Use of rifabutin to treat tuberculosis in a cardiac transplant recipient: A case report
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OBJECTIVE: Tuberculosis is an important concern following organ transplantation. Unfortunately, several antituberculosis drugs interact with immunosuppressants. This report describes our experience with rifabutin (RBT) in the treatment of acute tuberculosis in a cardiac transplant recipient. CASE: A 61-year-old cardiac transplant recipient developed tuberculosis meningitis during treatment of miliary tuberculosis. RBT was given for 27 days concomitantly with cyclosporine (CsA). CsA concentrations at 0 hour (C0) decreased within 3 days of starting RBT. The serum concentration-curve from 0 to 12 hours (AUC0-12h)/dose 7 days after starting RBT therapy decreased by 28%, compared to the values before RBT therapy. The apparent clearance at both 7 and 21 days after starting RBT therapy was 1.4 times higher than before RBT therapy. CONCLUSION: RBT has fewer drug-drug interactions than rifampin and should be preferentially used for the treatment of tuberculosis in transplant patients treated with CsA. Close monitoring of CsA blood concentration during RBT therapy minimized the risk of under- or over-immunosuppression in a cardiac transplant patient.
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Temporary biventricular support with extracorporeal membrane oxygenation: a feasible therapeutic approach for cardiogenic shock with multiple organ failure.

Various strategies using a ventricular assist device (VAD) are applied to rescue Interagency Registry for Mechanically Assisted Circulatory Support profile 1 (Profile-1) patients. However, the optimal use of VAD in Profile-1 patients has not been completely elucidated. We retrospectively reviewed 23 Profile-1 patients [mean age 36.9 ± 16.6 years, 14 males; 11 with non-ischemic cardiomyopathy (NICM), 9 with fulminant myocarditis (FM), 2 with ischemic cardiomyopathy (ICM), and 1 with peripartum cardiomyopathy (PPCM); 18 with pre-operative percutaneous extracorporeal membrane oxygenation (p-ECMO) support] who underwent VAD implantation from 2011 to 2015 at our institution. Nine initially received left VAD (LVAD) alone (NICM in 9, ICM in 2 with ICM, and FM in 1), one with NICM received biventricular VAD (BiVAD; n = 1), and 10 received LVAD combined with right ventricular support using an ECMO circuit (BiVAD-ECMO) (FM in 8, NICM in 1, and PPCM in 1). Paracorporeal VAD was used in all patients. ECMO was used for the patients with severe pulmonary edema, inflammation, anemia, and thrombopenia. The BiVAD patient died 1.4 months after VAD implantation. The overall survival was comparable between patients with BiVAD-ECMO and LVAD (2-year survival, 80.0 and 75.0%, respectively). Three VAD strategies were initially applied in Profile-1 patients. Among them, the BiVAD-ECMO strategy is a promising therapeutic option to rescue Profile-1 patients with multiple organ failure.

889 days of support on hydrodynamic bearing rotation mode of the DuraHeart™ for bridge-to-heart transplantation.

A 49-year-old man with ischemic cardiomyopathy and tricuspid regurgitation underwent a DuraHeart implantation and tricuspid annuloplasty for bridge-to-heart transplantation. On postoperative day 393, the magnetic levitation system suddenly broke down, and the pump system went into hydrodynamic bearing rotation (HD) mode without causing relevant symptoms. The controller was exchanged with one that adapted to the HD mode. No significant hemodynamic changes or indications of hemolysis were observed. On postoperative day 982, the pump temporarily stopped nine times. The patient refused pump exchange despite our strong recommendation for it. After 1283 days of DuraHeart support (889 days in HD mode) without hemolysis or neurologic events, he underwent heart transplantation. The DuraHeart manufacturer's analysis revealed much damage to the insulation and fatigue fractures of the conductors, which had resulted in temporary cessation of function and failure of the magnetic levitation system. This was a rare case of long-term support under the DuraHeart HD mode.

Low partial pressure of end-tidal carbon dioxide predicts left ventricular assist device implantation in patients with advanced chronic heart failure.

