Lung ultrasonography derived B-line scores as predictors of left ventricular end-diastolic pressure and pulmonary artery wedge pressure.

BACKGROUND: Non-invasive assessment of elevated left ventricular end-diastolic pressure (LVEDP) and pulmonary artery wedge pressure (PAWP) in patients with heart diseases is challenging. Lung ultrasonography (LUS) is a promising modality for predicting LVEDP and PAWP. METHODS: Fifty-seven stable ambulatory patients who underwent right and left heart catheterization were included. Following the procedures, LUS was performed in twenty-eight ultrasonographic zones, and the correlation between five different LUS derived B-line scores with LVEDP and PAWP was examined. RESULTS: The B-line index correlated with LVEDP and PAWP, with coefficients of 0.45 (p = 0.006) and 0.30 (p = 0.03), respectively. B-line index showed an AUC of 0.76 for identifying LVEDP > 15 mmHg (p = 0.01) and an AUC of 0.73 for identifying PAWP > 15 mmHg (p = 0.008). Overall, scores performances were similar in predicting LVEDP or PAWP > 15 mmHg. A B-line index ≥ 28 was significantly associated with LVEDP > 15 mmHg (OR: 9.97) and PAWP > 15 mmHg (OR: 6.61), adjusted for age and indication for heart catheterization. CONCLUSIONS: LUS derived B-line scores are moderately correlated with PAWP and LVEDP in patients with heart diseases. A B-line index ≥ 28 can be used to predict elevated LVEDP and PAWP with high specificity.

Prevalence and prediction of obstructive coronary artery disease in patients referred for valvular heart surgery.

Current guidelines recommend a coronary evaluation before valvular heart surgery (VHS). Diagnostic coronary angiography is recommended in patients with known coronary artery disease (CAD) and those with high pretest probability of CAD. In patients with low or intermediate pretest probability of CAD, the guidelines recommend coronary computed tomographic angiography. However, there are no tools available to objectively assess a patient's risk for obstructive CAD before VHS. To address this deficit, 5,360 patients without histories of CAD who underwent diagnostic coronary angiography as part of preoperative evaluation for VHS were identified. Obstructive CAD was defined as ≥50% stenosis in ≥1 artery. Of the patients assessed, 1,035 (19.3%) were found to have obstructive CAD. Through multivariate analysis, age, gender, diabetes, renal dysfunction, hyperlipidemia, and a family history of premature CAD were found to be associated with the presence of obstructive CAD (p <0.001 for all). After adjustment, the specific dysfunctional valve was not associated with the presence of obstructive CAD. Patients were then randomly split into derivation and validation cohorts. Within the derivation cohort, using only age, gender, and the presence or absence of risk factors, a model was constructed to predict the risk for obstructive CAD (C statistic 0.766, 95% confidence interval 0.750 to 0.783). The risk prediction model performed well within the validation cohort (C statistic 0.767, 95% confidence interval 0.751 to 0.784, optimism 0.004). The bias-corrected C statistic for the model was 0.765 (95% confidence interval 0.748 to 0.782). In conclusion, this novel risk prediction tool can be used to objectively risk-stratify patients who undergo preoperative evaluation before VHS and to facilitate appropriate triage to computed tomographic angiography or diagnostic coronary angiography.

Heart failure in women is different than in men; should treatment be different?

Women with heart failure differ from their male counterparts in a number of ways, including etiology, pattern of cardiac remodeling, and prognosis. They may even respond differently to medical therapy. But until prospective, sex-specific studies show that we should do otherwise, we recommend that women with heart failure be treated the same as men, according to established guidelines.

The impact of donor gender on cardiac peri-transplantation ischemia injury.

BACKGROUND: Cardiac allografts from female donors have been shown to be associated with increased risk of transplant vasculopathy. However, the influence of donor gender on peri-transplantation ischemic injury has not been evaluated. METHODS: A total of 361 patients (mean age, 52 +/- 10 years) underwent cardiac transplantation between January 1998 and December 2002. Patients were divided into 4 groups according to their donor-recipient gender status: Group A, male-male, 156; Group B, male-female, 37; Group C, female-male, 114; and Group D, female-female, 54. Serial right ventricular endomyocardial biopsy specimens were evaluated for ischemic injury during the first 4 weeks after transplantation. RESULTS: Patients were similar in baseline characteristics. An increased incidence of ischemic injury complicated by fibrosis (12.9%, p = 0.03) and subsequent development of transplant vasculopathy (Kaplan-Meier 6-year freedom from vasculopathy, 53.4%; p = 0.012) was noted in Group D. No survival difference was observed among the 4 groups, however. In Group D (F-F), 2 patients underwent retransplantation and 2 patients underwent revascularization. CONCLUSIONS: The transplantation of a female cardiac allograft into a female recipient is associated with increased risk of ischemic injury complicated by fibrosis and subsequent transplant vasculopathy.

