The introduction of second-generation implantable continuous-flow ventricular assist devices (VADs), such as Heartmate II (HM-II; St. Jude Medical, Inc., formerly Thoratec Corporation, Pleasanton, CA), has significantly improved not only the prognosis but also the quality of life of patients with advanced heart failure. However, an abrupt increase in thromboembolic events has been recently reported in patients with HM-II and the risk of and efforts to decrease future thromboembolic events are being investigated.1 With respect to risk assessment, hemolysis with high lactate dehydrogenase (LDH) levels in patients with HM-II has been reported to be associated with a higher incidence of future thrombosis-related adverse outcomes compared with patients without hemolysis.2 , 3 However, not all patients with VADs with high LDH levels develop thrombotic events, since high LDH levels are not direct surrogates for VAD-related thrombosis.
Transcranial Doppler (TCD) is the only clinical method to directly visualize the microembolic signals (MES) in circulating blood. It is widely used to noninvasively evaluate the risk of cerebral embolism in patients with cardiogenic embolism or carotid stenosis.4 Previous studies have investigated the clinical relevance of TCD and its association with thromboembolic events in patients with first generation VADs.5–7 However, no reports have been published in patients with currently available VADs except for one case presentation reported by our group.8 We, therefore, aimed to elucidate the clinical relevance of TCD detection of MES in patients with HM-II.
This study is a prospective cross-sectional study with follow-up. Patients with HM II who underwent TCD examinations from November 2014 to October 2015 were enrolled and followed-up until June 2016 (see Methods, Supplemental Digital Content, http://links.lww.com/ASAIO/A218). Transcranial Doppler was performed using the Nicolet SONARA system (Natus Medical Incorporated, San Carolos, CA) at a depth of 50–65 mm using the trans-temporal acoustic bone window to observe the Doppler flow in the M1 segment of the middle cerebral artery. Microembolic signals were defined as short, transient, high intensity (> 3 dB), and unidirectional signals with a chirping sound in the Doppler flow of the middle cerebral artery, and were quantified by counting them for 30 minutes. In the patients with a large number of MES counts (> 15 counts/30 min), another set of TCD examination under oxygen inhalation (6 L/min) was performed to discriminate between solid and gaseous emboli.9 Furthermore, if a patient developed a thromboembolic event that included hemolysis (LDH > 600 IU/l) during the study period, TCD was performed again (Supplemental methods).
Twenty patients (mean age, 42.2 ± 10.6 years; 17 males) with HM-II underwent TCD examinations (Table 1). The mean interval between VAD implantation and the initial TCD examination was 290.3 ± 239.7 days. Three patients demonstrated low MES counts (one with six counts and two with one MES count each) and one patient who developed hemolysis at the time of the initial TCD examination demonstrated 146 MES counts (case 1).8 The rest of the patients were free of MES at baseline examinations. After the baseline TCD examination, three patients underwent further TCD examinations since they developed hemolysis and/or thromboembolic events during the follow-up period. Case 1 developed persistent hemolysis 5 months after the initial examination and 2,970 MES counts were detected when the LDH value rose to approximately 1,000 IU/l. Furthermore, the MES counts were reduced by oxygen inhalation (2,970 [room air] to 1,724 counts [oxygen inhalation]), and the patients did not develop any thromboembolic events other than hemolysis (see Figure, Supplemental Digital Content, http://links.lww.com/ASAIO/A219 [Supplemental Figure A, B]). The patient with no MES counts in the initial TCD examination developed transient ischemic stroke with LDH elevation 8 months later (case 2), and multiple MES counts with no reduction on oxygen inhalation were repeatedly detected on days 10 and 14 following stroke (46 [room air] to 63 counts [oxygen inhalation], and 248 [room air] to 258 counts [oxygen inhalation]; [Figure 1], see Figure, Supplemental Digital Content, http://links.lww.com/ASAIO/A219 [Supplemental Figure C, D, E]). The patient with no MES counts in the initial TCD examination developed transient renal embolism 18 months later (case 3), and the MES count on the next day of the event was not reduced by oxygen inhalation (18 [room air] to 17 [oxygen inhalation]).
This study provides several novel findings associated with thromboembolic events and hemolysis in patients with HM-II. First, MES are rarely detected in stable patients with HM-II. However, they can be detected in patients who develop hemolysis and/or thromboembolic events. Second, TCD examination under oxygen inhalation revealed that, both, solid and gaseous emboli exist in patients with HM-II.
Previous studies of first generation pulsatile-flow VADs reported that the quantity of MES can be detected even in the absence of thromboembolic complications.10 Pulsatile-flow systems with a mechanical heart valve inside the pump may cause cavitations that can be detected by TCD examination. In contrast, our study demonstrated that multiple MES were detected only in patients with hemolysis or acute thromboembolic events. Therefore, detection of MES with TCD examination in patients with HM-II represents a form of VAD-related abnormal state such as thromboembolism.
With respect to the clinical significance of solid and gaseous emboli, we do not have a definitive conclusion. However, our experiences with cases 1, 2, and 3 are strongly suggestive of the clinical importance of these different types of MES. In case 1, the patient presented only with hemolysis without acute ischemic stroke. It is noteworthy that oxygen inhalation resulted in a drastic reduction of MES counts, suggesting that gaseous emboli were the predominant components of the MES. In contrast, in cases 2 and 3, where the patients presented with ischemic stroke and transient renal embolism, respectively, oxygen inhalation did not result in a substantial reduction in MES counts, suggesting that solid emboli were the predominant component of MES. From these findings, we propose that solid emboli detected by TCD examination may represent a higher risk of thromboembolic events than gaseous emboli and the differentiation between the emboli may contribute to developing a novel diagnostic algorithm for patients with HM-II and hemolysis.
In conclusion, MES can be detected in patients with acute or recent thromboembolic events including hemolysis. Furthermore, TCD examinations have the potential to differentiate between solid and gaseous emboli, which may be useful for more precise risk stratification of thromboembolic events in patients with HM-II complicated by hemolysis.
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ventricular assist device; transcranial Doppler; micro-embolic signals; thromboembolic event; hemolysis
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