Methods and Results— In total, 111 patients (109 men and 2 women) received a 1-hour infusion of 5, 10, and 15 mg SLV320, an adenosine A1 receptor antagonist, placebo, or 40 mg furosemide. Mean age was 57.9 years, mean ejection fraction was 28.1%, 82 patients were of New York Heart Association class II, and 29 patients were of New York Heart Association class III. Hemodynamic parameters (heart rate, blood pressure, pulmonary capillary wedge pressure, mean pulmonary arterial pressure, systemic vascular resistance, right atrial pressure, and cardiac output) were determined. Kidney function was assessed by cystatin C measurements and by analysis of urine output and urine electrolytes. In addition, pharmacokinetics of SLV320 and ex vivo inhibition of adenosine A1 receptor activity were performed. SLV320 was well tolerated, and no serious adverse events were observed. Heart rate, blood pressure, pulmonary capillary wedge pressure, mean pulmonary arterial pressure, right atrial pressure, and cardiac output were not altered by any dose of SLV320. Pulmonary capillary wedge pressure was significantly (P=0.04) decreased by furosemide (–6.2±5.9 mm Hg). Systemic vascular resistance was significantly (P=0.04) increased in the furosemide group (+166.70±261.87 dynes · s^–1 · cm^–5), whereas all SLV320 groups showed no significant alterations of systemic vascular resistance. Changes from baseline cystatin C plasma concentrations decreased after 10 mg SLV320 (–0.093±0.137 mg/L, P=0.046), whereas furosemide resulted in a significant (P=0.03) increase of cystatin C (+0.052±0.065 mg/L) versus baseline. All values represent mean changes±SD from baseline at 3 hours postdosing: SLV320 (10 and 15 mg) increased significantly sodium excretion and diuresis compared with placebo during the 0- to 6-hour collection period postdosing.

Conclusions— SLV320 infusion shows no immediate effects on cardiac hemodynamics. SLV320 might improve glomerular filtration rate while simultaneously promoting natriuresis and diuresis.

Clinical Trial Registration— clinicaltrials.gov Indentifier: NCT00160134.

Methods and Results— Ucn2 and furosemide were administered for 3 hours, both singly and combined, in 7 sheep with pacing-induced heart failure. Compared with time-matched controls, separate Ucn2 and furosemide administration significantly increased urine output (furosemide>Ucn2), urine sodium (furosemide>Ucn2), potassium (furosemide>Ucn2), and creatinine excretion (Ucn2>furosemide) and creatinine clearance (Ucn2>furosemide). Compared with furosemide treatment alone, Ucn2+furosemide produced a further diuresis (P<0.05), natriuresis (P<0.05), and a sustained increase in creatinine excretion (P<0.05) and clearance (P<0.05), without additional potassium elimination. All active treatments reduced mean arterial pressure (Ucn2+furosemide=furosemide>Ucn2), left atrial pressure (Ucn2+furosemide>Ucn2>furosemide), and peripheral resistance (Ucn2+furosemide=Ucn2>furosemide), whereas only Ucn2, singly and in combination with furosemide, increased cardiac output and dP/dt(max). In contrast to the increase in plasma renin activity elicited by furosemide alone, Ucn2 and Ucn2+furosemide markedly reduced plasma renin activity. All active treatments decreased plasma aldosterone (Ucn2+furosemide=Ucn2>furosemide), whereas only Ucn2 and Ucn2+furosemide reduced vasopressin and natriuretic peptide concentrations.

Conclusion— Ucn2 cotreatment with furosemide enhanced hemodynamic and renal function and diuretic responsiveness (without additional potassium depletion) in experimental heart failure. Furthermore, Ucn2 reversed furosemide-induced increases in plasma renin activity and induced greater decreases in plasma aldosterone and vasopressin. These data indicate that adjunct Ucn2 therapy with diuretics in heart failure is beneficial.

Methods and Results— This is a retrospective study of 354 subjects in the African American Heart Failure Trial Genetic Risk Assessment in Heart Failure substudy. In the corin variant group (n=50) compared with corin nonvariant group (n=300), BNP-32 (amino acids 77 to 108) was lower (190 pg/mL versus 340 pg/mL, P=0.007), but the ratio of unprocessed BNP_{1 to 108}/processed BNP-32 was significantly higher (P=0.05). Stratified analyses were conducted because of evidence of significant interaction between the corin I555(P568) allele and treatment assignment. In the placebo arm, multivariable analysis demonstrated that the corin I555(P568) allele was associated with increased risk for death or heart failure hospitalization (relative risk 3.49; 95% CI, 1.45 to 8.39; P=0.005); however, in the treatment arm (fixed-dose combination isosorbide-dinitrate/hydralazine), the corin I555(P568) allele was not associated with adverse outcomes.

Conclusions— We have identified a pharmacogenomic interaction in blacks with systolic heart failure. The corin I555(P568) allele is associated with an increased risk for death or heart failure hospitalization in patients receiving standard neurohormonal blockade, but the addition of fixed-dose combination isosorbide-dinitrate/hydralazine ameliorates this risk. A plausible mechanism for this pharmacogenomic interaction is the impaired processing of BNP in carriers of the corin I555(P568) allele as compared with noncarriers.

Methods and Results— Two hundred fifty-three patients diagnosed with systolic (n=211) or diastolic (n=42) HF (age: 61.9±10.1 years; New York Heart Association Class: 2.2±0.78) underwent a 6MWT and a symptom-limited CPET evaluation and were prospectively followed up. During the 4-year tracking period, there were 43 cardiac-related deaths with an annual cardiac mortality rate of 8.7%. The 6MWT distance correlated with CPET-derived variables (ie, peak Vo₂, Vo₂ at anaerobic threshold, and Ve/Vco₂ slope) and was significantly reduced in proportion with lower peak Vo₂ and higher Ve/Vco₂ slope classes and presence of an exercise oscillatory breathing (EOB) pattern (P<0.01). However, no significant differences were observed in distance covered between survivors and nonsurvivors (353.2±95.8 m versus 338.5±76.4 m; P=NS). At univariate and multivariate Cox proportional analyses, the association of the 6MWT distance with survival was not significant either as a continuous or dicotomized variable (≤300 m). Conversely, CPET-derived variables emerged as prognostic with the strongest association found for EOB (systolic HF) and Ve/Vco₂ slope (entire population with HF and patients with a 6MWT≤300 m).

Conclusions— The 6MWT is confirmed to be a simple and reliable first-line test for quantification of exercise intolerance in patients with HF. However, there is no supportive evidence for its use as a prognostic marker in alternative to or in conjunction with CPET-derived variables.

