen diameter narrowing. Multiple fenestrations were observed in one valve. Histopathological examination confirmed commissural fusion, with varying changes in valve layer structure without evidence of inflammatory infiltration at the site of fusion. Commissural fusion was associated with continuous aortic valve closure during cf-LVAD support (P = 0.03). LVAD-induced aortic valve insufficiency developed in all patients with commissural fusion and in 67% of patients without fusion. Age, duration of cf-LVAD support and aetiology of heart failure (ischaemic vs dilated cardiomyopathy) were not associated with the degree of fusion. CONCLUSIONS: Aortic valve commissural fusion after support with cf-LVADs is a non-inflammatory process leading to changes in valve layer structure that can be observed in >50% of cf-LVAD patients. This is the first study showing that patients receiving full cf-LVAD support without opening of the valve have a significantly higher risk of developing commissural fusion than patients on partial support.

Simulation of changes in myocardial tissue properties during left ventricular assistance with a rotary blood pump.

We considered a mathematical model to investigate changes in geometric and hemodynamic indices of left ventricular function in response to changes in myofiber contractility and myocardial tissue stiffness during rotary blood pump support. Left ventricular assistance with a rotary blood pump was simulated based on a previously published biventricular model of the assisted heart and circulation. The ventricles in this model were based on the one-fiber model that relates ventricular function to myofiber contractility and myocardial tissue stiffness. The simulations showed that indices of ventricular geometry, left ventricular shortening fraction, and ejection fraction had the same response to variations in myofiber contractility and myocardial tissue stiffness. Hemodynamic measures showed an inverse relation compared with geometric measures. Particularly, pulse pressure and arterial dP/dtmax increased when myofiber contractility increased, whereas increasing myocardial tissue stiffness decreased these measures. Similarly, the lowest pump speed at which the aortic valve remained closed increased when myofiber contractility increased and decreased when myocardial tissue stiffness increased. Therefore, simultaneous monitoring of hemodynamic parameters and ventricular geometry indirectly reflects the status of the myocardial tissue. The appropriateness of this strategy will be evaluated in the future, based on in vivo studies.

Circulating growth differentiation factor-15 correlates with myocardial fibrosis in patients with non-ischaemic dilated cardiomyopathy and decreases rapidly after left ventricular assist device support.

AIMS: Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine and is emerging as a biomarker of cardiac remodelling. Left ventricular assist devices (LVADs) provide unloading of the left ventricle, resulting in partial reverse remodelling. Our aim was to study GDF-15 in patients with a non-ischaemic dilated cardiomyopathy (DCM) during LVAD support. METHODS AND RESULTS: We analysed circulating GDF-15 in 30 patients before and 1, 3, and 6 months after LVAD implantation and before heart transplantation or explantation. In addition, mRNA and protein expression of GDF-15 were evaluated in myocardial tissue obtained prior to and after LVAD support. Circulating GDF-15 was significantly higher before LVAD implantation as compared with healthy controls (P < 0.001). After 1 month of mechanical support, GDF-15 levels were significantly decreased compared with pre-implantation levels (P < 0.001) and remained stable thereafter. Circulating GDF-15 was significantly correlated with kidney function and the severity of myocardial fibrosis. Interestingly, GDF-15 mRNA and protein expression in the myocardium were hardly detectable. CONCLUSIONS: High circulating levels of GDF-15 in patients with end-stage non-ischaemic DCM correlate with myocardial fibrosis and kidney function and decline strongly after 1 month of mechanical unloading, remaining stable thereafter. However, cardiac mRNA and protein expression of GDF-15 are very low, suggesting that the heart is not an important source of GDF-15 production in these patients.

Cerebrovascular complications of left ventricular assist devices.

