Innovations in Ventricular Assist Devices for End-Stage Heart Failure.

The number of patients with end-stage heart failure (HF) continues to increase over time, but there has been little change in the availability of organs for cardiac transplantation, intensifying the demand for left ventricular assist devices (LVADs) as a bridge to transplantation. There is also a growing number of patients with end-stage HF who are not transplant candidates but may be eligible for long-term support with an LVAD, known as destination therapy. Due to this increasing demand, LVAD technology has evolved, resulting in transformative improvements in outcomes. Additionally, with growing clinical experience patient management continues to be refined, leading to iterative improvements in outcomes. With outcomes continuing to improve, the potential benefit from LVAD therapy is being considered for patients earlier in their course of advanced HF. We review recent changes in technology, patient management, and implant decision making in LVAD therapy.

Honoring 50 Years of Clinical Heart Transplantation in Circulation: In-Depth State-of-the-Art Review.

Heart transplantation has become a standard therapy option for advanced heart failure. The translation of heart transplantation from innovative experiments to long-term clinical success has married prescient insights with discipline and organization in the domains of surgical techniques, organ preservation, immunosuppression, organ donation and transplantation logistics, infection control, and long-term graft surveillance. This review explores the key milestones of the past 50 years of heart transplantation and discusses current challenges and promising innovations on the clinical horizon.

Quality of life and metrics of achievement in long-term adult survivors of pediatric heart transplant.

Many children who undergo heart transplantation will survive into adulthood. We sought to examine the QOL and capacity for achievement in long-term adult survivors of pediatric heart transplantation. Adults >18 yr of age who received transplants as children (≤18 yr old) and had survived for at least 10 yr post-transplant completed two self-report questionnaires: (i) Ferrans & Powers QLI, in which life satisfaction is reported as an overall score and in four subscale domains and is then indexed from 0 (very dissatisfied) to 1 (very satisfied); and (ii) a "Metrics of Life Achievement" questionnaire regarding income, education, relationships, housing status, and access to health care. A total of 20 subjects completed the survey. The overall mean QLI score was 0.77 ± 0.16. Subjects were most satisfied in the family domain (0.84 ± 0.21) and least satisfied in the psychological/spiritual domain (0.7 ± 0.28). Satisfaction in the domains of health/functioning and socioeconomic were intermediate at 0.78 and 0.76, respectively. Most respondents had graduated from high school, reported a median annual income >$50 000/yr, and lived independently. Adult survivors of pediatric heart transplant report a good QOL and demonstrate the ability to obtain an education, work, and live independently.

Effect of rapamycin therapy on coronary artery physiology early after cardiac transplantation.

BACKGROUND: Rapamycin has been shown to reduce anatomical evidence of cardiac allograft vasculopathy, but its effect on coronary artery physiology is unknown. METHODS: Twenty-seven patients without angiographic evidence of coronary artery disease underwent measurement of fractional flow reserve (FFR), coronary flow reserve (CFR), and the index of microcirculatory resistance (IMR) within 8 weeks and then 1 year after transplantation using a pressure sensor/thermistor-tipped guidewire. Measurements were compared between consecutive patients who were on rapamycin for at least 3 months during the first year after transplantation (rapamycin group, n = 9) and a comparable group on mycophenolate mofetil (MMF) instead (MMF group, n = 18). RESULTS: At baseline, there was no significant difference in FFR, CFR, or IMR between the 2 groups. At 1 year, FFR declined significantly in the MMF group (0.87 +/- 0.06 to 0.82 +/- 0.06, P = .009) but did not change in the rapamycin group (0.91 +/- 0.05 to 0.89 +/- 0.04, P = .33). Coronary flow reserve and IMR did not change significantly in the MMF group (3.1 +/- 1.7 to 3.2 +/- 1.0, P = .76; and 27.5 +/- 18.1 to 19.1 +/- 7.6, P = .10, respectively) but improved significantly in the rapamycin group (2.3 +/- 0.8 to 3.8 +/- 1.4, P < .03; and 27.0 +/- 11.5 to 17.6 +/- 7.5, P < .03, respectively). Multivariate regression analysis revealed that rapamycin therapy was an independent predictor of CFR and FFR at 1 year after transplantation. CONCLUSION: Early after cardiac transplantation, rapamycin therapy is associated with improved coronary artery physiology involving both the epicardial vessel and the microvasculature.

QT dispersion is not associated with sudden cardiac death or mortality in heart transplant recipients.