Methods and Results— We prospectively analyzed the relationship between serum uric acid concentration at baseline and subsequent heart failure among the participants of the Framingham Offspring cohort (n=4912; mean baseline age, 36 years; 52% women). By using Cox regressions, we calculated the risk of heart failure with increasing serum uric acid after adjusting for sex, age, smoking, body mass index, renal dysfunction, diuretics, systolic blood pressure, valvular heart disease, diabetes, alcohol, and use of antihypertensive medications. The incidence rates of heart failure were 6-fold higher among those at the highest quartile of serum uric acid (>6.3 mg/dL) compared with those at the lowest quartile (<3.4 mg/dL). The adjusted hazard ratio for the highest quartile of serum uric acid compared with the lowest was 2.1 (1.04 to 4.22). The relationship between hyperuricemia and heart failure was found in participants without metabolic syndrome and other subgroups as well.

Conclusions— Hyperuricemia is a novel, independent risk factor for heart failure in a group of young general community dwellers. This has implications for development of preventive strategies for heart failure.

Methods and Results— Consecutive subjects with heart failure of any cause and severity were enrolled (n=867), and survivors were followed for a median period of 594 days (25th to 75th percentile, 435 to 840). Mean age was 70±13 years, 41% were female, New York Heart Association class distribution I through IV was 15%/29%/41%/15%, and 49% had preserved left ventricular ejection function. At follow-up, 34% of the patients had died. Low levels of any risk factor (ie, body mass index, total cholesterol, and systolic blood pressure in the low tertile) indicated the highest mortality risk. After adjustment for age, sex, New York Heart Association class, and ejection fraction, ≥2 risk factors in the high tertile indicated a relative reduction in mortality risk of 51% (hazard ratio, 0.49; 95% CI, 0.35 to 0.68; P=0.001) compared with subjects with 3 risk factors in the low tertile. Further adjustment for cause of heart failure, relevant comorbidities, medication, and biomarkers attenuated this association only modestly (hazard ratio, 0.63; 95% CI, 0.45 to 0.89; P=0.009).

Conclusion— In patients with heart failure, mortality risk counterintuitively increased on a cumulative scale with lower levels of body mass index, total cholesterol, and systolic blood pressure, irrespective of the type and severity of heart failure. Future studies need to identify whether risk factor control as presently recommended should be advocated in all patients with heart failure.

Methods and Results— We identified 13 063 adult patients with acute heart failure who had cardiac arrest at 457 hospitals participating in the National Registry of Cardiopulmonary Resuscitation between January 1, 2000 and December 31, 2007. Neurological status was determined on admission and discharge by cerebral performance category with neurologically intact survival (NIS)=cerebral performance category 1 (no) or 2 (moderate dysfunction) and non-NIS=cerebral performance category 3 (severe dysfunction), 4 (coma), or 5 (brain death). Factors available prearrest (demographics, preexisting conditions, and interventions in-place) were assessed for association with NIS using multivariable logistic regression, initially without then with adjustment for arrest-related variables and hospital characteristics. NIS occurred in 2307 patients (17.7%) and was associated by adjusted odds ratio with 18 prearrest factors; 4 positively and 14 negatively. The association (odds ratio; 95% CI) was strongest for 4 specific variables: acute stroke (0.38; 0.25 to 0.58), history of malignancy (0.49; 0.39 to 0.63), vasopressor use (0.50; 0.43 to 0.59), and assisted or mechanical ventilation (0.53; 0.45 to 0.61).

Conclusions— A number of prearrest factors seem to be associated with NIS, the majority inversely. Consideration of these before cardiac arrest could enhance the resuscitative decision-making process for patients with acute heart failure.

Methods and Results— We studied 99 335 patients surviving first hospitalization for heart failure (HF) from 1997 to 2005. Use of HF medication and antidepressants (divided into tricyclic antidepressants [TCA] and SSRI) was determined by prescription claims. Risk of overall and cardiovascular death associated with antidepressants, HF medication, and coadministration of these 2 drug classes was estimated by Cox proportional hazard analyses. Propensity adjusted models were performed as sensitivity analysis. During the study period, there were 53 988 deaths, of which 83.0% were due to cardiovascular causes (median follow-up, 1.9 years; 5, 95% fractiles, 0.04 to 7.06 years). Use of β-blockers was associated with decreased risk of cardiovascular death (hazard ratio [HR], 0.77; 95% CI, 0.75 to 0.79). Antidepressants were prescribed to 19 411 patients, and both TCA and SSRI were associated with increased risk of overall and cardiovascular death (TCA: HR, 1.33; CI, 1.26 to 1.40; and HR, 1.25; CI, 1.17 to 1.32; SSRI: HR, 1.37; CI, 1.34 to 1.40; and HR, 1.34; CI, 1.30 to 1.38, respectively). Coadministration of SSRI and β-blockers was associated with a higher risk of overall and cardiovascular death compared with coadministration of β-blockers and TCA (P for interaction <0.01).

Conclusions— Use of antidepressants in patients with HF was associated with worse prognosis. Coadministration of SSRIs and β-blockers was associated with increased risk of overall death and cardiovascular death compared with coadministration of TCAs and β-blockers. To further clarify this, clinical trials testing the optimal antidepressant strategy in patients with HF are warranted.

Methods and Results— We analyzed echocardiographic data obtained within 6 months of listing for heart transplant and clinical data from 261 children with dilated cardiomyopathy who were included in both the Pediatric Cardiomyopathy Registry and the Pediatric Heart Transplant Study. Median time to listing after diagnosis was 1.9 months and to transplant after listing was 0.8 months. There were 42 deaths (29 waiting and 13 within 6 months after transplant). We found a significant age-dependent association of LV end-diastolic dimension z score (n=204, 31 deaths) with death controlling for race, transplant status, and medical insurance. The association was strongest for infants younger than 6 months at diagnosis (hazard ratio 1.47, P=0.008) and was not significant in children older than 5 years at diagnosis. A similar interaction was identified between age and LV end-systolic dimension z score (P=0.04). Neither LV function nor mass was associated with death, overall, or in subgroups.

Conclusions— The severity of LV dilation at listing for heart transplant is associated with outcome in infants and young children with dilated cardiomyopathy, whereas the severity of LV systolic dysfunction is not. These findings should be considered in risk stratification of these children at listing.