Left ventricular assist devices (LVADs) are increasingly being used as a bridge to heart transplantation or destination therapy. It is unclear which antithrombotic regimen should be used to reduce the risk of stroke. We systematically reviewed the literature on all types of antithrombotic regimens and stroke in patients with any type of LVADs. Our primary outcome measure was the mean incidence of any type of stroke. Twenty-six articles were selected as relevant, comprehending 1989 patients with a mean LVAD support of 200 days (range 30-621). The mean proportion of patients affected with stroke was 20% (range 0-55%), with a mean incidence of 0.74 (range 0-6.91) events/patient-year. Support with HeartMate II and a regimen of postoperative heparin converted to coumarins, acetylsalicylic acid (ASA) and dipyridamole resulted in 0.17 (mean; range 0.06-0.29) strokes/patient-year. HeartMate II support and the same regime without heparin was associated with 0.07 (mean; range 0.03-0.11) strokes/patient-year. A Novacor device with heparin, converted to coumarins, was associated with 3.82 (mean; range 1.03-6.91) strokes/patient-year, while ASA added to this regime resulted in 0.97 ischaemic strokes/patient-year (mean; range 0.53-1.48). Other combinations of assist devices and antithrombotic regimes were investigated in one or two studies only. This systematic review provides risk estimates for stroke for various LVADs and antithrombotic regimes. Our findings indicate that the postoperative use of heparin in HeartMate II patients is doubtful, and suggest an important role for antiplatelet drugs to prevent stroke in patients supported with a Novacor device.

Noninvasive continuous arterial blood pressure monitoring with Nexfin®.

BACKGROUND: If invasive measurement of arterial blood pressure is not warranted, finger cuff technology can provide continuous and noninvasive monitoring. Finger and radial artery pressures differ; Nexfin® (BMEYE, Amsterdam, The Netherlands) measures finger arterial pressure and uses physiologic reconstruction methodologies to obtain values comparable to invasive pressures. METHODS: Intra-arterial pressure (IAP) and noninvasive Nexfin arterial pressure (NAP) were measured in cardiothoracic surgery patients, because invasive pressures are available. NAP-IAP differences were analyzed during 30 min. Tracking was quantified by within-subject precision (SD of individual NAP-IAP differences) and correlation coefficients. The ranges of pressure change were quantified by within-subject variability (SD of individual averages of NAP and IAP). Accuracy and precision were expressed as group average ± SD of the differences and considered acceptable when smaller than 5 ± 8 mmHg, the Association for the Advancement of Medical Instrumentation criteria. RESULTS: NAP and IAP were obtained in 50 (34-83 yr, 40 men) patients. For systolic, diastolic, mean arterial, and pulse pressure, median (25-75 percentiles) correlation coefficients were 0.96 (0.91-0.98), 0.93 (0.87-0.96), 0.96 (0.90-0.97), and 0.94 (0.85-0.98), respectively. Within-subject precisions were 4 ± 2, 3 ± 1, 3 ± 2, and 3 ± 2 mmHg, and within-subject variations 13 ± 6, 6 ± 3, 9 ± 4, and 7 ± 4 mmHg, indicating precision over a wide range of pressures. Group average ± SD of the NAP-IAP differences were -1 ± 7, 3 ± 6, 2 ± 6, and -3 ± 4 mmHg, meeting criteria. Differences were not related to mean arterial pressure or heart rate. CONCLUSION: Arterial blood pressure can be measured noninvasively and continuously using physiologic pressure reconstruction. Changes in pressure can be followed and values are comparable to invasive monitoring.

Functional and haemodynamic recovery after implantation of continuous-flow left ventricular assist devices in comparison with pulsatile left ventricular assist devices in patients with end-stage heart failure.

