Marc A. Simon

Association Between Extracellular Matrix Expansion Quantified by Cardiovascular Magnetic Resonance and Short-Term Mortality

Background— Extracellular matrix expansion may be a fundamental feature of adverse myocardial remodeling, it appears to be treatable, and its measurement may improve risk stratification. Yet, the relationship between mortality and extracellular matrix is not clear because of difficulties with its measurement. To assess its relationship with outcomes, we used novel, validated cardiovascular magnetic resonance techniques to quantify the full spectrum of extracellular matrix expansion not readily detectable by conventional cardiovascular magnetic resonance. Methods and Results— We recruited 793 consecutive patients at the time of cardiovascular magnetic resonance without amyloidosis or hypertrophic cardiomyopathy as well as 9 healthy volunteers (ages 20–50 years). We measured the extracellular volume fraction (ECV) to quantify the extracellular matrix expansion in myocardium without myocardial infarction. ECV uses gadolinium contrast as an extracellular space marker based on T1 measures of blood and myocardium pre— and post–gadolinium contrast and hematocrit measurement. In volunteers, ECV ranged from 21.7% to 26.2%, but in patients it ranged from 21.0% to 45.8%, indicating considerable burden. There were 39 deaths over a median follow-up of 0.8 years (interquartile range 0.5–1.2 years), and 43 individuals who experienced the composite end point of death/cardiac transplant/left ventricular assist device implantation. In Cox regression models, ECV related to all-cause mortality and the composite end point (hazard ratio, 1.55; 95% confidence interval, 1.27–1.88 and hazard ratio, 1.48; 95% confidence interval, 1.23–1.78, respectively, for every 3% increase in ECV), adjusting for age, left ventricular ejection fraction, and myocardial infarction size. Conclusions— ECV measures of extracellular matrix expansion may predict mortality as well as other composite end points (death/cardiac transplant/left ventricular assist device implantation).

Prognostic Importance of Quantitative Exercise Doppler Echocardiography in Asymptomatic Valvular Aortic Stenosis

Background—In patients with asymptomatic valvular aortic stenosis, exercise testing may help to stratify the clinical risk. However, data are limited, and the role of quantitative exercise Doppler echocardiography has never been investigated. Methods and Results—Sixty-nine consecutive patients with severe asymptomatic aortic stenosis (aortic valve area <1 cm2) who prospectively underwent quantitative Doppler echocardiographic measurements at rest and during semisupine exercise test were followed up for 15±7 months. Of these, 26 had an abnormal response to exercise [occurrence of ≥1 of the following findings: angina, dyspnea, ≥2 mm ST segment depression, or fall or small (<20 mm Hg) rise in systolic blood pressure during the test] and 18 presented cardiac events during follow-up (symptoms in 2 patients, acute pulmonary edema in 2, aortic valve replacement in 12, and cardiac death in 2). In univariate analysis, patients who had cardiac events exhibited a higher increase in both peak (29±16 versus 22±14 mm Hg; P=0.019) and mean (23±8 versus 12±7 mm Hg; P=0.000003) transvalvular pressure gradients, whereas the left ventricular ejection fraction reached at peak stress was lower. These patients experienced more frequently symptoms during exercise (14 of 18 versus 12 of 51; P=0.0008). By multivariate Cox regression analysis, independent predictors of cardiac events were as follows: an increase in mean transaortic pressure gradient by ≥18 mm Hg during exercise (P=0.0015), an abnormal exercise test (P=0.0026), and an aortic valve area <0.75 cm2 (P=0.0031). Exercise Doppler echocardiographic findings provided incremental prognostic value over resting echocardiographic and exercise electrocardiographic parameters. Conclusions—Quantitative Doppler exercise echocardiography could be useful to identify a high-risk subset of patients with asymptomatic valvular aortic stenosis and help for clinical decision making.

Myocardial Recovery Using Ventricular Assist Devices Prevalence, Clinical Characteristics, and Outcomes

