Cardiac transplantation after bridged therapy with continuous flow left ventricular assist devices.

INTRODUCTION: Cardiac transplantation is an effective surgical therapy for end-stage heart failure. Patients (pts) may need to be bridged with a continuous flow left ventricular assist device (CF-LVAD) while on the transplant list as logistic factors like organ availability are unknown. Cardiac transplantation post-LVAD can be a surgically challenging procedure and outcome in these pts is perceived to be poorer based on experience with earlier generation pulsatile flow pumps. Data from a single institution comparing these pts with those undergoing direct transplantation in the present era of continuous flow device therapy are limited. AIM: Evaluate results of cardiac transplantation in pts bridged with a CF-LVAD (BTx) and compare outcomes with pts undergoing direct transplantation (Tx) in a single institution. RESULTS: From June 2007 till January 2012, 106 pts underwent cardiac transplantation. Among these, 37 (35%) pts (51±11 years; 85% male) were bridged with a CF-LVAD (BTx), while 70 (65%) comprised the Tx group (53±12 years; 72% males). The median duration of LVAD support was 227 (153,327) days. During the period of LVAD support, 10/37 (27%) pts were upgraded to status 1A and all were successfully transplanted. Median hospital stay in the BTx (14 days) was slightly longer than the Tx group (12 days) but not statistically significant (p=0.21). In-hospital mortality in the BTx (5%) and Tx (1%) were comparable (p=0.25). Estimated late survival in the BTx cohort was 94±7, 90±10 and 83±16% at the end of one, two and three years, respectively which was comparable to 97±4%, 93±6% and 89±9% for the Tx group (p=0.50). CONCLUSION: Cardiac transplantation after LVAD implant can be performed with excellent results. Patients can be supported on the left ventricular assist device even for periods close to a year with good outcome after cardiac transplantation.

Sirolimus as primary immunosuppression attenuates allograft vasculopathy with improved late survival and decreased cardiac events after cardiac transplantation.

BACKGROUND: We retrospectively analyzed the potential of sirolimus as a primary immunosuppressant in the long-term attenuation of cardiac allograft vasculopathy progression and the effects on cardiac-related morbidity and mortality. METHODS AND RESULTS: Forty-five cardiac transplant recipients were converted to sirolimus 1.2 years (0.2, 4.0) after transplantation with complete calcineurin inhibitor withdrawal. Fifty-eight control subjects 2.0 years (0.2, 6.5 years) from transplantation were maintained on calcineurin inhibitors. Age, sex, ejection fraction, and time from transplantation to baseline intravascular ultrasound study were not different (P>0.2 for all) between the groups; neither were secondary immunosuppressants and use of steroids. Three-dimensional intravascular ultrasound studies were performed at baseline and 3.1 years (1.3, 4.6 years) later. Plaque index progression (plaque volume/vessel volume) was attenuated in the sirolimus group (0.7±10.5% versus 9.3±10.8%; P=0.0003) owing to reduced plaque volume in patients converted to sirolimus early (<2 years) after transplantation (P=0.05) and improved positive vascular remodeling (P=0.01) in patients analyzed late (>2 years) after transplantation. Outcome analysis in 160 consecutive patients maintained on 1 therapy was performed regardless of performance of intravascular ultrasound examinations. Five-year survival was improved with sirolimus (97.4±1.8% versus 81.8±4.9%; P=0.006), as was freedom from cardiac-related events (93.6±3.2% versus 76.9±5.5%; P=0.002). CONCLUSIONS: Substituting calcineurin inhibitor with sirolimus as primary immunosuppressant attenuates long-term cardiac allograft vasculopathy progression and may improve long-term allograft survival owing to favorable coronary remodeling. Because of the lack of randomization and retrospective nature of our analysis, the differences in outcome should be interpreted cautiously, and prospective clinical trials are required.

TPMT genetic variants are associated with increased rejection with azathioprine use in heart transplantation.