AIMS: Caused by ageing of the population, better survival from ischaemic heart disease, and improved treatment of chronic heart disease, the incidence of heart failure has increased enormously. Worldwide, left ventricular assist devices (LVADs) are increasingly being used as a bridge or alternative to heart transplantation. In this study, we investigated whether there is difference in functional and haemodynamic recovery after implantation of pulsatile and continuous-flow pumps. METHODS AND RESULTS: We compared laboratory and echocardiographic data and exercise performance in patients with end-stage heart failure, before and 3 months after implantation of pulsatile and continuous-flow LVADs. A significant improvement in all laboratory parameters after implantation of both types of LVADs was seen, as well as a significant decrease in heart rate and LV dimensions, indicating better haemodynamics and cardiac recompensation. This improvement was better for the pulsatile device, probably due to higher plasma levels and higher LV dimensions before implantation. Exercise capacity strongly improved: 3 months after implantation of pulsatile and continuous-flow LVADs, peak VO(2) was 20.2 ± 4.8 vs. 18.3 ± 4.8 mL/kg/min (P = 0.09) (53 ± 12 vs. 49 ± 11% of predicted for age and gender) (P = 0.28). CONCLUSION: Pulsatile and continuous-flow LVADs result in extensive haemodynamic recovery and exercise performance compatible with daily life activities. Exercise performance with continuous-flow LVADs is equal to that with pulsatile devices. This, in combination with improved survival of the newer devices, allows its use as an alternative to heart transplantation in selected patients.

Osteopontin: a potential biomarker for heart failure and reverse remodeling after left ventricular assist device support.

BACKGROUND: Left ventricular assist device (LVAD) support in end-stage heart failure (HF) leads to recovery of the patient's condition, size reduction of cardiomyocytes, and also volume reduction and change in the composition of the extracellular matrix (ECM). Myocardial expression of ECM osteopontin (OPN) protein increases with the severity of HF. We analyzed whether OPN messenger RNA expression in heart tissue and/or OPN protein in plasma are associated with reverse remodeling during LVAD support. METHODS: Plasma and heart tissue specimens of 22 end-stage HF patients before and after LVAD implantation and subsequent heart transplantation (HTx) were used to determine the concentrations of OPN protein (EIA) and OPN messenger RNA (mRNA) by quantitative polymerase chain reaction. Immunohistochemistry (IHC) and in situ hybridization (ISH) were performed to locate OPN protein and mRNA. RESULTS: The high OPN protein levels in plasma of HF patients did not differ significantly before and after LVAD support in ischemic heart disease (IHD) (pre-LVAD 167 ± 32 ng/ml; post-LVAD 165 ± 28 ng/ml) and in dilated cardiomyopathy (DCM) (pre-LVAD 99 ± 12 ng/ml; post-LVAD (142 ± 6 ng/ml). The OPN plasma levels after HTx decreased to control levels (IHD, 48 ± 6; DCM, 40 ± 5; control, 31 ± 3 ng/ml). In contrast, expression of OPN mRNA in heart biopsy specimens decreased significantly after LVAD support (the relative quantity decreased > 90% in IHD and 50% in DCM). ISH and IHC revealed that OPN was present in cardiomyocytes and in the ECM. CONCLUSIONS: Levels of OPN mRNA in the myocardium of HF patients showed a significant decrease after LVAD support but OPN protein expression did not. LVAD support only induced a decrease of OPN plasma levels in individual patients, whereas OPN plasma levels reduced significantly in all patients after HTx.

[Peripartum cardiomyopathy in young women]. / Peripartum-cardiomyopathie bij jonge vrouwen.

Two women aged 26 and 41 were diagnosed with peripartum cardiomyopathy (PPCM). They presented with shortness of breath and oedematous ankles. The first woman presented in her 37th week of pregnancy. Her father had had dilated cardiomyopathy. A caesarean section was carried out. Her left ventricular function declined and she was therefore treated by means of an Impella heart pump and later, a left-ventricular assisting device. She eventually underwent urgent heart transplantation and recovered. The second woman presented 6 weeks after having given birth to twins. She was treated with a diuretic, an ACE inhibitor, a beta blocker and recovered. PPCM is a rare and potentially life-threatening form of dilated cardiomyopathy with left-ventricular systolic dysfunction that affects women in late pregnancy or in the early puerperium. Its pathogenesis is poorly understood. The generation of a cardiotoxic prolactin subfragment appears to play a key role in the pathophysiology. PPCM is difficult to diagnose as the initial complaints may be interpreted as the normal physiologic changes of pregnancy. In addition, prior definitions emphasising strict time windows, the lack of awareness and the rarity of the full-blown disease have sometimes resulted in the condition being overlooked and misdiagnosed.