Methods and Results— Ten-day-old rabbits (n=6 per time point, total n=48) that underwent pulmonary artery banding were euthanized at 2 to 8 weeks after pulmonary artery banding, and comparisons were made with age-matched sham controls. LV performance (myocardial performance index) decreased during the progression of RVH, although the LV ejection fraction was maintained. In addition, RVH caused significant septal displacement, reduced septal contractility, and decreased LV end-systolic and end-diastolic dimensions, resulting in LV diastolic dysfunction with the appearance of preserved ejection fraction. Significant septal and LV free-wall apoptosis (myocyte-specific TUNEL and activated caspase-3), fibrosis (Masson trichrome stain), and reduced capillary density (CD31 immunostaining) occurred in the pulmonary artery banding group after 6 to 8 weeks (all P<0.05).

Conclusion— This is the first study showing that pressure overload of the right ventricular resulting in RVH causes LV diastolic dysfunction while preserving ejection fraction through mechanical and molecular effects on the septum and LV myocardium. In particular, the development of RVH is associated with septal and LV apoptosis and reduced LV capillary density.

Methods and Results— We measured the plasma levels of biomarkers such as BNP, ALD, adrenocorticotropic hormone, serum cortisol, and oxidized low-density lipoprotein (oxLDL), a biomarker of oxidative stress, in 319 consecutive symptomatic patients with chronic heart failure, and we followed these patients for a mean period of 33 months. During the follow-up period, 29 patients had cardiac events (death or hospitalization). Plasma levels of BNP, ALD, adrenocorticotropic hormone, oxLDL, and serum cortisol (16.8±1.8 µg/dL versus 12.4±0.3 µg/dL, P=0.01) were significantly higher in patients with cardiac events than in those without cardiac events. On stepwise multivariate analyses, high levels of BNP (P=0.0003), renin (P=0.002), cortisol (P=0.02), and oxLDL (P=0.002) were independent predictors of cardiac events, but ALD and adrenocorticotropic hormone levels were not. In patients with serum cortisol ≥12.5 µg/dL, the hazard ratio of cardiac events in patients with oxLDL ≥12 U/mL was 3.5 compared with that in patients with oxLDL <12 U/mL (P=0.008).

Conclusions— These findings indicate that serum cortisol levels were a complementary and incremental cardiac event risk predictor in combination with BNP in patients with chronic heart failure and that cardiac event prediction based on cortisol levels was influenced by oxidative stress.

Methods and Results— In 7448 patients with heart failure (75.2±11.5 years; 49.9% men) discharged from the hospital in Ontario, Canada, we examined the association of systolic blood pressure (SBP) and diastolic blood pressure with long-term survival. Parametric survival analysis was performed, and survival time ratios were determined according to discharge blood pressure group. A total of 25 427 person-years of follow-up were examined. In those with left ventricular ejection fraction ≤40%, median survival was decreased by 17% (survival time ratio, 0.83; 95% CI, 0.71 to 0.98; P=0.029) when discharge SBP was 100 to 119 mm Hg and decreased by 23% (survival time ratio, 0.77; 95% CI, 0.62 to 0.97; P=0.024) when discharge SBP was <100 mm Hg, compared with those in the reference range of 120 to 139 mm Hg. Survival time ratios were 0.75 (95% CI, 0.60 to 0.92; P=0.007) and 0.75 (95% CI, 0.53 to 1.07; P=0.12) when discharge SBPs were 140 to 159 and ≥160 mm Hg, respectively. In those with left ventricular ejection fraction >40%, survival time ratios were 0.69 (95% CI, 0.51 to 0.93), 0.83 (95% CI, 0.71 to 0.99), 0.95 (95% CI, 0.80 to 1.14), and 0.76 (95% CI, 0.61 to 0.95) for discharge SBPs <100, 100 to 119, 140 to 159, and ≥160 mm Hg, respectively.

Conclusions— In this long-term population-based study of patients with heart failure, the association of discharge SBP with mortality followed a U-shaped distribution. Survival was shortened in those with reduced or increased values of discharge SBP.

Methods and Results— Our main findings were (1) patients with chronic HF (n=188) had increased plasma levels of CXCL16, which correlated with disease severity. (2) Left ventricular tissue from patients with end-stage HF (n=8) showed enhanced CXCL16 levels compared with nonfailing left ventricular (n=6) as assessed by Western blotting. (3) In mice with postmyocardial infarction HF, expression of CXCL16, as assessed by real-time RT-PCR, was increased in the infarcted and the noninfarcted areas of left ventricular 3 and 7 days after coronary ligation, indicating early onset of CXCL16 production. Furthermore, mice exposed to aortic banding had enhanced CXCL16 expression in left ventricular, indicating that CXCL16 expression is not related to ischemia alone. (4) In vitro, CXCL16 promoted proliferation and impaired collagen synthesis in myocardial fibroblasts, and in cardiomyocytes and myocardial fibroblasts, CXCL16 increased matrix metalloproteinase activity, primarily reflecting increased matrix metalloproteinase-2 levels. (5) By using specific inhibitors, we showed that the effect of CXCL16 on fibroblasts involved activation of Jun N-terminal kinase.

Conclusion— We show enhanced myocardial CXCL16 expression in experimental and clinical HF. The effect of CXCL16 on cardiomyocytes and fibroblasts suggests a role for CXCL16 in matrix remodeling and ultimately in the development of HF.

Methods and Results— To determine the contribution of SMAD-dependent signaling to cardiac remodeling, we performed transaortic constriction in SMAD3 null (SMAD3^–/–) and littermate control mice (age, 10 to 12 weeks). Cumulative survival 20 days after transaortic constriction was significantly less in the SMAD3^–/– mice when compared with littermate controls (43.6% versus 90.9%, P<0.01). Transaortic constriction resulted in a significant increase in cardiac hypertrophy in the SMAD3^–/– mice, denoted by an increase in the heart weight to tibial length ratio and increased myocyte cross-sectional area. Loss of SMAD3 signaling also resulted in a significant 60% decrease in myocardial fibrosis (P<0.05). A microRNA microarray showed that 55 microRNAs were differentially expressed in littermate and SMAD3^–/– mice and that 10 of these microRNAs were predicted to bind to genes that regulate the extracellular matrix. Of these 10 candidate microRNAs, both miR-25 and miR-29a were sufficient to decrease collagen gene expression when transfected into isolated cardiac fibroblasts in vitro.

Conclusions— The results suggest that SMAD3 signaling plays dual roles in the heart: one beneficial role by delimiting hypertrophic growth and the other deleterious by modulating myocardial fibrosis, possibly through a pathway that entails accumulation of microRNAs that decrease collagen gene expression.