OBJECTIVES: Azathioprine (AZA) is an important immunosuppressant drug used in heart transplantation (HTX). Consensus guidelines recommend that patients with thiopurine S-methyltransferase (TPMT) genetic variants be started on lower AZA dose because of higher active metabolite levels and risk of adverse events. However, in-vitro lymphocyte proliferation assays performed in participants with inactive TPMT alleles have suggested that AZA use may result in decreased immunosuppressant efficacy as compared with wild-type (WT) individuals. The objective of this study was therefore to determine the effect of TPMT genetic variation on AZA efficacy or prevention of rejection in HTX recipients treated with AZA. PARTICIPANTS AND METHODS: We genotyped 93 HTX recipients treated with AZA and measured erythrocyte TPMT enzyme activity. Acute rejection was monitored by routine endomyocardial biopsies. RESULTS: There were 83 WT and 10 heterozygote (HZ) HTX recipients. TPMT activity level was lower in HZ compared with WT (13.1±2.8 vs. 21±4.5 U/ml red blood cell, P<0.001). Despite similar AZA dose, HZ developed severe rejection earlier (P<0.001), and the total rejection score was higher (P=0.02) than WT. AZA was discontinued more frequently in HZ (P=0.01) because of rejection. The incidence of leukopenia was similar between the groups (40 vs. 43%, P=1.0). CONCLUSION: HTX recipients with TPMT genetic variant alleles who are treated with AZA develop acute rejection earlier, more frequently, and of greater severity. These patients, despite having lower TPMT enzymatic activity, should be monitored carefully for possible increased risk of acute rejection.

Dual anti-platelet therapy after coronary artery bypass grafting: is there any benefit? A systematic review and meta-analysis.

BACKGROUND: Anti-platelet therapy is an important component of medical therapy post coronary artery bypass grafting (CABG). While aspirin administration is a Class I indication after CABG, the benefit of concomitant clopidogrel is a controversial issue. METHODS: We searched OVID Medline, Cochrane, Scopus, and EMBASE for randomized control trials and observational studies comparing aspirin ± placebo to aspirin + clopidogrel after CABG. RESULTS: Eleven articles (five randomized control trials and six observational studies) including 25,728 patients met inclusion criteria. Early saphenous vein graft occlusion was reduced with the use of dual anti-platelet therapy (risk ratio (RR) = 0.59, 95% CI 0.43-0.82, p = 0.02). In-hospital or 30-day mortality was lower with aspirin + clopidogrel (0.8%) compared to aspirin alone (1.9%) (p < 0.0001), while risk of angina or perioperative myocardial infarction was comparable (RR = 0.60, 95% CI 0.31-1.14, p = 0.12). Patients treated with aspirin + clopidogrel demonstrated a trend towards a higher incidence of major bleeding episodes as compared to patients treated with aspirin alone (RR = 1.17, 95% CI 1.00-1.37, p = 0.05). In a pooled analysis of studies involving off-pump CABG compared to aspirin alone, dual anti-platelet therapy reduced the risk of perioperative myocardial infarction and saphenous graft occlusion by 68% (47% to 71%) and 55% (2% to 79%) respectively. CONCLUSION: Dual anti-platelet therapy after CABG improved early saphenous vein graft patency, but may increase the risk of bleeding. The use of dual anti-platelet therapy appears to be most beneficial in patients undergoing off-pump CABG. Prospective randomized studies are necessary to determine whether this beneficial effect of dual therapy is also achieved in patients undergoing on pump CABG.

Clinical Characteristics and Outcomes of Clostridioides difficile Infection in Patients With Left Ventricular Assist Device.

The literature regarding Clostridioides difficile infection (CDI) in left ventricular assist devices (LVADs) patients is limited. Therefore, we aimed to characterize the clinical course, risk factors, management, and outcomes of LVAD patients who developed CDI. Adult patients who underwent LVAD placement during 2010-2022 and developed CDI were included. To determine risk factors and outcomes, we matched CDI patients with LVAD patients who did not develop CDI. Each CDI case was matched with up to two control subjects by age, sex, and time from LVAD implantation. Forty-seven of 393 LVAD patients (12.0%) developed CDI. The median time from LVAD implantation to CDI was 147 days (interquartile range 22.5-647.0). The most common CDI treatment was oral vancomycin (n = 26, 55.3%). Thirteen patients (27.7%) required treatment extension because of a lack of clinical response. Three patients (6.4%) developed recurrent CDI. When 42 cases were matched to 79 control subjects, antibiotic exposure within 90 days was significantly associated with CDI (adjusted odds ratio 5.77; 95% confidence interval, 1.87-17.74; p = 0.002). Moreover, CDI was associated with 1 year mortality (adjusted hazard ratio 2.62; 95% confidence interval, 1.18-5.82; p = 0.018). This infection occurs most often within the first year after LVAD implantation and was associated with 1 year mortality. Antibiotic exposure is an important risk for CDI.