Background—Ventricular assist devices (VADs) are important bridges to cardiac transplantation. VAD support may also function as a bridge to ventricular recovery (BTR); however, clinical predictors of recovery and long-term outcomes remain uncertain. We examined the prevalence, characteristics, and outcomes of BTR subjects in a large single center series. Methods and Results—We implanted VADs in 154 adults at the University of Pittsburgh from 1996 through 2003. Of these implants, 10 were BTR. This included 2/80 (2.5%) ischemic patients (supported 42 and 61 days, respectively). Both subjects had surgical revascularization, required perioperative left VAD support, and were alive and transplant-free at follow up (232 and 1319 days, respectively). A larger percentage of nonischemic patients underwent BTR (8/74, 11%; age 30±14; 88% female; left ventricular ejection fraction 18±6%; supported 112±76 days). Three had myocarditis, 4 had post-partum cardiomyopathy (PPCM), and 1 had idiopathic cardiomyopathy. Five received biventricular support. After explantation, ventricular function declined in 2 PPCM patients who then required transplantation. Ventricular recovery in the 6 nonischemic patients surviving transplant-free was maintained (left ventricular ejection fraction 54±5%; follow-up 1.5±0.9 years). Overall, 8 of 10 BTR patients are alive and free of transplant (follow-up 1.6±1.1 years). Conclusions—In a large single center series, BTR was evident in 11% of nonischemic patients, and the need for biventricular support did not preclude recovery. For most BTR subjects presenting with acute inflammatory cardiomyopathy, ventricular recovery was maintained long-term. VAD support as BTR should be considered in the care of acute myocarditis and PPCM.

Myocardial extracellular volume fraction quantified by cardiovascular magnetic resonance is increased in diabetes and associated with mortality and incident heart failure admission

AIMS Diabetes may promote myocardial extracellular matrix (ECM) expansion that increases vulnerability. We hypothesized that: (i) type 2 diabetes would be associated with quantitative cardiovascular magnetic resonance (CMR) measures of myocardial ECM expansion, i.e. extracellular volume fraction (ECV); (ii) medications blocking the renin-angiotensin-aldosterone system (RAAS) would be associated with lower ECV; and (iii) ECV in diabetic individuals would be associated with mortality and/or incident hospitalization for heart failure. METHODS AND RESULTS We enrolled 1176 consecutive patients referred for CMR without amyloidosis and computed ECV from measures of the haematocrit and myocardial and blood T1 pre- and post-contrast. Linear regression modelled ECV; Cox regression modelled mortality and/or hospitalization for heart failure. Diabetic individuals (n = 231) had higher median ECV than those without diabetes (n = 945): 30.2% (IQR: 26.9-32.7) vs. 28.1% (IQR: 25.9-31.0), respectively, P < 0.001). Diabetes remained associated with higher ECV in models adjusting for demographics, comorbidities, and medications (P < 0.001). Renin-angiotensin-aldosterone system blockade was associated with lower ECV (P = 0.028) in multivariable linear models. Over a median of 1.3 years (IQR: 0.8-1.9), 38 diabetic individuals had events (21 incident hospitalizations for heart failure; 24 deaths), and ECV was associated with these events (HR: 1.52, 95% CI: 1.21-1.89 per 3% ECV increase) in multivariable Cox regression models. CONCLUSION Diabetes is associated with increased ECV. Extracellular volume fraction detects amelioration of ECM expansion associated with RAAS blockade, and is associated with mortality and/or incident hospitalization for heart failure in diabetic individuals. Extracellular matrix expansion may be an important intermediate phenotype in diabetic individuals that is detectable and treatable.

Incidence and Patterns of Adverse Event Onset During the First 60 Days After Ventricular Assist Device Implantation

BACKGROUND Although ventricular assist devices (VADs) provide effective treatment for end-stage heart failure, VAD support remains associated with significant risk for adverse events (AEs). To date there has been no detailed assessment of the incidence of a full range of AEs using standardized event definitions. We sought to characterize the frequency and timing of AE onset during the first 60 days of VAD support, a period during which clinical observation suggests the risk of incident AEs is high. METHODS A retrospective analysis was performed utilizing prospectively collected data from a single-site clinical database including 195 patients aged 18 or greater receiving VADs between 1996 and 2006. Adverse events were coded using standardized criteria. Cumulative incidence rates were determined, controlling for competing risks (death, transplantation, recovery-wean). RESULTS During the first 60 days after implantation, the most common AEs were bleeding, infection, and arrhythmias (cumulative incidence rates, 36% to 48%), followed by tamponade, respiratory events, reoperations, and neurologic events (24% to 31%). Other events (eg, hemolysis, renal, hepatic events) were less common (rates <15%). Some events (eg, bleeding, arrhythmias) showed steep onset rates early after implantation. Others (eg, infections, neurologic events) had gradual onsets during the 60-day period. Incidence of most events did not vary by implant era (1996 to 2000 vs 2001 to 2006) or by left ventricular versus biventricular support. CONCLUSIONS Understanding differential temporal patterns of AE onset will allow preventive strategies to be targeted to the time periods when specific AE risks are greatest. The AE incidence rates provide benchmarks against which future studies of VAD-related risks may be compared.