BACKGROUND: This study aimed to clarify the prognostic impact of partial pressure of end-tidal carbon dioxide (PETCO2) in patients with advanced chronic heart failure (HF). METHODS: Forty-eight patients (mean age 43.1±11.9years, 32 males) with chronic HF (44 with non-ischemic and 4 with ischemic cardiomyopathy) were prospectively enrolled. Echocardiography, blood tests, pulmonary function testing, and PETCO2 measurements were performed as noninvasive tests, whereas right heart catheterization and arterial blood gas analysis were conducted as invasive tests. The primary end point of this study was left ventricular assist device (LVAD) implantation or cardiac death. RESULTS: Eighteen patients underwent LVAD implantation at the Interagency Registry for Mechanically Circulatory Support (INTERMACS) profile 3 during the follow-up period, and no patient died. PETCO2 was significantly lower in a stepwise manner with New York Heart Association functional class (class I or II, 34.2±9.3mmHg vs. class III or IV, 27.7±2.5mmHg; p<0.001). Univariate and multivariate Cox proportional hazard models and time-dependent receiver operating characteristic curve analysis revealed that PETCO2≤31mmHg is an independent noninvasive predictor of LVAD implantation. Univariable and multivariable linear regression analyses showed that pulmonary arterial pressure was independently and highly correlated with PETCO2 (r2=-0.512, p<0.001). CONCLUSIONS: Among various noninvasive clinical parameters investigated, PETCO2 was the independent predictor of LVAD implantation at the INTERMACS profile 3 in patients with chronic HF. Pulmonary congestion may significantly contribute to decreases in PETCO2 in patients with HF.

Donor-Transmitted Atherosclerosis Associated With Worsening Cardiac Allograft Vasculopathy After Heart Transplantation: Serial Volumetric Intravascular Ultrasound Analysis.

BACKGROUND: The influence of preexisting donor-transmitted atherosclerosis (DA) on cardiac allograft vasculopathy (CAV) development remains unclear. METHODS: We performed 3-dimensional intravascular ultrasound (3D-IVUS) analysis in 42 heart transplantation (HTx) recipients at 2.1 ± 0.9 months (baseline) and 12.2 ± 0.4 months post-HTx, as well as consecutive 3D-IVUS analyses up to 3 years post-HTx in 35 of the 42 recipients. Donor-transmitted atherosclerosis was defined as a maximal intimal thickness of 0.5 mm or greater at baseline. Changes in volumetric IVUS parameters were compared in recipients with (DA group) and without DA (DA-free group) at baseline, 1 year, and 3 years post-HTx. RESULTS: Donor-transmitted atherosclerosis was observed in 57.1% of 42 recipients. The DA group exhibited a significantly greater increase in plaque volume at 1 year post-HTx (P < 0.001), leading to increased percent plaque volume (plaque volume/vessel volume, [%]) (P < 0.001) and decreased luminal volume (P = 0.021). Donor-transmitted atherosclerosis was independently associated with a greater increase in percent plaque volume during the first post-HTx year (P = 0.011). From 1 to 3 years post-HTx, the DA group underwent continuous reduction in luminal volume (P = 0.022). These changes resulted in a higher incidence of angiographic CAV at 3 years post-HTx in the DA group (58.8% vs 5.6%, P = 0.002). CONCLUSIONS: This volumetric IVUS study suggests that DA correlates with the worsening change in CAV several years post-HTx. Donor-transmitted atherosclerosis recipients may require more aggressive treatment to prevent subsequent CAV progression.

Successful treatment of near-fatal fulminant myocarditis using bi-ventricular assist device support.

Fulminant myocarditis is a rare but fatal serious disease that may cause prolonged native cardiac dysfunction with multiorgan failure despite temporary mechanical circulatory support with percutaneous venoatrial extracorporeal membrane oxygenation (VA-ECMO) or intraaortic balloon pumping (IABP). A 26-year-old man with fulminant myocarditis developed life-threatening multiorgan failure after 8 days support by VA-ECMO and IABP. He was transferred to our institution with prolonged cardiac dysfunction on hospital day 8; massive pulmonary edema developed into severe pulmonary dysfunction. Immediately after admission, VA-ECMO and IABP were switched to a paracorporeal pneumatic left ventricular assist device (LVAD) and right centrifugal ventricular assist device with an ECMO circuit shunting from the right ventricle to the pulmonary artery (RVAD-ECMO). After intensive care focusing on respiratory dysfunction, ECMO was successfully weaned, and the right ventricular assist device was switched to a durable paracorporeal pneumatic right ventricular assist device. The paracorporeal bi-ventricular assist devices were finally replaced with an implantable non-pulsatile LVAD on hospital day 181. Currently, 1 year after discharge, the patient is at home awaiting heart transplantation. Combined LVAD and RVAD-ECMO appear to be useful for resolving severe pulmonary edema due to unnecessarily long VA-ECMO support as well as kidney or liver dysfunction caused by circulatory collapse.