Methods and Results— EPDCs and cardiomyocyte progenitor cells were isolated from human adult atrial appendages, expanded in culture, and transplanted separately or together into the infarcted mouse myocardium (total cell number, 4x10⁵). Cardiac function was determined 6 weeks later (9.4T MRI). Coculturing increased proliferation rate and production of several growth factors, indicating a mutual effect. Cotransplantation resulted in further improvement of cardiac function compared with single cell-type recipients (P<0.05), which themselves demonstrated better function than vehicle-injected controls (P<0.05). However, in contrast to our hypothesis, no graft-derived cardiomyocytes were observed within the 6-week survival, supporting that not only EPDCs but also cardiomyocyte progenitor cells acted in a paracrine manner. Because injected cell number and degree of engraftment were similar between groups, the additional functional improvement in the cotransplantation group cannot be explained by an increased amount of secreted factors but rather by an altered type of secretion.

Conclusion— EPDCs and cardiomyocyte progenitor cells synergistically improve cardiac function after myocardial infarction, probably instigated by complementary paracrine actions. Our results demonstrate for the first time that synergistically acting cells hold great promise for future clinical regeneration therapy.

Methods and Results— Hearts from transplant recipients and unused donors were failing (n=12; mean ejection fraction, 24%) or nonfailing (n=9; mean ejection fraction, 59%) and similar in age (44 years) and sex (70% male). We measured the 1-AR subtypes in multiple regions of both ventricles by quantitative real-time reverse-transcription polymerase chain reaction and radioligand binding. All 3 1-AR subtype mRNAs were present, and 1A mRNA was most abundant (65% of total 1-AR mRNA). However, only 1A and 1B binding were present, and the 1B was most abundant (60% of total). In failing hearts, 1A and 1B binding was not downregulated, in contrast with β1-ARs.

Conclusions— Our data show for the first time that the 1A and 1B subtypes are both present in human myocardium, but 1D binding is not, and the 1 subtypes are not downregulated in heart failure. Because 1 subtypes in the human heart are similar to those in the mouse, where adaptive and protective effects of 1 subtypes are most convincing, it might become feasible to treat heart failure with a drug targeting the 1A and/or 1B.

Methods and Results— Under baseline conditions, isolated cardiac myocytes from TG mice showed an increased incidence of early afterdepolarizations compared with wild-type myocytes (P<0.05). CaMKII inhibition (AIP) completely abolished these afterdepolarizations in TG cells (P<0.05). Increasing intracellular Ca stores using ISO (10^–8 M) induced a larger amount of delayed afterdepolarizations and spontaneous action potentials in TG compared with wild-type cells (P<0.05). This seems to be due to an increased sarcoplasmic reticulum (SR) Ca leak because diastolic [Ca]_i rose clearly on ISO in TG but not in wild-type cells (+20±5% versus +3±4% at 10^–6 M ISO, P<0.05). In parallel, SR Ca leak assessed by spontaneous SR Ca release events showed an increased Ca spark frequency (3.9±0.5 versus 2.0±0.4 sparks per 100 µm^–1·s^–1, P<0.05). However, CaMKII inhibition (either pharmacologically using KN-93 or genetically using an isoform-specific CaMKII-knockout mouse model) significantly reduced SR Ca spark frequency, although this rather increased SR Ca content. In parallel, ISO increased the incidence of early (54% versus 4%, P<0.05) and late (86% versus 43%, P<0.05) nonstimulated events in TG versus wild-type myocytes, but CaMKII inhibition (KN-93 and KO) reduced these proarrhythmogenic events (P<0.05). In addition, CaMKII inhibition in TG mice (KN-93) clearly reduced ISO-induced arrhythmias in vivo (P<0.05).

Conclusions— We conclude that CaMKII contributes to cardiac arrhythmogenesis in TG CaMKII_C mice having heart failure and suggest the increased SR Ca leak as an important mechanism. Moreover, CaMKII inhibition reduces cardiac arrhythmias in vitro and in vivo and may therefore indicate a potential role for future antiarrhythmic therapies warranting further studies.

Methods and Results— All studies were performed using human cardiac tissue obtained from (1) hearts not matched for transplantation (nonfailing), (2) at the time of cardiac transplant (failing), or (3) paired samples at the time of VAD implant (pre-VAD) and removal (post-VAD). The expression of brain naturetic peptide, leptin, leptin receptor, and tumor necrosis factor mRNA was measured, and the protein expression of leptin and its receptor was examined by Western blot and immunofluorescent staining of cardiac sections. The assessment of leptin signaling was performed by measuring the phosphorylation state of the leptin receptor. The phosphorylation state of signal transducer and activator of transcription-3 and AMP-activated kinase proteins were also measured. All data are expressed as mean±SEM with a statistical significance in failing relative to nonfailing groups determined by Student independent t test, and the significance between pre- and post-VAD groups determined by paired t test. In failing human hearts, the mRNA expressions of leptin and its receptor were increased 5.4±0.3-fold (P<0.05) and 4.5±0.3-fold (P<0.05), respectively, with similar changes in protein. The phosphorylation state of both the leptin receptor and signal transducer and activator of transcription-3 proteins were increased 1.4±0.1-fold (P<0.05), and the level of phosphorylated AMP-activated kinase protein was increased 1.9±0.2-fold (P<0.05). Mechanical unloading of the failing human heart with a VAD resulted in no change in tumor necrosis factor expression but a marked decrease in leptin production to 1.7±0.1% (P<0.05) and leptin receptor expression to 3.0±0.2% (P<0.05) of pre-VAD levels. Phosphorylation of the leptin receptor, signal transducer and activator of transcription-3, and AMP-activated kinase were also decreased to 45±7%, 75±8%, and 58±8% of pre-VAD values, respectively (P<0.05 for all values).

Conclusions— These results indicate that the failing human heart increases expression of leptin and its receptor and that mechanical unloading downregulates this increase. Further, a cardioprotective role for leptin in the failing human heart is suggested through the activation of signal transducer and activator of transcription-3 and AMP-activated kinase signaling.

Methods and Results— IL-33 protected cultured cardiomyocytes from hypoxia-induced apoptosis, and this cardioprotection was partially inhibited by sST2. IL-33 induced expression of the antiapoptotic factors XIAP, cIAP1, and survivin. To define the cardioprotective role of IL-33 in vivo, we performed a blinded and randomized study of ischemia/reperfusion in rats. IL-33 reduced cardiomyocyte apoptosis, suppressed caspase-3 activity, and increased expression of IAP family member proteins. IL-33 decreased both infarct and fibrosis volumes at 15 days; furthermore, both echocardiographic and hemodynamic studies revealed that IL-33 improved ventricular function. To determine whether cardioprotection by IL-33 is mediated through ST2 signaling, a randomized and blinded study of ST2^–/– versus wild-type littermate mice was performed in 98 mice subjected to MI. At 4 weeks after MI, IL-33 reduced ventricular dilation and improved contractile function in wild-type mice but not in ST2^–/– mice. Finally, IL-33 improved survival after MI in wild-type but not in ST2^–/– mice.