RV-pulmonary arterial coupling predicts outcome in patients referred for pulmonary hypertension

Objective Prognosis in pulmonary hypertension (PH) is largely determined by RV function. However, uncertainty remains about what metrics of RV function might be most clinically relevant. The purpose of this study was to assess the clinical relevance of metrics of RV functional adaptation to increased afterload. Methods Patients referred for PH underwent right heart catheterisation and RV volumetric assessment within 48 h. A RV maximum pressure (Pmax) was calculated from the RV pressure curve. The adequacy of RV systolic functional adaptation to increased afterload was estimated either by a stroke volume (SV)/end-systolic volume (ESV) ratio, a Pmax/mean pulmonary artery pressure (mPAP) ratio, or by EF (RVEF). Diastolic function of the RV was estimated by a diastolic elastance coefficient β. Survival analysis was via Cox proportional HR, and Kaplan–Meier with the primary outcome of time to death or lung transplant. Results Patients (n=50; age 58±13 yrs) covered a range of mPAP (13–79 mm Hg) with an average RVEF of 39±17% and ESV of 143±89 mL. Average estimates of the ratio of end-systolic ventricular to arterial elastance were 0.79±0.67 (SV/ESV) and 2.3±0.65 (Pmax/mPAP-1). Transplantation-free survival was predicted by right atrial pressure, mPAP, pulmonary vascular resistance, β, SV, ESV, SV/ESV and RVEF, but after controlling for right atrial pressure, mPAP, and SV, SV/ESV was the only independent predictor. Conclusions The adequacy of RV functional adaptation to afterload predicts survival in patients referred for PH. Whether this can simply be evaluated using RV volumetric imaging will require additional confirmation.

Noninvasive Estimation of Pulmonary Vascular Resistance in Pulmonary Hypertension

Background: Determination of pulmonary vascular resistance (PVR) in patients with suspected or known pulmonary hypertension (PH) requires right heart catheterization. Our purpose was to use Doppler echocardiography to estimate PVR in patients with PH. Methods: Patient population consisted of 52 patients (53 ± 12 years; 35 females) who underwent Doppler echocardiography and right heart catheterization within 24 hours of each other. The ratio of peak tricuspid regurgitation velocity (TRV) and right ventricular outflow time‐velocity integral (VTIRVOT) was measured via transthoracic echocardiography and correlated to invasively determined PVR. A linear regression equation was generated to determine PVR by echocardiography based upon the TRV/VTIRVOT ratio. PVR by echocardiography was compared to invasive PVR using Bland‐Altman analysis. Results: Significant correlation was demonstrated between TRV/VTIRVOT and PVR by catheterization (r = 0.73; P < 0.001). However, Bland‐Altman analysis showed that agreement between PVR determined by echocardiography and invasive PVR was poor (bias = 0; standard deviation = 4.3 Wood units). In a subset of patients with invasive PVR < 8 Wood units (26 patients), correlation between TRV/VTIRVOT and invasive PVR was strong (r = 0.94; P < 0.001). In these patients, agreement between PVR by echocardiography and invasive PVR was satisfactory (bias = 0; standard deviation = 0.5 Wood units). There was no correlation between TRV/VTIRVOT and invasive PVR in patients with PVR > 8 Wood units (n = 26; r = 0.17). Conclusion: While TRV/VTIRVOT correlates significantly with PVR, using it to estimate PVR in a PH patient population cannot be recommended.

Granulocyte–macrophage colony-stimulating factor (GM-CSF) to increase efficacy of intensive sequential chemotherapy with etoposide, mitoxantrone and cytarabine (EMA) in previously treated acute myeloid leukemia: a multicenter randomized placebo-controlled trial (EMA91 Trial)

The EMA86 study showed efficacy of intensive sequential chemotherapy with mitoxantrone, 12 mg/m2 day on days 1–3, etoposide, 200 mg/m2/day as a continuous infusion on days 8–10 and cytarabine (araC), 500 mg/m2/day as continuous infusion on days 1–3 and 8–10 (EMA regimen) in previously treated patients with AML. The goal of the EMA91 study was to determine whether administration of GM-CSF between the two sequences of EMA chemotherapy and during the second sequence could increase therapeutic efficacy by potentially increasing leukemic cell recruitment into the S phase of cell cycle before the second sequence. One hundred and ninety-two patients aged less than 65 years with previously treated AML received GM-CSF, 5 μg/kg/day or placebo from day 4 to day 8 of EMA chemotherapy. One hundred and twenty were refractory and 72 were in first relapse after a complete remission (CR) of more than 6 months duration. CR rates after one course of chemotherapy were 65% in the GM-CSF group (refractory: 51%; first relapse: 89%), not significantly different from the 59% CR rate (refractory: 46%; first relapse: 81%) in the placebo group. Median time to recovery of neutrophils was 38 and 37 days and median time to last platelet transfusion 32 and 32 days respectively in the GM-CSF and placebo groups. WHO grade ≥ 3 non-hematologic toxicities were mainly sepsis (45% and 51%, respectively) and mucositis (34% and 31%) and did not differ between the two groups. Toxic death rate was 5% and 8%, respectively, in the GM-CSF and placebo groups. Patients achieving CR were scheduled to receive six courses of maintenance with reduced-dose EMA. Time to progression tended to be longer in the GM-CSF group (median 154 vs 115 days, progression-free rate at 18 months 33% vs 19%, P = 0.08), particularly in refractory patients (P = 0.06). However, at the current follow-up, this did not translate into a significantly longer disease-free survival and survival. Cell cycle studies showed increased recruitment of cells in the S phase between day 4 and day 8 in the GM-CSF group compared to placebo (P = 0.006). However, this did not significantly relate to prognosis in this cohort of patients. GM-CSF might marginally increase efficacy of sequential chemotherapy without increasing its toxicity in the absence of any detected relationship between this effect and observed leukemic cell recruitment into the cell cycle.