Interaction between Warfarin and Linezolid in Patients with Left Ventricular Assist System in Japan.

OBJECTIVE: The purpose of this study was to investigate the possible interaction between warfarin and linezolid in patients with a left ventricular assist system (LVAS) for the treatment of severe heart failure. METHODS: Patients with LVAS who were treated with linezolid for the treatment of infections from January 2003 to March 2013 were identified from medical records. The impact of linezolid on the clotting function, as well as the dose of warfarin during the first 10 days of linezolid therapy, was investigated. The mean prothrombin time-international normalized ratio (PT-INR) and mean doses of warfarin during 7 days before and 10 days after the initiation of linezolid therapy were calculated for individual patients. The PT-INR per mg of WF dose on the previous day (X) was calculated. The warfarin dose, PT-INR, and warfarin sensitivity index (WSI) value before and after the initiation of linezolid were compared to evaluate the impact of linezolid on the effect of warfarin. RESULTS: Sixteen patients were enrolled in the study. Although the mean PT-INR increased from 3.74 to 4.06, no significant difference was observed (p=0.05). A significant difference was observed in the mean dose of warfarin before and after the initiation of linezolid administration, with a decrease from 3.23 to 2.69 mg/day (p=0.001). In contrast, the mean WSI value significantly increased from 1.37 to 1.82 (p=0.014). After 10 days of linezolid administration, the mean X values increased over the baseline value by 31.7%. CONCLUSION: These findings suggest that co-administration of linezolid results in increased PT-INR in patients with LVAS treated with warfarin.

Suppressive effects of conversion from mycophenolate mofetil to everolimus for the development of cardiac allograft vasculopathy in maintenance of heart transplant recipients.

BACKGROUND: Whether converting to everolimus (EVL) from mycophenolate mofetil (MMF) during the maintenance period after heart transplantation (HTx) reduces cardiac allograft vasculopathy (CAV) progression remains unclear. We sought to determine the effect of converting from MMF with standard-dose calcineurin inhibitors (CNIs) to EVL with low-dose CNIs on CAV progression. METHODS: We retrospectively reviewed the medical records of 63 HTx recipients who survived at least at 1 year after HTx. Twenty-four recipients were converted from MMF to EVL (EVL group, 2.2 ± 2.3 years after HTx), while 39 recipients were maintained on MMF (MMF group, 2.4 ± 2.2 years after HTx). The EVL group underwent three-dimensional intravascular ultrasound (3D-IVUS) analysis before and 1 year after conversion to EVL, and these data were compared with data from 2 consecutive IVUS in the MMF group. RESULTS: IVUS indices in the EVL group at 1 year after conversion did not show increased CAV development, whereas a significant increase in %plaque volume (p=0.006) and decrease in lumen volume (p<0.001) were observed in the MMF group. EVL conversion was significantly associated with smaller increases in %plaque volume (p=0.004) and smaller decreases in lumen volume (p=0.017). IVUS indices in the late EVL conversion group (≥ 2 years) also did not exhibit increased CAV development, while those in the MMF group did. CONCLUSIONS: Conversion to EVL from MMF in maintenance periods after HTx may decrease the rate of CAV progression based on IVUS indices.

Incidence, etiology, and outcome of primary graft dysfunction in adult heart transplant recipients: a single-center experience in Japan.