Conclusion— IL-33 prevents cardiomyocyte apoptosis and improves cardiac function and survival after MI through ST2 signaling.

Methods and Results— Fifteen dogs were randomized into control (n=7) and VNS (n=8) groups. All dogs underwent 8 weeks of high-rate ventricular pacing (at 220 bpm for the first 4 weeks to develop HF and another 4 weeks at 180 bpm to maintain HF). Concomitant VNS, at an intensity reducing sinus rate 20 bpm, was delivered together with the ventricular pacing in the VNS group. At 4 and 8 weeks of ventricular pacing, both left ventricular end-diastolic and -systolic volumes were lower and left ventricular ejection fraction was higher in the VNS group than in the control group. Heart rate variability and baroreflex sensitivity improved in the VNS dogs. Rises in plasma norepinephrine, angiotensin II, and C-reactive protein levels, ordinarily expected in this model, were markedly attenuated with VNS treatment.

Conclusions— Chronic VNS improves cardiac autonomic control and significantly attenuates HF development in the canine high-rate ventricular pacing model. The therapeutic benefit of VNS is associated with pronounced anti-inflammatory effects. VNS is a novel and potentially useful therapy for treating HF.

Methods and Results— This study examined the hypothesis that HF promotes a loss of myosin protein from single skeletal muscle fibers, which in turn reduces contractile performance. Ten patients with chronic HF and 10 controls were studied. Muscle atrophy was not evident in patients, and groups displayed similar physical activity levels, suggesting that observed differences reflect the effects of HF and not muscle atrophy or disuse. In single muscle fibers, patients with HF showed reduced myosin heavy chain protein content (P<0.05) that manifested as a reduction in functional myosin-actin cross-bridges (P<0.05). No evidence was found for a generalized loss of myofilament protein, suggesting a selective loss of myosin. Accordingly, single muscle fiber maximal Ca²⁺-activated tension was reduced in myosin heavy chain I fibers in patients (P<0.05). However, tension was maintained in myosin heavy chain IIA fibers in patients because a greater proportion of available myosin heads were bound to actin during Ca²⁺ activation (P<0.01).

Conclusions— Collectively, our results show that HF alters the quantity and functionality of the myosin molecule in skeletal muscle, leading to reduced tension in myosin heavy chain I fibers. Loss of single fiber myosin protein content represents a potential molecular mechanism underlying muscle weakness and exercise limitation in patients with HF.

Methods and Results— Olmsted County residents presenting with heart failure from July 2004 to September 2007 were recruited to undergo biomarker measurement. We investigated whether addition of C-reactive protein, B-type natriuretic peptide, and troponin T to a model including established risk indicators improved 1-year mortality risk prediction using the c statistic, integrated discrimination improvement, and net reclassification improvement. Among 593 participants, the mean age was 76.4 years, and 48% were men. After 1 year of follow-up, 122 (20.6%) participants had died. Patients with C-reactive protein (<11.8 mg/L), B-type natriuretic peptide (<350 pg/mL), and troponin T (≤0.01 ng/mL) less than the median had low 1-year mortality (3.3%), whereas those with 2 or 3 biomarkers greater than the median had markedly increased mortality (30.8% and 35.5%, respectively). The addition of 2 or more biomarkers to the model offered greater improvement in 1-year mortality risk prediction than use of a single biomarker. The combination of C-reactive protein and B-type natriuretic peptide resulted in an increase in the c statistic from 0.757 to 0.810 (P<0.001), an integrated discrimination improvement gain of 7.1% (P<0.001), and a net reclassification improvement of 22.1% (P<0.001). Use of all 3 biomarkers offered no incremental gain (integrated discrimination improvement gain 0.7% versus C-reactive protein+B-type natriuretic peptide, P=0.065).

Conclusions— Biomarkers improved 1-year mortality risk prediction beyond established indicators. The use of a 2-biomarker combination was superior to a single biomarker in risk prediction, though addition of a third biomarker conferred no added benefit.

Methods and Results— We used data from the multi-institutional prospectively collected United Network for Organ Sharing open transplantation cohort to review 18 240 adult patients who received orthotopic heart transplantation from 1999 to 2007. Four donor recipient strata were identified (male donor/male recipient, N=10 750; female donor/female recipient, N=2201; male donor/female recipient, N=2121; and female donor/male recipient, N=3168). The primary end point of all cause posttransplant mortality was compared among groups using a Cox proportional hazard regression model with additional propensity adjustment. Female recipients, irrespective of donor sex, had 3.6% lower overall survival at 5 years posttransplant (P=0.003). Men who received organs from male donors had the highest cumulative survival at 5 years (74.5%). Men receiving female hearts had a 15% increase in the risk of adjusted cumulative mortality (hazard ratio, 1.15; 95% CI, 1.02 to 1.30; P=0.02). No significant increase in the relative hazard for death occurred for women receiving opposite sex donor organs (1.24; 0.92 to 1.35; P=0.31).

Conclusions— The United Network for Organ Sharing data set has provided a large sample examining donor recipient sex pairing in orthotopic heart transplantation. Men receiving organs for same sex donors have significantly improved short- and long-term survival. No survival advantage was seen for women with same sex donors.

Methods and Results— BQ-123, an ET-1 receptor-A antagonist, was infused into a coronary artery (40 nmol/min for 60 minutes) of 18 subjects, 6±4 years after transplantation. Vasomotor responses were measured in the infused artery and in a noninfused control artery in patients with (n=10) and without (n=8) advanced TCA (108 total coronary segments). Changes in diameters were compared at 15-minute intervals up to 60 minutes. Contribution of ET-1 to coronary constrictor tone was assessed by comparing vasodilation from BQ-123 with that of the maximal vasodilator nitroglycerin (200-µg intracoronary bolus).

BQ-123 dilated coronary arteries of transplanted patients (8.4% at 60 minutes versus –0.4% in noninfused arteries, P<0.001). Dilation was greater for arteries with advanced TCA defined as diameter stenosis ≥15% (dilation 15.2% with versus 0.6% without advanced TCA, P=0.004). Judged against the response to nitroglycerin, ET-1 accounted for 53.2% of coronary tone in advanced TCA but only 12.9% without advanced TCA.

Conclusions— This study shows for the first time in humans that ET-1 is an important mediator of coronary vasoconstriction in TCA and accounts for >50% of the increased vasomotor tone. Therapeutic targeting of ET-1 may retard the development of TCA.