Determinants of recovery from severe posterior reversible encephalopathy syndrome.

Objective Few outcome data are available about posterior reversible encephalopathy syndrome (PRES). We studied 90-day functional outcomes and their determinants in patients with severe PRES. Design 70 patients with severe PRES admitted to 24 ICUs in 2001–2010 were included in a retrospective cohort study. The main outcome measure was a Glasgow Outcome Scale (GOS) of 5 (good recovery) on day 90. Main Results Consciousness impairment was the most common clinical sign, occurring in 66 (94%) patients. Clinical seizures occurred in 57 (81%) patients. Median mean arterial pressure was 122 (105–143) mmHg on scene. Cerebral imaging abnormalities were bilateral (93%) and predominated in the parietal (93%) and occipital (86%) white matter. Median number of brain areas involved was 4 (3–5). Imaging abnormalities resolved in 43 (88%) patients. Ischaemic and/or haemorrhagic complications occurred in 7 (14%) patients. The most common causes were drug toxicity (44%) and hypertensive encephalopathy (41%). On day 90, 11 (16%) patients had died, 26 (37%) had marked functional impairments (GOS, 2 to 4), and 33 (56%) had a good recovery (GOS, 5). Factors independently associated with GOS<5 were highest glycaemia on day 1 (OR, 1.22; 95%CI, 1.02–1.45, p = 0.03) and time to causative-factor control (OR, 3.3; 95%CI, 1.04–10.46, p = 0.04), whereas GOS = 5 was associated with toxaemia of pregnancy (preeclampsia/eclampsia) (OR, 0.06; 95%CI, 0.01–0.38, p = 0.003). Conclusions By day 90 after admission for severe PRES, 44% of survivors had severe functional impairments. Highest glycaemia on day 1 and time to causative-factor control were strong early predictors of outcomes, suggesting areas for improvement.

Pulsatile left ventricular assist device support as a bridge to decision in patients with end-stage heart failure complicated by pulmonary hypertension

BACKGROUND Severe pulmonary hypertension (PH) in heart failure (HF) is a risk factor for adverse outcomes after heart transplantation (HTx). Left ventricular assist devices (LVADs) improve pulmonary hemodynamics, but our understanding of the degree of improvement and the effect on outcomes is still evolving. METHODS We reviewed invasive pulmonary hemodynamics from 58 consecutive patients receiving LVAD support as a bridge to HTx from 1996 to 2003. The primary outcome was change in baseline transpulmonary gradient (TPG) during LVAD support and after HTx/recovery. The secondary outcome was post-HTx survival. RESULTS All patients (age, 49 +/- 14 years, 79% male, 40% ischemic) received a pulsatile LVAD (median support, 97 days; interquartile range [IQR], 31-222). Hemodynamic measurements were obtained at baseline (median, 1 day; IQR, 1-3), during early (median, 1 day; IQR, 0-4) and late (median, 75 days; IQR, 24-186) LVAD support, and after HTx/recovery (median, 28 days; IQR, 17-40). Improvement in TPG occurred throughout LVAD support and was sustained after HTx/recovery. Levels of TPG reductions in patients with a baseline TPG in the highest quartile (14.1-26.0 mm Hg) were 8.6 +/- 3.5 vs 6.5 +/- 3.1 mm Hg in the lowest quartile (2.0-7.7 mm Hg) during LVAD support (p = 0.102), with 90% vs 100% 30-day post-HTx survival (P = 0.113). CONCLUSION Pulmonary hemodynamics and post-HTx survival were similar after pulsatile LVAD support in patients with and without pre-implant PH. LVAD support may be a useful strategy to reverse PH in carefully selected patients, thus improving candidacy for HTx.