Donor and recipient characteristics, as well as donor-recipient matching, affect clinical outcomes after heart transplantation (HTx). This study aimed to clarify how donor and recipient characteristics affect the clinical course after HTx. The medical records of all the patients who underwent HTx at the National Cerebral and Cardiovascular Center from 1999 to 2014 were retrospectively reviewed. Sixty-one patients (48 males) underwent HTx. Six recipients (9.8 %) developed primary graft dysfunction (PGD) determined by criteria recently established at a consensus conference. Development of PGD was associated with high-dose inotropic support for the donor heart and a history of stroke in the recipient (p = 0.04 and p = 0.002, respectively). Recipients with PGD had higher right atrial pressure (RAP) and lower cardiac output (CO) compared with those without PGD at 6 months after HTx (RAP, 6.8 ± 3.6 vs. 2.8 ± 2.2 mmHg, p < 0.001; CO, 4.6 ± 0.8 l vs. 5.8 ± 1.2 l/min, p = 0.02). With respect to survival, patients with PGD had a 5-year survival rate equivalent to those without PGD (83.3 vs. 93.3 %, p = 0.23). High-dose inotropic support for the donor heart and a history of stroke in the recipient are significant predictive factors for the development of PGD. However, recipients with PGD demonstrate mid-term survival comparable to those without PGD.

Risk Stratification for Cardiac Allograft Vasculopathy in Heart Transplant Recipients - Annual Intravascular Ultrasound Evaluation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) limits long-term success after heart transplant. We assessed the post-transplant risk factors for CAV development. METHODS AND RESULTS: Patients who underwent heart transplant between May 1999 and December 2013 were included in this study. Patients (n=54) were divided into 2 groups according to the presence or absence of CAV progression after transplant. Coronary angiogram and intravascular ultrasound were conducted within 5-11 weeks after transplant, at 12 months, and annually thereafter. Scheduled endomyocardial biopsies were performed after transplant or whenever acute cellular rejection (ACR) or antibody-mediated rejection was suspected. Twenty-five of 54 patients (46.2%) had CAV progression. ACR ≥ International Society for Heart and Lung Transplantation grade 2 (ACR ≥ 2) and donor age >50 years were significantly associated with CAV development compared with ACR <2 and donor age <50 years. Patients with no history of ACR ≥ 2 and donor age ≤50 years had a significantly low risk of developing CAV compared with the other groups. CONCLUSIONS: Donor age and history of ACR ≥ 2 are independent risk factors for CAV development. Identifying patients at risk of developing CAV is important for appropriate direction of resources and intensity of follow-up.

Serum Brain Natriuretic Peptide Concentration 60 Days After Surgery as a Predictor of Long-Term Prognosis in Patients Implanted With a Left Ventricular Assist Device.

Mechanical circulatory support by a left ventricular assist device (LVAD) is used to bridge patients with advanced heart failure to transplant or as a definitive treatment. We retrospectively sought predictors of long-term outcome in a cohort of 83 patients who had undergone LVAD treatment. We subjected perioperative clinical data of patients to statistical analysis to establish parameters associated with all-cause mortality, and the cutoff values, sensitivity, and specificity of those that had a statistically significant relation with survival. Mean follow-up was 717 days (standard deviation, 334 days; range, 17-1,592 days). Fourteen patients (16.8%) died, but nine (10.8%) were weaned from support. Serum brain natriuretic peptide (BNP) concentration measured 60 days after implantation was significantly associated with all-cause mortality. The optimal BNP cutoff value to predict death during LVAD support was 322 pg/ml, with a sensitivity of 71.4% and specificity of 79.8%. Two-year survival was 92.0% in those with 60 days serum BNP concentration <322 pg/ml compared with 70.5% in those in whom it was ≥322 pg/ml (p = 0.003). The relation between BNP and survival likely reflects recovery of native myocardial function and improvements in global health and should assist clinicians in the on-going management of long-term LVAD therapy.

Acute response test to adaptive servo-ventilation, a possible modality to assessing the reversibility of pulmonary vascular resistance.

Since pulmonary hypertension (PH) due to left-sided heart failure (HF) with elevated pulmonary vascular resistance (PVR) is contraindication for heart transplantation (HTx), correct evaluation of reversibility in PVR is essential for adequate therapeutic decision-making. However, guidelines or recommended protocols for pharmacological testing to evaluate the reversibility of PVR have not been established yet. In this report, we presented a 34-year-old male with advanced HF complicated by severe PH with high PVR [5.93 Wood units (WU)] who was deemed eligible for HTx. To evaluate his HTx candidacy, oxygen inhalation test was applied during right heart catheterization (RHC) and PVR was drastically decreased to 2.29 WU. At that time, acute response test to adaptive servo-ventilation (ASV) was also applied and use of ASV temporarily but substantially decreased PVR to 2.15 WU. From the results of both oxygen inhalation test and acute response test to ASV, reversibility of PVR in this patient was confirmed, and the patient was approved as HTx candidate and received left ventricular assist device (LVAD) implantation for bridge to transplant. After LVAD implantation, PVR substantially and persistently decreased to 2.4 WU. These findings indicate that acute response test to ASV during RHC may be a possible modality to evaluate the reversibility of PVR in HF patients with PH complicated by elevated PVR.