Methods and Results— Intracoronary infusion of BMC was performed in 33 patients with DCM by using an over-the-wire balloon catheter. Left ventricular contractility at baseline and after 3 months was assessed by analysis of left ventricular angiograms. Coronary hemodynamics were determined by intracoronary Doppler wire measurements. After 3 months, regional wall motion of the target area (contractility from –1.08±0.39 to –0.97±0.47 SD/chord, P=0.029) and global left ventricular ejection fraction (from 30.2±10.9 to 33.4±11.5%, P<0.001) were improved. Increase of regional contractile function was directly related to the functionality of the infused cells as measured by their colony-forming capacity. Minimal vascular resistance index was significantly reduced in the BMC-treated vessel after 3 months (from 1.53±0.63 to 1.32±0.61 mm Hg · s/cm; P=0.002, n=24), whereas no changes were observed in the reference vessel (from 1.60±0.45 to 1.49±0.45 mm Hg · s/cm; P=0.133, n=13). Twelve months after BMC infusion, N-terminal prohormone brain natriuretic peptide (NT-proBNP) serum levels were decreased, suggesting a beneficial effect on left ventricular remodeling processes (from 1610±993 to 1473±1147 pg/mL; P=0.038 for logNT-proBNP, n=26).

Conclusions— Intracoronary administration of BMC seems to be associated with improvements in cardiac contractile and microvascular function in patients with DCM. Thus, randomized blinded studies are warranted to evaluate potential clinical benefits of intracoronary BMC administration in patients with DCM.

Methods and Results— This retrospective cohort study using administrative claims data included veterans 65 years and older receiving bisoprolol, carvedilol, or metoprolol succinate for which prescribing physicians indicated treatment was for heart failure. We compared those exposed to a general practitioner–pharmacist collaborative home medication review with those who did not receive the service. The service includes physician referral, a home visit by an accredited pharmacist to identify medication-related problems, and a pharmacist report with follow-up undertaken by the physician. Kaplan-Meier analyses and Cox proportional hazards models were used to compare time until next hospitalization for heart failure between the exposed and unexposed groups. There were 273 veterans exposed to a home medicines review and 5444 unexposed patients. Average age in both groups was 81.6 years (no significant difference). The median number of comorbidities was 8 in the exposed group and 7 in the unexposed (P<0.0001). Unadjusted results showed a 37% reduction in rate of hospitalization for heart failure at any time (hazard ratio, 0.63; 95% CI, 0.44 to 0.89). Adjusted results showed a 45% reduction (hazard ratio, 0.55; 95% CI, 0.39 to 0.77) among those who had received a home medicines review compared with the unexposed patients.

Conclusion— Medicines review in the practice setting is effective in delaying time to next hospitalization for heart failure in those treated with heart failure medicines.

Methods and Results— We measured baseline Lp-PLA₂ antigen and activity in 3991 men and women without baseline CHF or cardiovascular disease who were participating in the Cardiovascular Health Study, a prospective observational study of adults 65 years or older. Cox proportional hazards models adjusted for age, sex, clinic site, race, low-density and high-density lipoprotein cholesterol, body mass index, systolic and diastolic blood pressure, hypertension, smoking status, pack-years, and diabetes were used to calculate hazard ratios and 95% CIs for incident CHF. Further models adjusted for coronary disease events during follow-up and C-reactive protein. Eight hundred twenty-nine participants developed CHF during 12.1 years. Adjusted hazard ratios for CHF with Lp-PLA₂ in the fourth compared with the first quartile were 1.44 (95% CI, 1.16 to 1.79) for Lp-PLA₂ antigen and 1.06 (95% CI, 0.84 to 1.32) for activity. Adjustment for incident coronary disease attenuated the hazard ratio for Lp-PLA₂ antigen to 1.26 (95% CI, 1.02 to 1.57), adjustment for C-reactive protein had minimal impact.

Conclusions— Lp-PLA₂ antigen was associated with risk of future CHF in older people, independent of CHF and coronary risk factors, and partly mediated by coronary disease events. Further clinical and basic research is needed to better understand the role of Lp-PLA₂ in CHF.

Methods and Results— One hundred sixty male adult rats were divided in 3 groups: sham sedentary (n=40), AR sedentary (n=80), and AR trained (n=40). Training consisted in treadmill running for up to 30 minutes, 5 times per week for 9 months, at a maximal speed of 20 m/minute. All sham-operated animals survived the entire course of the protocol. After 9 months, 65% of trained animals were alive compared with 46% of sedentary ones (P=0.05). Ejection fractions remained in the normal range (all above 60%) and LV masses between AR groups were similar. There was significantly less LV fibrosis in the trained group and lower LV filling pressures and improved echocardiographic diastolic parameters. Heart rate variability was also improved by exercise.

Conclusion— Our data show that moderate endurance training is safe, does not increase the rate of developing heart failure, and most importantly, improves survival in this animal model of chronic LV volume overload. Exercise improved LV diastolic function, heart rate variability, and reduced myocardial fibrosis.

Methods and Results— In response to MI (induced by left anterior descending artery ligation), there was a persistent increase in ACE2 protein in the infarct zone in wild-type mice, whereas loss of ACE2 enhanced the susceptibility to MI, with increased mortality, infarct expansion, and adverse ventricular remodeling characterized by ventricular dilation and systolic dysfunction. In ACE2-deficient hearts, elevated myocardial levels of Ang II and decreased levels of Ang 1-7 in the infarct-related zone was associated with increased production of reactive oxygen species. ACE2 deficiency leads to increased matrix metalloproteinase (MMP) 2 and MMP9 levels with MMP2 activation in the infarct and peri-infarct regions, as well as increased gelatinase activity leading to a disrupted extracellular matrix structure after MI. Loss of ACE2 also leads to increased neutrophilic infiltration in the infarct and peri-infarct regions, resulting in upregulation of inflammatory cytokines, interferon-, interleukin-6, and the chemokine, monocyte chemoattractant protein-1, as well as increased phosphorylation of ERK1/2 and JNK1/2 signaling pathways. Treatment of Ace2^–/y-MI mice with irbesartan, an AT1 receptor blocker, reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, infarct size, MMP activation, and myocardial inflammation, ultimately resulting in improved post-MI ventricular function.

Conclusions— We conclude that loss of ACE2 facilitates adverse post-MI ventricular remodeling by potentiation of Ang II effects by means of the AT1 receptors, and supplementing ACE2 can be a potential therapy for ischemic heart disease.