Artificial Intelligence-Derived Electrocardiogram Assessment of Cardiac Age and Molecular Markers of Senescence in Heart Failure.

OBJECTIVE: To ascertain whether heart failure (HF) itself is a senescent phenomenon independent of age, and how this is reflected at a molecular level in the circulating progenitor cell niche, and at a substrate level using a novel electrocardiogram (ECG)-based artificial intelligence platform. PATIENTS AND METHODS: Between October 14, 2016, and October 29, 2020, CD34+ progenitor cells were analyzed by flow cytometry and isolated by magnetic-activated cell sorting from patients of similar age with New York Heart Association functional classes IV (n = 17) and I-II (n = 10) heart failure with reduced ejection fraction and healthy controls (n = 10). CD34+ cellular senescence was quantitated by human telomerase reverse transcriptase expression and telomerase expression by quantitative polymerase chain reaction, and senescence-associated secretory phenotype (SASP) protein expression assayed in plasma. An ECG-based artificial intelligence (AI) algorithm was used to determine cardiac age and difference from chronological age (AI ECG age gap). RESULTS: CD34+ counts and telomerase expression were significantly reduced and AI ECG age gap and SASP expression increased in all HF groups compared with healthy controls. Expression of SASP protein was closely associated with telomerase activity and severity of HF phenotype and inflammation. Telomerase activity was more closely associated with CD34+ cell counts and AI ECG age gap. CONCLUSION: We conclude from this pilot study that HF may promote a senescent phenotype independent of chronological age. We show for the first time that the AI ECG in HF shows a phenotype of cardiac aging beyond chronological age, and appears to be associated with cellular and molecular evidence of senescence.

Differential phenotype and behavior in culture of CD34 positive cells from peripheral blood and adipose tissue.

The localization and quantification of endothelial progenitor cells (EPCs) are controversial. Circulating CD34 + cells in blood have been identified as EPCs and as biomarkers of cardiovascular disease. We discuss in this paper the current data describing differential phenotype and behavior in vitro of CD34 positive cells from the circulation and adipose tissue (AT). We also describe in brief our own findings from CD34 + cells isolated from leukopheresis cones derived from healthy platelet donors and from patients undergoing bariatric surgery. We conclude that CD34 + cells in blood and in AT are different in antigenic profile and behavior in culture. The findings described assert that CD34 + cells detected in blood previously identified as biomarkers of cardiovascular disease are predominantly HPCs rather than EPCs, and that true CD34 + EPCs can be readily identified and extracted from AT, supportive of the current evidence which suggests EPCs are resident in the tissue vasculature.

The Role of Genetic Testing in the Evaluation of Dilated Cardiomyopathies.

We present an adolescent African American male admitted to the cardiac intensive care unit with cardiogenic shock and acute respiratory failure. Through an overview of his presentation, diagnostic workup, and treatment, we demonstrate the clinical utility of genetic testing in the evaluation of unexplained dilated cardiomyopathies.

Acoustic Properties of Axial and Centrifugal Flow Left Ventricular Assist Devices and Prediction of Pump Thrombosis.