Peritransplant ischemic injury is associated with up-regulation of stromal cell-derived factor-1.

OBJECTIVES: We evaluated chimerism and stromal cell-derived factor-1 (SDF-1) expression in response to peritransplant ischemic injury following human heart transplantation. BACKGROUND: Myocardial ischemia has been shown to trigger mobilization of stem cells to the heart in animal experiments. METHODS: Between January 1998 and April 2002, a total of 114 male recipients received hearts from female donors. Of these 114 recipients, 26 had evidence of ischemic injury on their initial heart biopsies (ischemia group). These were compared to the remaining 88 patients (control group). Heart biopsy specimens obtained initially at one week and at one year after transplant were evaluated from 20 matched patients of each group for the presence of Y chromosome-containing nuclei. The SDF-1 messenger ribonucleic acid (mRNA) and protein expression were also evaluated on initial heart biopsy specimens. RESULTS: At one week, Y chromosome-containing nuclei were significantly increased in the ischemia group (0.68% vs. 0.04%; p < 0.0001) compared to the control group. These were positive for the stem cell factor receptor c-kit. A significant 3.3-fold increased mRNA expression (p = 0.001) and 2.8-fold increased protein expression (p = 0.01) of SDF-1 was noted in the ischemia group. At one year, Y chromosome was detected in 0.29% of cardiomyocyte nuclei in the ischemia group but none in the control group. The ischemia group had poorer survival and increased vasculopathy. CONCLUSIONS: This is the first report to describe chimerism and up-regulation of SDF-1 in human heart transplantation in response to ischemic injury.

Systemic activation of integrin alphaVbeta3 in donors with spontaneous intracerebral hemorrhage is associated with subsequent development of vasculopathy in the heart transplant recipient.

BACKGROUND: Recipients of hearts from donors with spontaneous intracerebral hemorrhage (ICH) are at increased risk of allograft vasculopathy compared with trauma donors. We have recently shown that the vitronectin receptor (integrin alpha(V)beta3) is upregulated in transplant vasculopathy. We hypothesized that donor ICH is associated with systemic activation of alpha(V)beta3 in the donor before transplantation. METHODS: We evaluated mRNA expressions of alpha(V)beta3 (TaqMan PCR) in endomyocardial biopsy samples at 1-week post-transplant in 20 recipients from ICH donors and 20 recipients from trauma donors. To investigate whether systemic activation of alpha(V)beta3 was present in the donor before transplantation, alpha(V)beta3 expression was also evaluated in the corresponding donor spleen lymphocytes. All patients underwent serial coronary intravascular ultrasound to evaluate for coronary vasculopathy. The baseline characteristics were similar except for increased donor age in the ICH Group. RESULTS: The ICH Group showed significant increased mRNA expression of alpha(V)beta3 in the heart biopsy samples (3.8-fold, p = 0.012) and in the corresponding donor spleen lymphocytes (3.5-fold, p = 0.014) compared with the Trauma Group. At 1 year, the ICH Group also showed increased progression of coronary vasculopathy. Multivariate regression analysis found that donor lymphocytic alpha(V)beta3 mRNA expression was independently associated with increased risk of vasculopathy (odds ratio, 1.9; 95% CI, 1.21-3.98, p = 0.03). CONCLUSIONS: Our report demonstrates the presence of systemic activation of alpha(V)beta3 in donors with spontaneous intracerebral hemorrhage and its association with the subsequent development of allograft vasculopathy in the recipient.

The effect of combined Angiotensin-converting enzyme inhibition and calcium antagonism on allograft coronary vasculopathy validated by intravascular ultrasound.

BACKGROUND: Hypertension is a potential risk factor for allograft coronary vasculopathy. We evaluated the efficacy of angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists, and their combined use, on the development of coronary vasculopathy in hypertensive heart transplant recipients. METHODS: Eighty-two heart transplant recipients underwent serial intravascular ultrasound (IVUS) analysis at baseline (within 1 month) and at 1 year after transplantation and were evaluated for the development of coronary vasculopathy. Patients were divided into 4 groups. Nineteen normotensive recipients received no treatment, control (Group A). Hypertensive patients were treated with either ACE inhibitors (Group B, n = 37), calcium antagonists (Group C, n = 16), or both (Group D, n = 10). RESULTS: We found a significant reduction in IVUS indices of coronary vasculopathy in heart transplant recipients who used a combination of an ACE inhibitor and a calcium antagonist compared with recipients who used either drug alone (p < 0.05). This synergistic efficacy was independent of the baseline indices evaluated in a multivariate regression analysis model and was noted despite comparable mean arterial pressure among the 3 hypertensive groups at 1 year, thus suggesting the presence of a synergistic anti-proliferative effect beyond the anti-hypertensive efficacy. CONCLUSIONS: The combined use of an ACE inhibitor and a calcium antagonist is more effective than the individual use of either drug alone on the development of coronary vasculopathy in cardiac transplant recipients. Large randomized clinical trials are warranted to evaluate such a synergistic efficacy.