Methods and Results— Mass spectroscopy showed that the mutant cTnC was expressed approximately equimolar with wild-type cTnC. Contraction was compared in skinned ventricular myocytes from the cTnC G159D patient and nonfailing donor heart. Maximal Ca²⁺-activated force was similar in cTnC G159D and donor myocytes, but the Ca²⁺ sensitivity of cTnC G159D myocytes was higher (EC₅₀ G159D/donor=0.60). Thin filaments reconstituted with skeletal muscle actin and human cardiac tropomyosin and troponin were studied by in vitro motility assay. Thin filaments containing the mutation had a higher Ca²⁺ sensitivity (EC₅₀ G159D/donor=0.55±0.13), whereas the maximally activated sliding speed was unaltered. In addition, the cTnC G159D mutation blunted the change in Ca²⁺ sensitivity when TnI was dephosphorylated. With wild-type troponin, Ca²⁺ sensitivity was increased (EC₅₀ P/unP=4.7±1.9) but not with cTnC G159D troponin (EC₅₀ P/unP=1.2±0.1).

Conclusions— We propose that uncoupling of the relationship between phosphorylation and Ca²⁺ sensitivity could be the cause of the dilated cardiomyopathy phenotype. The differences between these data and previous in vitro results show that native phosphorylation of troponin I and troponin T and other posttranslational modifications of sarcomeric proteins strongly influence the functional effects of a mutation.

Methods and Results— In 299 patients with recent onset dyspnea or peripheral edema presenting to primary care, plasma urocortin 1 and other vasoactive hormones were assayed, and echocardiography was performed. Heart failure was present in 74 patients (25%) according to predefined diagnostic criteria. Urocortin 1 levels were increased in patients with heart failure and were related to functional class, clinical signs of heart failure, echocardiographic indicators of left ventricular dimensions and function, plasma creatinine, and concurrent circulating levels of plasma natriuretic peptides, adrenomedullin, and endothelin 1.

Conclusions— Plasma urocortin 1 is elevated in heart failure (in proportion to the degree of cardiac dysfunction) in concert with the generalized neurohormonal activation seen in this condition. Urocortin levels predict heart failure independent of age, history of previous myocardial infarction, diabetes, hypertension, fractional shortening, and N-terminal prohormone brain natriuretic peptide levels.

Methods and Results— New Zealand white rabbits underwent a pulmonary artery banding procedure to induce pressure overload. After 10 weeks, the animals were euthanized, hearts removed, and suitable trabeculae harvested from the free wall of the right ventricle. Twitch contractions, calibrated bis-fura-2 calcium transients, and myofilament calcium sensitivity (potassium contractures) were measured at frequencies of 1, 2, 3, and 4 Hz. The force frequency response, relaxation frequency response, and calcium frequency relationships were significantly blunted, and diastolic tension significantly increased with frequency in the pulmonary artery banding rabbits compared with sham-operated animals. Myofilament calcium sensitivity was virtually identical at 1 Hz in the treatment versus sham group (pCa 6.11±0.03 versus 6.11±0.06), but the frequency-dependent desensitization that takes place in the sham group (pCa 0.14±0.06, P<0.05) was not observed in the pulmonary artery banding animals (pCa 0.02±0.05). Analysis of myofilament protein phosphorylation revealed that the normally observed frequency-dependent phosphorylation of troponin-I is lost in pulmonary artery banding rabbits.

Conclusions— The frequency-dependent myofilament desensitization is significantly impaired in right ventricular hypertrophy and contributes to the frequency-dependent elevation of diastolic tension in hypertrophy.

Methods and Results— Sheep left atrial myocytes were stained with di-4-ANEPPS. Nearly all control cells had an extensive t-tubule network resulting in each voxel in the cell being nearer to a membrane (sarcolemma or t-tubule) than would otherwise be the case. T-tubules decrease the distance of 50% of voxels from a membrane from 3.35±0.15 to 0.88±0.04 µm. During depolarization, intracellular Ca²⁺ rises simultaneously at the cell periphery and center. In heart failure induced by rapid ventricular pacing, there was an almost complete loss of atrial t-tubules. The distance of 50% of voxels from a membrane increased to 2.04±0.08 µm, and there was a loss of early Ca²⁺ release from the cell center.

Conclusion— Sheep atrial myocytes possess a substantial t-tubule network that synchronizes the systolic Ca²⁺ transient. In heart failure, this network is markedly disrupted. This may play an important role in changes of atrial function in heart failure.

Methods and Results— We performed a cohort study of 603 patients with pulmonary hypertension from 1982 to 2006, and studied the utility of exercise treadmill test as a predictor of abnormal hemodynamics and death. We used multivariable linear regression to determine whether exercise capacity, measured in metabolic equivalents, was associated with abnormal hemodynamics, and we used a Cox proportional hazards model to determine whether decreased exercise capacity predicted death. Mean age was 50±15 years, 76% were women, 63% had World Health Organization category I pulmonary arterial hypertension, and 23% were World Health Organization functional classes I and II. Mean exercise capacity was 3.7±2.2 metabolic equivalents. Decreased exercise capacity was independently associated with elevated right atrial and mean pulmonary artery pressure, decreased cardiac index, and increased pulmonary vascular resistance. During median follow-up of 4.6 years, 36% of the patients died. Decreased exercise capacity was associated with mortality (multivariable hazard ratio, 1.18; 95% CI, 1.01 to 1.37 for each 1-metabolic equivalent decrease in exercise capacity; P=0.031; P=0.052 after adjusting for invasive hemodynamic variables). Decreased exercise capacity also predicted mortality in functional classes I–II patients, 24% of whom died (hazard ratio, 1.53; 95% CI, 1.04 to 2.26 for each 1-metabolic equivalent decrease in exercise capacity; P=0.032), although this association did not persist after adjusting for invasive hemodynamic variables (P=0.63).

Conclusions— Reduced exercise capacity on exercise treadmill test is associated with worse hemodynamics and is a predictor of mortality in patients with pulmonary hypertension.

Methods and Results— We conducted a randomized controlled trial of patients with acute heart failure in 10 academic and community emergency departments. The experimental group received serial B-type natriuretic peptide testing (at 3, 6, 9, and 12 hours then daily). The control group received usual care. Our outcomes were hospital length of stay, 30-day readmission rate, and all-cause mortality.