OBJECTIVE: To characterize the properties of the audible tones produced by current left ventricular assist device (LVAD) pumps approved for use, and to ascertain if changes in those may be present in the setting of pump thrombosis. PATIENTS AND METHODS: From August 31, 2016, to January 16, 2020, LVAD recipients consented to have surface recordings obtained using a high-fidelity digital stethoscope. Audio data were analyzed using digital recording and editing software to produce an acoustic spectrogram by Fast Fourier transformation. RESULTS: Recordings were obtained in 53 patient encounters (27 HeartMate II, 19 HeartWare and 7 HeartMate 3). In 12 patients (9 HeartMate II, 3 HeartWare) there was a clinical concern for pump thrombosis. In all patients and pump models, a fundamental frequency was noted, and the second and third harmonics were also clearly detectable. Where thrombosis occurred in the HeartMate II pump, the absolute (normal -46.9 [-57.5,-42.9] dB vs thrombosis -41.4 [-49.8,-26.8] dB; P=.08) and relative (normal 0.72 [0.62, 0.92] vs thrombosis 0.95 [0.86, 1.24]; P=.01) third harmonic frequencies were increased in amplitude. Where paired data were available, an increase in the absolute and relative third harmonic frequencies was observed in all patients. In the case of the HeartWare device, a consistent difference in harmonic amplitudes in the setting of thrombosis could not be identified. CONCLUSION: A consistent pattern of fundamental and harmonic frequencies is common to all LVADs currently approved for use. Alterations in the amplitude of higher order harmonics may signal the onset of pump thrombosis in axial flow LVADs.

Heart-After-Liver Transplantation Attenuates Rejection of Cardiac Allografts in Sensitized Patients.

BACKGROUND: In patients undergoing heart transplantation, significant allosensitization limits access to organs, resulting in longer wait times and high waitlist mortality. Current desensitization strategies are limited in enabling successful transplantation. OBJECTIVES: The purpose of this study was to describe the cumulative experience of combined heart-liver transplantation using a novel heart-after-liver transplant (HALT) protocol resulting in profound immunologic protection. METHODS: Reported are the results of a clinical protocol that was instituted to transplant highly sensitized patients requiring combined heart and liver transplantation at a single institution. Patients were dual-organ listed with perceived elevated risk of rejection or markedly prolonged waitlist time due to high levels of allo-antibodies. Detailed immunological data and long-term patient and graft outcomes were obtained. RESULTS: A total of 7 patients (age 43 ± 7 years, 86% women) with high allosensitization (median calculated panel reactive antibody = 77%) underwent HALT. All had significant, unacceptable donor specific antibodies (DSA) (>4,000 mean fluorescence antibody). Prospective pre-operative flow cytometric T-cell crossmatch was positive in all, and B-cell crossmatch was positive in 5 of 7. After HALT, retrospective crossmatch (B- and T-cell) became negative in all. DSA fell dramatically; at last follow-up, all pre-formed or de novo DSA levels were insignificant at <2,000 mean fluorescence antibody. No patients experienced >1R rejection over a median follow-up of 48 months (interquartile range: 25 to 68 months). There was 1 death due to metastatic cancer and no significant graft dysfunction. CONCLUSIONS: A heart-after-liver transplantation protocol enables successful transplantation via near-elimination of DSA and is effective in preventing adverse immunological outcomes in highly sensitized patients listed for combined heart-liver transplantation.

Ventricular tachycardia and preload deficiency post LVAD - The importance of integrated assessment.

Ventricular tachycardia (VT) is common in LVAD recipients, and although often well tolerated, may result in symptoms and ICD therapies, and therefore require further evaluation and treatment. However, preload deficiency may also contribute to the development of ventricular tachycardia after LVAD implantation by provoking inflow cannula related VT. In this report, three cases are described where ventricular tachycardia was evaluated by integrated assessment utilizing echo and the HeartWare HVAD console, and successfully treated by modification of LV loading conditions.

Vasoprotective effects of human CD34+ cells: towards clinical applications.

BACKGROUND: The development of cell-based therapeutics for humans requires preclinical testing in animal models. The use of autologous animal products fails to address the efficacy of similar products derived from humans. We used a novel immunodeficient rat carotid injury model in order to determine whether human cells could improve vascular remodelling following acute injury. METHODS: Human CD34+ cells were separated from peripheral buffy coats using automatic magnetic cell separation. Carotid arterial injury was performed in male Sprague-Dawley nude rats using a 2F Fogarty balloon catheter. Freshly harvested CD34+ cells or saline alone was administered locally for 20 minutes by endoluminal instillation. Structural and functional analysis of the arteries was performed 28 days later. RESULTS: Morphometric analysis demonstrated that human CD34+ cell delivery was associated with a significant reduction in intimal formation 4 weeks following balloon injury as compared with saline (I/M ratio 0.79 +/- 0.18, and 1.71 +/- 0.18 for CD34, and saline-treated vessels, respectively P < 0.05). Vasoreactivity studies showed that maximal relaxation of vessel rings from human CD34+ treated animals was significantly enhanced compared with saline-treated counterparts (74.1 +/- 10.2, and 36.8 +/- 12.1% relaxation for CD34+ cells and saline, respectively, P < 0.05) CONCLUSION: Delivery of human CD34+ cells limits neointima formation and improves arterial reactivity after vascular injury. These studies advance the concept of cell delivery to effect vascular remodeling toward a potential human cellular product.