Evaluation of micro-emboli in a patient with ventricular assist device support with hemolysis.

The clinical relevance of transcranial Doppler (TCD) detection of micro-embolic signals (MES) in patients with ventricular assist devices (VADs) has been described. However, all of the previous studies concerning TCD in patients with VADs were conducted in patients with old devices; the clinical relevance of TCD in patients with newer devices has not been fully elucidated. We recently encountered a patient with a continuous-flow VAD with hemolysis. TCD monitoring was useful for the direct evaluation of micro-emboli in this patient. A 50-year-old male who underwent HeartMate II(®) VAD (Thoratec Corporation; Pleasanton, CA) implantation with a diagnosis of ischemic cardiomyopathy 15 months prior was admitted to our institution because of findings suggestive of hemolysis, such as elevated lactate dehydrogenase (LDH) and total bilirubin. Unfractionated heparin was started after admission and hemolysis gradually improved. On admission, TCD detected 146 MES during 30 min of monitoring. During the hospital course, the MES count decreased to 20 signals on hospital day 4 and further decreased to 2 signals on hospital day 15 along with decreases in LDH and total bilirubin. Since hemolysis in VAD patients is thought to be associated with thromboembolic outcomes, MES detected by TCD indicate subclinical micro-emboli. TCD monitoring may be useful for assessing the risk of thromboembolic events in newer continuous-flow VAD patients through direct visualization of micro-emboli.

Restrictive myocardium with an unusual pattern of apical hypertrophic cardiomyopathy.

Loeffler endocarditis is a fibrous restrictive cardiomyopathy thought to be caused by persistent eosinophilia. It is difficult to diagnose, and the prognosis is often poor if the underlying eosinophilia is not promptly recognized and treated. We describe the case of a middle-aged woman treated for hypertrophic cardiomyopathy first detected during a routine check-up at age 35years but whose symptoms gradually progressed over the next 14years. Right ventricular biopsy showed extensive fibrosis of the endocardial tissue, and right heart catheterization revealed right heart failure and a low cardiac output state. Ultimately, she became reliant on inotropic and mechanical cardiovascular support, but we were not able to bridge her to transplant. Autopsy findings were typical of endocardial fibroelastosis, but she had not suffered from any tropical disease or traveled to high-risk areas. The presence of abnormal capillary proliferation suggested a diagnosis of Loeffler endocarditis. Nonetheless, apart from a 6-month period of eosinophilia 7years before her death, a history of well-controlled asthma and several drug sensitivities, we were unable to definitively identify the disease trigger. It is critical to diagnose and treat the underlying eosinophilia of Loeffler endocarditis to avoid a poor prognosis. This case highlights the importance of considering the diagnosis of eosinophilic endomyocarditis in patients with an unusual pattern of apical hypertrophic cardiomyopathy (or myocardial fibrosis of unknown etiology), even when there is no apparent history of eosinophilia.

Left coronary artery occlusion caused by a large thrombus on the left coronary cusp in a patient with a continuous-flow ventricular assist device.

Despite continual improvements in ventricular assist device (VAD) therapy, various clinical issues are emerging. Importantly, various types of thromboembolic complications have been reported to date. Recently, we encountered a rare continuous-flow VAD-related thromboembolic event that resulted in acute myocardial infarction. A 26-year-old female who just underwent HeartMate II(®) VAD implantation suddenly developed widespread anterolateral myocardial infarction on postoperative day 16. Echocardiography and aortography revealed a large thrombus on the left coronary cusp of the aortic valve that almost completely occluded the left coronary ostium. After VAD implantation, her aortic valve did not open, even at relatively low pump speeds; this was thought to be one of the causes for thrombus formation. Continuous suction of blood from the left ventricle and non-pulsatile flow into the ascending aorta resulted in a continuously closed aortic valve and stagnation of blood in the coronary cusp. Furthermore, both small body size (body surface area <1.3 m(2)) and postoperative right ventricular failure may have exacerbated blood stagnation and thrombus formation in this patient. We should have adjusted the anticoagulation and antiplatelet therapy protocols based on the patient's condition. She underwent off-pump coronary artery bypass surgery and remained in clinically stable condition afterwards.