Is there an association between ephedra and heart failure? a case series.

BACKGROUND: Ephedra is a sympathomimetic commonly used for the purposes of athletic performance enhancement and weight loss. It is known to be associated with gastrointestinal and psychiatric manifestations. We report here on 6 cases of dilated cardiomyopathy associated with ephedra use. METHODS AND RESULTS: Over a period of 18 months, 6 patients attending our outpatient department with new onset heart failure were noted to have exposure to ephedra. The case record was reviewed and detailed clinical and echocardiographic data were extracted. All 6 patients (4 males) had left ventricular dysfunction at presentation (mean ejection fraction 20 +/- 5%) and were treated with conventional heart failure pharmacotherapy. All patients discontinued ephedra use as advised. New York Heart Association class improved from class III in 5 patients (class II in 1 patient) to class I, within a median of 6 months (range 3-96). Ejection fraction improved to a mean of 47 +/- 6%. CONCLUSIONS: Ephedra may be associated with left ventricular systolic dysfunction. Withdrawal of this agent, in conjunction with proven pharmacotherapy, results in a significant improvement in functional status and left ventricular ejection fraction. We recommend specific enquiry into the use of over-the-counter supplements, particularly ephedra and its derivatives, when being evaluated with heart failure symptoms. These cases illustrate the potential risk of ephedra and provide additional support for the recent decision to ban this supplement.

Systemic up-regulation of angiotensin II type 1 receptor in cardiac donors with spontaneous intracerebral hemorrhage.

Donor spontaneous intracerebral hemorrhage (ICH) is a potential risk factor for morbidity and mortality after cardiac transplantation. We hypothesized that donor ICH is associated with systemic up-regulation of angiotensin II receptor type 1 (AT1R). We evaluated mRNA expression of AT1R and AT2R in donor spleen lymphocytes and in heart biopsies from 20 recipients of hearts from donors with spontaneous ICH which were compared with 20 recipients from trauma donors. Heart biopsies showed 4.7-fold increased mRNA expression of AT1R (p < 0.0001) in the ICH group compared with the Trauma group. The ICH group also showed 2.6-fold (p < 0.01) increased mRNA expression of AT1R in the donor spleen lymphocytes, suggesting the presence of systemic activation before transplantation. At 1 year, the ICH group had increased coronary vasculopathy by vascular ultrasound. Using multivariate regression analysis, mRNA expression of AT1R in the donor spleen lymphocytes was found to be a strong independent predictor of transplant vasculopathy (odds ratio = 4.397, CI = 1.243-15.553, adjusted p = 0.02). This is the first report to describe splenic up-regulation of AT1R in the presence of spontaneous ICH and its association with subsequent development of transplant vasculopathy.

Impact of donor spontaneous intracranial hemorrhage on outcome after heart transplantation.

Donor cause of death has been suggested to have a significant impact on cardiac transplant morbidity and mortality. Our objective was to evaluate the impact of donor spontaneous intracranial bleeding on clinical outcome after heart transplantation. A group of 160 recipients underwent cardiac transplantation from donors with spontaneous intracranial bleeding (ICB group). These were compared with 197 recipients who were transplanted from trauma donors (Trauma group). A higher 4-year mortality rate was noted in the ICB group (24% vs. 14%, p=0.015). ICB as a cause of donor death was an independent predictor of recipient mortality (adjusted hazard ratio 2.02, 95% CI 1.27-3.40, p<0.0001). Compared with the Trauma group, the ICB group had an increased incidence of post-transplant graft dysfunction during the first week of transplant (10% vs. 3%, p=0.007), and higher incidence of interstitial myocardial fibrosis on their endomyocardial biopsies within 4 weeks of transplant (21% vs. 9%, p=0.0012). There was a trend towards an increased rate of allograft vasculopathy in the ICB group (competing risks adjusted hazard ratio 1.39, 95% CI 0.90-2.13, p = 0.14).

Quilty lesions are associated with increased expression of vitronectin receptor (alphavbeta3) and subsequent development of coronary vasculopathy.