Ventricular Arrhythmias in Patients With Left Ventricular Assist Device (LVAD).

PURPOSE OF REVIEW: Left ventricular assist device (LVAD) implantation is a well-known treatment option for patients with advanced heart failure refractory to medical therapy and is recognized both as bridge to transplant and a destination therapy. The risk of ventricular arrhythmias (VAs) is common after LVAD implantation. We review the pathophysiology and recent advances in the management of VA in LVAD patients. RECENT FINDINGS: VAs are most likely to occur in the early post-operative periods after LVAD implantation and a prior history of VA is the most important risk factor. Post-LVAD VAs are usually well tolerated with less morbidity and decreased risk of sudden cardiac death. However, risk of right heart failure in the setting of persistent VAs is being increasingly recognized. The mechanisms of post-LVAD VAs may vary depending on the time from LVAD implantation. Electrical remodeling may play an important role in the immediate post-implant phase. Preexisting myocardial scar and to a lesser extent mechanical irritation from the LVAD cannula are important in the later phases. Most LVAD patients have a previously placed implantable cardioverter-defibrillator (ICD). The benefit of implanting a new ICD in LVAD patients is unknown and should be individualized. For ICD programming, a conservative strategy with higher detection zones and prolonged time to detection is usually recommended aiming to minimize ICD shocks. More aggressive programming is appropriate if the VA results in hemodynamic instability. Antiarrhythmic drugs including amiodarone, mexiletine, and beta blockers are usually the first-line therapy for VAs. Catheter ablation has been shown to be safe and effective in LVAD recipients with recurrent VAs not responsive to antiarrhythmic drugs. LVAD-related VA is most frequently reentrant secondary to myocardial scar and usually well tolerated. Management options include antiarrhythmic drugs and catheter ablation.

Baseline Thromboelastogram as a Predictor of Left Ventricular Assist Device Thrombosis.

Left ventricular assist device (LVAD) pump thrombosis occurs in up to 8.4% of patients within 3-months postimplantation. Thromboelastography (TEG) could be used to signal hypercoagulability at LVAD implantation to predict patients at high risk for thrombosis. We sought to evaluate whether TEG maximum amplitude (MA) hypercoagulability (MA ≥69 mm) at the time of LVAD implantation predicts pump thrombosis. A single center, retrospective, nested case-control study was conducted using patients from January 1, 2005, to March 31, 2015. Each pump thrombosis case was matched to two control subjects based on age ± 5 years, sex, and duration of follow-up. A multivariable logistic regression analysis was performed on the matched sets; the odds ratio with 95% confidence interval (CI) was calculated to estimate the relative risk. Thirty-seven age- and sex-matched case-control sets were included for a total of 111 study participants. TEG-MA hypercoagulability occurred in 10.8% of the case group versus 6.8% of controls. There was no association between TEG-MA hypercoagulability and device thrombosis (odds ratio 1.71, 95% confidence interval 0.42-7.05, p = 0.46). Utilization of baseline TEG-MA hypercoagulability to detect individuals at risk for LVAD thrombosis is a novel concept. This study found no significant association between TEG-MA and LVAD thrombosis.

Timing of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor initiation and allograft vasculopathy progression and outcomes in heart transplant recipients.