BACKGROUND: Sudden cardiac death (SCD) has been shown to be a significant cause of death after heart transplantation. QT dispersion (QTd) is associated with SCD in several high-risk populations. We hypothesized that QTd would predict mortality and SCD in heart transplantation patients. METHODS: We examined the clinical charts and most recent electrocardiograms (ECGs) for patients who received heart transplants at Stanford University Medical Center during the period 1981-1995. QTd was measured with all 12 leads and the precordial leads. Analysis was performed by a single reader blinded to patient outcomes. RESULTS: A total of 346 patients who had undergone transplantation had available ECGs and known outcomes; 155 of these patients died, and 42 of these deaths were attributed to SCD. The 12-lead mean QTd was not significantly different between outcome groups: patients who survived had a 12-lead mean QTd of 58 +/- 29 milliseconds and those who died had a 12-lead mean QTd of 61 +/- 32 milliseconds (P = .57). Patients who died from SCD had a 12-lead mean QTd of 57 +/- 31 milliseconds (P = .40), and those who died of other causes had a 12-lead mean QTd of 59 +/- 34 milliseconds (P = .36 vs those who died of SCD). Similarly, the precordial-lead mean QTd did not differ significantly between the different outcome groups. CONCLUSIONS: We found no correlation between QTd and SCD or mortality in heart transplant recipients. Until additional studies prove a positive association, QTd should not be used as a prognostic marker in these patients.

Changes in coronary anatomy and physiology after heart transplantation.

Cardiac allograft vasculopathy (CAV) is a progressive process involving the epicardial and microvascular coronary systems. The timing of the development of abnormalities in these 2 compartments and the correlation between changes in physiology and anatomy are undefined. The invasive evaluation of coronary artery anatomy and physiology with intravascular ultrasound, fractional flow reserve, coronary flow reserve, and the index of microcirculatory resistance (IMR) was performed in the left anterior descending coronary artery during 151 angiographic evaluations of asymptomatic heart transplant recipients from 0 to >5 years after heart transplantation (HT). There was no angiographic evidence of significant CAV, but during the first year after HT, fractional flow reserve decreased significantly (0.89 +/- 0.06 vs 0.85 +/- 0.07, p = 0.001), and percentage plaque volume derived by intravascular ultrasound increased significantly (15.6 +/- 7.7% to 22.5 +/- 12.3%, p = 0.0002), resulting in a significant inverse correlation between epicardial physiology and anatomy (r = -0.58, p <0.0001). The IMR was lower in these patients compared with those > or =2 years after HT (24.1 +/- 14.3 vs 29.4 +/- 18.8 units, p = 0.05), suggesting later spread of CAV to the microvasculature. As the IMR increased, fractional flow reserve increased (0.86 +/- 0.06 to 0.90 +/- 0.06, p = 0.0035 comparing recipients with IMRs < or =20 to those with IMRs > or =40), despite no difference in percentage plaque volume (21.0 +/- 11.2% vs 20.5 +/- 10.5%, p = NS). In conclusion, early after HT, anatomic and physiologic evidence of epicardial CAV was found. Later after HT, the physiologic effect of epicardial CAV may be less, because of increased microvascular dysfunction.

Prevalence, patterns of development, and prognosis of right bundle branch block in heart transplant recipients.

Right bundle branch block (RBBB) is the most common electrocardiographic abnormality in heart transplant recipients, but the cause remains unknown, data regarding the prognosis are conflicting, and all previous studies have been limited to <100 patients. This was a study of patients who underwent heart transplantation at Stanford University Medical Center from 1981 to 1995 with known outcomes and >or=2 available electrocardiograms (ECGs). Outcomes were assessed in those with and without conduction disturbances recorded from the ECGs closest to the time of transplantation and the most recent ECGs. Of the 322 heart transplant recipients studied, 141 (44%) died over a mean follow-up of 9 +/- 3.5 years, and 40 (13%) died of sudden cardiac death. In the first ECG obtained, a mean of 1.8 +/- 2.4 years after transplantation, 44 patients (14%) had incomplete RBBB and 26 (8%) had RBBB; in the second ECG, obtained a mean of 5.6 +/- 3.7 years after transplantation, 59 patients (18%) had incomplete RBBB and 63 (20%) had RBBB. Increasing time from transplantation was associated with a greater likelihood for RBBB on the first and second ECGs (p = 0.001 and p <0.0001, respectively). QRS duration, incomplete RBBB, RBBB, or the development of RBBB was not associated with mortality or sudden cardiac death. In conclusion, although RBBB was the most common electrocardiographic abnormality in our study, the prevalence was lower than previously reported. The cause of RBBB appears to be largely related to events that occur well after transplantation, and the prognosis is benign.

Major advantages and critical challenge for the proposed United States heart allocation system.