BACKGROUND: Quilty lesions are common after heart transplantation; however, their relationship to vasculopathy has not been described. We tested the hypothesis that Quilty lesions are associated with increased expression of vitronectin receptor (alphavbeta3) and the subsequent development of coronary vasculopathy. METHODS: A total of 140 heart transplant recipients underwent coronary intravascular ultrasound at baseline and at 1 year after transplantation, and we measured the change in coronary maximal intimal thickness. Endomyocardial biopsy specimens taken within 8 weeks after transplantation showed Quilty lesions in 54 of 140 (39%) patients (Quilty group). We compared these results with the remaining 86 of 140 patients (61%) who had no evidence of Quilty lesions during the same period (control group). We evaluated 10 endomyocardial biopsy specimens from each group for alphavbeta3, using immunohistochemistry staining and immunoblotting. RESULTS: Quilty lesions stained positive for alphavbeta3, and Western blot analysis showed a 1.3-fold (p = 0.004) increase in expression of alphavbeta3. Compared with control, the Quilty group tended to have a greater incidence of post-transplant ischemic injury complicated by fibrosis (54% vs 38%, p = 0.08) and a greater reported incidence of "previous biopsy site" during the first 4 weeks after transplantation (48% vs 32%, p = 0.06). At 1 year, the Quilty group had a significant increase in the change in coronary maximal intimal thickness seen with intravascular ultrasound (0.54 +/- 0.34 vs 0.42 +/- 0.28 mm, p = 0.038). CONCLUSIONS: This is the first report to describe the association of Quilty lesions with coronary vasculopathy and its association with increased alphavbeta3 expression.

Early constriction or expansion of the external elastic membrane area determines the late remodeling response and cumulative lumen loss in transplant vasculopathy: an intravascular ultrasound study with 4-year follow-up.

BACKGROUND: Early constriction of the external elastic membrane (EEM) area has been observed after cardiac transplantation. The aim of this study was to compare the late disease process of transplant vasculopathy between coronary segments with early constrictive and expansive remodeling. METHODS: Serial intravascular ultrasound data obtained annually for 4 years after transplantation in 38 transplant recipients was available. In 135 matched segments from 59 coronary arteries ultrasound images were digitized at 1-mm intervals. Mean values of the external elastic membrane (EEM), lumen and intimal areas were calculated. On the basis of a decrease or increase in EEM area within the first year after transplantation, we defined segments with early constrictive remodeling (CR, n = 71) or early expansive remodeling (ER, n = 64). RESULTS: Annual changes in intimal area were similar between segments with early CR and ER throughout the follow-up period. However, during the second and third year, annual increases in EEM area were greater in segments with early CR than in segments with early ER (second year: 1.5 +/- 2.7 vs 0.6 +/- 2.8 mm(2), p = 0.052; third year: 1.3 +/- 2.5 vs -0.03 +/- 2.6 mm(2), p = 0.003). Despite this late expansion, segments with early CR showed a cumulative decrease in the EEM area and a greater lumen loss than segments with early ER (-2.5 +/- 3.4 vs -0.6 +/- 2.6 mm(2), p < 0.001). CONCLUSIONS: In transplant vasculopathy, the late remodeling response was different between segments with early constrictive and expansive remodeling, despite similar intimal thickening. Early constriction caused an overall decrease in EEM area and greater loss of lumen during follow-up.

Computerized scoring of histopathology for predicting coronary vasculopathy, validated by intravascular ultrasound.

BACKGROUND: Allograft coronary vasculopathy results from a complex interplay between immunologic and non-immunologic factors. We devised a computerized biopsy scoring method based on histopathology to predict the development of coronary vasculopathy. METHODS: One hundred forty heart transplant recipients underwent serial intravascular ultrasound analysis at baseline (within 1 month) and at 1 year after transplantation and were evaluated for development of coronary vasculopathy (change in coronary maximal intimal thickness, CMIT). We evaluated serial endomyocardial biopsy specimens for cellular rejection, vascular rejection, ischemia, and fibrosis. In a mathematical model, we computed a biopsy score in each patient based on the duration and severity of histopathology. RESULTS: We found a significant correlation between biopsy score (RY) and progression of coronary vasculopathy (r = 0.54, p = 0.001). Using a sensitivity analysis method, an RY value of > or =560 predicted development of coronary vasculopathy with a sensitivity of 86%, specificity of 62%, and diagnostic accuracy of 80%. Compared with patients with low-risk biopsy scores (RY < 560, n = 37), patients with high-risk biopsy scores (RY > or = 560, n = 103) had increased progression of coronary vasculopathy (CMIT, 0.59 +/- 0.29 vs 0.19 +/- 0.10 mm, p < 0.001) and worse 7-year event-free survival (60% vs 91%, p = 0.01). CONCLUSION: The biopsy score is an effective method for predicting the development of coronary vasculopathy and for predicting outcome in cardiac transplant recipients.