Paracorporeal ventricular assist device as a bridge to transplant candidacy in the era of implantable continuous-flow ventricular assist device.

Ventricular assist devices (VADs) have long been used as bridge to transplant therapy (BTT). Nipro-Toyobo paracorporeal pulsatile-flow VAD (nt-VAD) was the only device available until April 2011, when implantable continuous-flow VADs (cf-VADs) became available. Although cf-VADs are central to BTT, nt-VAD remains a necessary option. We aimed to clarify the role of nt-VAD in an era of increasing cf-VAD use. We retrospectively reviewed patients who underwent VAD implantation at the National Cerebral and Cardiovascular Center from May 2011 to March 2013. Characteristics were compared between the nt-VAD and cf-VAD groups. Twenty-nine patients (mean age 37.7 ± 11.1 years, 23 males) underwent VAD implantation. Fifteen patients initially received nt-VADs, although 4 were converted to cf-VADs. Of these 15 patients, 3 were too small for cf-VADs and 2 needed bilateral ventricular support. The remaining 10 patients received nt-VADs (7 patients at INTERMACS level 1 and 3 at level 2). The nt-VAD group patients had significantly more preoperative mechanical circulatory support and were in a more critical condition before VAD implantation than the cf-VAD group. The 2-year survival rate was not significantly different. Despite the critical conditions of nt-VAD patients, their overall survival is not statistically inferior to that of cf-VAD patients. nt-VAD is a good option as a BTC for the patient with urgent and critical condition.

A heart transplant candidate with severe pulmonary hypertension and extremely high pulmonary vascular resistance.

Fixed pulmonary hypertension (PH) is a contraindication for heart transplantation (HTx). Several studies showed that use of a left ventricular assist device (LVAD) in patients with fixed PH who were initially deemed ineligible for HTx effectively decreased pulmonary arterial pressure (PAP), thus permitting HTx. We recently encountered a candidate for HTx who had severe PH with extremely high pulmonary vascular resistance (PVR). A 27-year-old female who had been diagnosed with dilated-phase hypertrophic cardiomyopathy and who was approved for HTx at age 25 was referred to our institute because of severe fatigability with moderate dyspnea even at rest due to severe bilateral heart failure. Despite continuous inotrope infusion, the patient's symptoms were not relieved. Right heart catheterization (RHC) disclosed a PAP of 62/40 mmHg with severely reduced cardiac output (1.8 l/min). A PVR of 15.9 Wood units suggested progressive worsening of left ventricular function with almost irreversible remodeling of the pulmonary vasculature, and the patient was thought to be contraindicated for HTx. Following 3 weeks of aggressive medical treatment, repeat RHC demonstrated PVR lowering to 8.16 Wood units. This suggested it was likely that PVR could be reversed, and the patient underwent LVAD implantation. RHC performed after LVAD implantation showed a fall in PVR from the initial, extremely high measurement of 15.9 Wood units to 3.4 Wood units at 2 months postoperatively, and to 2.2 Wood units at 1 year. The patient is currently awaiting HTx with favorable LVAD support.

Aortic valve closure for rapidly deteriorated aortic insufficiency after continuous flow left ventricular assist device implantation.

A patient underwent aortic valve closure for de novo aortic insufficiency that had deteriorated to severe insufficiency during six months of support with a continuous flow left ventricular assist device (cf-LVAD). Aortic insufficiency was initially noted one month after LVAD implantation, and then deterioration quickly developed. Right heart catheterization revealed that when the rotational speed of the cf-LVAD was increased, the cardiac index was decreased by an increase in regurgitant volume, as shown by echocardiography. During surgery, fusion and shortening of the aortic leaflets as well as left coronary ostial occlusion were observed. Direct aortic closure improved hemodynamics. Thrombus formation on the aortic valve shown by echocardiography in the early postoperative period may be a trigger of aortic insufficiency. Control of the cf-LVAD rotational speed is likely required to prevent aortic insufficiency.