The proposed new United States allocation system incorporates extensive research into an elegant plan designed to reduce wait list mortality while preserving post-transplant outcomes. All architects are to be congratulated. However, the future cannot be reliably modeled from the past as listing practices will evolve in response to new criteria. The new system should provide a major advance if and only if it is combined with a commitment to limit the number of listed patients overall and within each high priority status to the number that could reasonably undergo timely transplantation.

Sex-related differences in age-associated downregulation of human ventricular myocardial ß1-adrenergic receptors.

BACKGROUND: With increasing age, human ventricular myocardium exhibits selective downregulation of ß1-adrenergic receptors (ß1-ARs). We tested the hypothesis that sex differences exist in age-related changes in ß1-ARs. METHODS: Left (LV) and right (RV) ventricular tissue was obtained from 61 unplaceable potential organ donor hearts ages 1 to 71 years with no known cardiac history and from LVs removed from 56 transplant recipients with idiopathic dilated cardiomyopathy. ß1-AR and ß2-AR densities, the frequency of ß1-AR389 gene variants, and ß-AR function were determined. RESULTS: Sex had a marked effect on the age-related decrease in ß1-ARs. Female LVs had more pronounced downregulation (by 42% [p < 0.001] vs 22% [p = 0.21] in 31 male LVs) comparing the youngest (average age, 15.3 ± 5.5 years) to the oldest (average age, 50.8 ± 9.1 years) sub-groups. On regression analyses, female LVs exhibited a closer relationship between ß1-AR density and age (r = -0.78, p <0.001 vs r = -0.46, p = 0.009 in males), with a second-degree polynomial yielding the best fit. There was no statistically significant relationship of ß1-ARs to age in female or male idiopathic dilated cardiomyopathy LVs. CONCLUSIONS: Sex affects age-related ß-AR downregulation in normal human ventricles, with females exhibiting more profound decreases with increasing age. The curvilinear relationship between age and receptor density that plateaus around age 40 in women suggests an effect of sex hormones on ß1-AR expression in the human heart.

Simultaneous assessment of fractional and coronary flow reserves in cardiac transplant recipients: Physiologic Investigation for Transplant Arteriopathy (PITA Study).

BACKGROUND: The utility of measuring fractional flow reserve (FFR) to assess cardiac transplant arteriopathy has not been evaluated. Measuring coronary flow reserve (CFR) as well as FFR could add information about the microcirculation, but until recently, this has required two coronary wires. We evaluated a new method for simultaneously measuring FFR and CFR with a single wire to investigate transplant arteriopathy. METHODS AND RESULTS: In 53 cases of asymptomatic cardiac transplant recipients without angiographically significant coronary disease, FFR and thermodilution-derived CFR (CFRthermo) were measured simultaneously with the same coronary pressure wire in the left anterior descending artery and compared with volumetric intravascular ultrasound (IVUS) imaging. The average FFR was 0.88+/-0.07; in 75% of cases, the FFR was less than the normal threshold of 0.94; and in 15% of cases, the FFR was < or =0.80, the upper boundary of the gray zone of the ischemic threshold. There was a significant inverse correlation between FFR and IVUS-derived measures of plaque burden, including percent plaque volume (r=0.55, P<0.0001). The average CFRthermo was 2.5+/-1.2; in 47% of cases, CFRthermo was < or =2.0. In 14%, the FFR was normal (> or =0.94) and the CFR was abnormal (<2.0), suggesting predominant microcirculatory dysfunction. CONCLUSIONS: FFR correlates with IVUS findings and is abnormal in a significant proportion of asymptomatic cardiac transplant patients with normal angiograms. Simultaneous measurement of CFR with the same pressure wire, with the use of a novel coronary thermodilution technique, is feasible and adds information to the physiological evaluation of these patients.

Glucose intolerance, as reflected by hemoglobin A1c level, is associated with the incidence and severity of transplant coronary artery disease.

OBJECTIVES: The possible effect of plasma hemoglobin A(1c) (HbA(1c)) on the development of transplant coronary artery disease (TxCAD) was investigated. BACKGROUND: Glucose intolerance is implicated as a risk factor for TxCAD. However, a relationship between HbA(1c) and TxCAD has not been demonstrated. METHODS: Plasma HbA(1c) was measured in 151 adult patients undergoing routine annual coronary angiography at a mean period of 4.1 years after heart transplantation. Intracoronary ultrasound (ICUS) was also performed in 42 patients. Transplant CAD was graded by angiography as none, mild (stenosis in any vessel < or =30%), moderate (31% to 69%), or severe (> or =70%) and was defined by ICUS as a mean intimal thickness (MIT) > or =0.3 mm in any coronary artery segment. The association between TxCAD and established risk factors was examined. RESULTS: Plasma HbA(1c) increased with the angiographic grade of TxCAD (5.6%, 5.8%, 6.4%, and 6.2% for none, mild, moderate, and severe disease, respectively; p < 0.05 for none vs. moderate or severe) and correlated with disease severity (r = 0.24, p < 0.05). The HbA(1c) level was higher in patients with MIT > or =0.3 mm than in those with MIT <0.3 mm (6.4% vs. 5.7%, p < 0.05). Multivariate logistic regression analysis identified HbA(1c) as an independent predictor of TxCAD, as detected by angiography or ICUS (odds ratios 1.9 and 2.4, 95% confidence intervals 1.5 to 6.3 [p = 0.010] and 1.3 to 4.2 [p < 0.005], respectively). CONCLUSIONS: Persistent glucose intolerance, as reflected by plasma HbA(1c), is associated with the occurrence of TxCAD and may play an important role in its pathogenesis.