AIMS: Early studies from the 1990s have shown that statins improve survival and attenuate cardiac allograft vasculopathy (CAV). However, little contemporary data are available on the incremental benefit of statins with the current use of new-generation immunosuppressive agents and the use of coronary intravascular ultrasound for assessment of CAV. We sought to investigate the effect of early statin (ES) as compared with late statin (LS) initiation after heart transplantation (HT) on long-term CAV progression and clinical outcomes in a large contemporary HT cohort. METHODS AND RESULTS: We analysed a cohort of 409 adult HT recipients. CAV progression was assessed by serial coronary intravascular ultrasound volumetric measurements of the differences between baseline and last follow-up plaque volume (PV) and plaque index (PV/vessel volume ratio). CAV progression and clinical outcomes were compared between the ES (<2 years after HT) and the LS (>2 years after HT) groups. During a median follow-up of 8.2 years, ES resulted in significantly lower change (Δ) of plaque index (+3.8% ± 1.7% vs. +8.2% ± 3.6%; P = 0.0008) and PV (+0.8 ± 0.3 vs. +1.9 ± 1.2; P = 0.045) compared with LS group. In a Cox proportional hazards regression model and after adjustment for baseline characteristics, ES was associated with a 52% decreased risk of CAV-associated events (hazard ratio 0.48, 95% confidence interval: 0.27-0.91; P = 0.025) and a 42% decreased risk of the composite endpoint of all-cause mortality and CAV-associated events (hazard ratio 0.58, 95% confidence interval: 0.38-0.91; P = 0.019). CONCLUSIONS: Early initiation of statin therapy after HT results in attenuated CAV progression as well as in decreased CAV-related events and mortality.

Long-Term Sirolimus for Primary Immunosuppression in Heart Transplant Recipients.

BACKGROUND: Small studies have reported superiority of sirolimus (SRL) over calcineurin inhibitor (CNI) in mitigating cardiac allograft vasculopathy (CAV) after heart transplantation (HT). However, data on the long-term effect on CAV progression and clinical outcomes are lacking. OBJECTIVES: The aim of this study was to test the long-term safety and efficacy of conversion from CNI to SRL as maintenance therapy on CAV progression and outcomes after HT. METHODS: A cohort of 402 patients who underwent HT and were either treated with CNI alone (n = 134) or converted from CNI to SRL (n = 268) as primary immunosuppression was analyzed. CAV progression was assessed using serial coronary intravascular ultrasound during treatment with CNI (n = 99) and after conversion to SRL (n = 235) in patients who underwent at least 2 intravascular ultrasound studies. RESULTS: The progression in plaque volume (2.8 ± 2.3 mm3/mm vs. 0.46 ± 1.8 mm3/mm; p < 0.0001) and plaque index (plaque volume-to-vessel volume ratio) (12.2 ± 9.6% vs. 1.1 ± 7.9%; p < 0.0001) were significantly attenuated when treated with SRL compared with CNI. Over a mean follow-up period of 8.9 years from time of HT, all-cause mortality occurred in 25.6% of the patients and was lower during treatment with SRL compared with CNI (adjusted hazard ratio: 0.47; 95% confidence interval: 0.31 to 0.70; p = 0.0002), and CAV-related events were also less frequent during treatment with SRL (adjusted hazard ratio: 0.35; 95% confidence interval: 0.21 to 0.59; p < 0.0001). Further analyses suggested more attenuation of CAV and more favorable clinical outcomes with earlier conversion to SRL (≤2 years) compared with late conversion (>2 years) after HT. CONCLUSIONS: Early conversion to SRL is associated with attenuated CAV progression and with lower long-term mortality and fewer CAV-related events compared with continued CNI use.

Ethical Analysis of Withdrawing Total Artificial Heart Support.

OBJECTIVES: To describe the characteristics of patients who undergo withdrawal of total artificial heart support and to explore the ethical aspects of withdrawing this life-sustaining treatment. PATIENTS AND METHODS: We retrospectively reviewed the medical records of all adult recipients of a total artificial heart at Mayo Clinic from the program's inception in 2007 through June 30, 2015. Management of other life-sustaining therapies, approach to end-of-life decision making, engagement of ethics and palliative care consultation, and causes of death were analyzed. RESULTS: Of 47 total artificial heart recipients, 14 patients or their surrogates (30%) requested withdrawal of total artificial heart support. No request was denied by treatment teams. All 14 patients were supported with at least 1 other life-sustaining therapy. Only 1 patient was able to participate in decision making. CONCLUSION: It is widely held to be ethically permissible to withdraw a life-sustaining treatment when the treatment no longer meets the patient's health care-related goals (ie, the burdens outweigh the benefits). These data suggest that some patients, surrogates, physicians, and other care providers believe that this principle extends to the withdrawal of total artificial heart support.