Effect of a change in gender on coronary arterial size: a longitudinal intravascular ultrasound study in transplanted hearts.

OBJECTIVES: We sought to document whether a physiologic change in gender has any effect on coronary arterial size. BACKGROUND: The coronary arteries are smaller in women, even after correction for body surface area (BSA). These differences may contribute to adverse clinical outcomes after coronary artery bypass graft surgery and myocardial infarction in women. In male and female transsexuals, pharmacologic doses of estrogens and androgens significantly influence vascular diameter. Thus, gender differences in the coronary vasculature may be a reflection of the hormonal environment. METHODS: In 86 patients who had undergone orthotopic heart transplantation, serial intravascular ultrasound studies of the proximal left anterior descending coronary artery (LAD) were analyzed. Changes in vessel area (VA) over the first or second post-transplant year were recorded, and comparisons were made between donor hearts that were transplanted in a patient of the same gender and those that were transplanted in a patient of the opposite gender. RESULTS: Vessel area of the proximal LAD increased over time in all patient groups. In hearts transplanted within the same gender and in male donor hearts transplanted to female recipients, the change was small and not significant. However, in hearts transplanted from female donors to male recipients, there was a substantial and highly significant increase in LAD VA (median 16.13 to 17.88 mm(2); p = 0.01). This increase was not explained by confounding due to changes in BSA or left ventricular wall thickness. CONCLUSIONS: This pattern of arterial remodeling early after heart transplantation supports a link between host gender and coronary arterial size.

Use of the implantable cardioverter-defibrillator in long-term survivors of orthotopic heart transplantation.

BACKGROUND: Orthotopic heart transplantation is considered an effective treatment for patients with refractory heart failure. The long-term survival of orthotopic heart transplantation recipients has increased over the last several decades, but many long-term survivors of orthotopic heart transplantation develop graft atherosclerosis and associated left ventricular dysfunction. The risk of sudden cardiac death in long-term survivors of orthotopic heart transplantation with these complications is believed to be high. There are no data on the usefulness of implantable cardioverter-defibrillators (ICDs) in this population; therefore, we report our early experience with ICD placement in such patients. OBJECTIVES: The purpose of this study was to examine the use of ICDs in adults who are long-term survivors of heart transplantation. METHODS: We retrospectively reviewed all adult patients who underwent orthotopic heart transplantation at Stanford University Hospital (Stanford, CA, USA) from 1980 to 2004. All patients who received an ICD after transplant were included in this study. We reviewed demographic data, medical history, ejection fraction, presence of graft atherosclerosis, indication for ICD placement, and any device therapy delivered. RESULTS: Of the 925 patients who had orthotopic heart transplantation during this time period, 493 patients were alive at the beginning of the year 2000. Of these patients, 10 ( approximately 2%) had subsequent placement of an ICD. All 10 patients were male. The average age at orthotopic heart transplantation was 37.8 years. The average age at ICD placement was 50.5 years. The average time from orthotopic heart transplantation to ICD placement was 14.6 years. The average ejection fraction at the time of implant was 46.5%. Five of the 10 patients had a low ejection fraction (within this subgroup, the average ejection fraction was 31%, range 15%-45%) and graft atherosclerosis. ICDs were placed because of symptomatic episodes of ventricular tachycardia (3 patients), low ejection fraction and severe graft atherosclerosis without symptoms (3 patients), and after thorough evaluation for otherwise unexplained syncope (4 patients). The average follow-up after device implantation was 13 months. Complications related to ICD placement were an infected ICD system requiring explant in one patient and a lead fracture in another patient. Three patients had subsequent appropriate shocks for ventricular arrhythmias, and one patient underwent a second orthotopic heart transplantation. One patient died of malignancy. CONCLUSION: Use of the ICD in long-term survivors of orthotopic heart transplantation should be considered in appropriately selected patients. Further data are needed regarding ICD use in this population.