There were 219 controls and 228 experimental patients. Mean age was 64 years, 49% were women, 58% were blacks, and 34% were whites. Groups were similar in baseline characteristics. Comparing the serial testing with the control group, there was no difference in length of stay (6.5 days [95% CI, 5.2 to 7.9] versus 6.5 days [95% CI, 5.6 to 7.3]; difference, 0.1 [95% CI, –1.7 to 1.5]), in-hospital mortality (2.2% [95% CI, 0.9 to 5.0] versus controls, 3.2% [95% CI, 1.6 to 6.5]; difference, 1.0% [95% CI, –2.3 to 4.5]), 30-day mortality (3.7% [95% CI, 1.8 to 7.5] versus 5.5% [95% CI, 3.0 to 9.8]; difference, 1.8% [95% CI, –2.8 to 6.5]), or hospital revisit rate (20.2% [95% CI, 15.0 to 26.6] versus 23.7% [95% CI, 18.0 to 30.6]; difference, 3.5% [95% CI, –5.1 to 12.1]).

Conclusions— In this study of 447 patients hospitalized for suspected heart failure, we were unable to demonstrate a benefit of serial testing with B-type natriuretic peptide in terms of hospital length of stay, mortality, or readmission rate.

Methods and Results— From 2000 to 2007 clinical and laboratory variables of 1033 consecutive outdoor patients with heart failure were evaluated. Follow-up (mean, 34.4 months) was available in 998 patients. The end point was defined as death from any cause or heart transplantation. A forward stepwise Cox proportional hazards regression model for sex-stratified data was used. Prevalence of elevated GGT was 42.9% in men (GGT >65 U/L) and 50.2% in women (GGT >38 U/L), which was higher than for sex- and age-matched healthy subjects (18.6% in men, 19.2% in women) derived from a large historical control group. GGT was associated with severity of heart failure as assessed by New York Heart Association class, left-ventricular ejection fraction, and amino-terminal pro-B-type natriuretic peptide. The end point was recorded in 302 patients. Compared with the lowest GGT quintile, sex-stratified hazard ratios for patients in the highest quintile were 2.88 (1.99 to 4.17) in the univariate model and 1.87 (1.28 to 2.74) in the adjusted model (P<0.001). Corresponding 5-year cumulative event rates were 47% and 74%, respectively. Adjusted hazard ratios for elevated GGT was 2.9 (1.64 to 5.17) for patients in New York Heart Association I/II, and 1.2 (0.75 to 2.05) for patients in New York Heart Association III/IV, respectively (P=0.003, for the GGT–New York Heart Association class interaction).

Conclusions— Prevalence of elevated GGT is high in patients with chronic heart failure. The GGT levels are associated with disease severity. Increased GGT is an independent predictor of death or heart transplantation. GGT may provide additional prognostic information, especially in patients with mild heart failure.

Methods and Results— Serum fibrosis markers were measured in 880 participants of the Cardiovascular Health Study (mean age 77±6 years, 48% women). Participants with systolic HF (n=131, left ventricular ejection fraction <55%) and those with diastolic HF (n=179, left ventricular ejection fraction ≥55%) were compared with controls (280 with cardiovascular risk factors, and 279 healthy individuals) using a nested case-control design. Fibrosis markers included carboxyl-terminal peptide of procollagen type I, carboxyl-terminal telopeptide of collagen type I, and amino-terminal peptide of procollagen type III. Echocardiography was used to document systolic and diastolic function parameters. Analysis of variance and logistic regression analysis (per tertile odds ratios [OR]), adjusted by age, gender, race, hypertension, atrial fibrillation, coronary heart disease, baseline serum glucose, serum cystatin C, serum creatinine, C-reactive protein, any angiotensin-converting enzyme inhibitor, spironolactone or any diuretic, NT-proBNP, and total bone mineral density were performed. Systolic HF was associated with significantly elevated carboxyl-terminal telopeptide of collagen type I (OR=2.6; 95% CI=1.2 to 5.7) and amino-terminal peptide of procollagen type III (OR=3.3; 95% CI=1.6 to 5.8), when adjusting for covariates. Associations of diastolic HF were significant for carboxyl-terminal telopeptide of collagen type I (OR=3.9; 95% CI=1.9 to 8.3) and amino-terminal peptide of procollagen type III (OR=2.7; 95% CI=1.4 to 5.4). HF was not associated with elevated carboxyl-terminal peptide of procollagen type I (P>0.10), and fibrosis markers did not significantly differ between HF with diastolic versus those with systolic dysfunction (P>0.10) whereas NT-proBNP mean values were higher in systolic heart failure than in diastolic heart failure (P<0.0001).

Conclusions— Fibrosis markers are significantly elevated in elderly individuals with diastolic or systolic HF. These associations remained significant when adjusting for covariates relevant to the aging process.

Methods and Results— One hundred thirty-four dyspneic patients with and without decompensated heart failure had echocardiography during index admission and vital status was ascertained at 4 years. Echocardiographic and clinical correlates of sST2 as well as independent predictors of death at 4 years were identified. sST2 correlated with left ventricular end-systolic dimensions/volumes and left ventricular ejection fraction. sST2 was inversely associated with right ventricular fractional area change (=–0.18; P=0.046), higher right ventricular systolic pressure (=0.26; P=0.005), and right ventricular hypokinesis (P<0.001) and was correlated with tissue Doppler Ea wave peak velocity, but not to other indices of diastolic function. In multivariate regression, independent predictors of sST2 included right ventricular systolic pressure (t=2.29; P=0.002), left ventricular ejection fraction (t=–2.15; P=0.05) and dimensions (end systolic, t=2.57; end diastolic, t=2.98; both P<0.05), amino-terminal pro-B-type natriuretic peptide (t=3.31; P=0.009), heart rate (t=2.59; P=0.01), and presence of jugular venous distension (t=2.00; P=0.05). In a Cox proportional hazards model that included echocardiographic results and other biomarkers, sST2 independently predicted death at 4 years (hazard ratio=2.70; P=0.003).

Conclusions— Among dyspneic patients with and without acute heart failure, sST2 concentrations are associated with prevalent cardiac abnormalities on echocardiography, a more decompensated hemodynamic profile and are associated with long-term mortality, independent of echocardiographic, clinical, or other biochemical markers of risk.

Methods and Results— In a retrospective analysis of 112 inotrope-dependent patients with stage D heart failure who were not transplant candidates at enrollment, we investigated the relationship between choice of dobutamine or milrinone and mortality. Half the patients were on dobutamine (mean dose, 5.4±2.5 µg/kg per minute) and half on milrinone (mean dose, 0.4±0.2 µg/kg per minute). Those on dobutamine tended to be older (63 years old versus 54 years old), male (86% versus 79%), and fewer had implantable cardioverter-defibrillators (57% versus 74%). During a median follow-up time of 130 days (range, 2 to 2345 days), there were 85 deaths (76% of cohort) and 55 rehospitalizations. Use of dobutamine compared with milrinone was associated with higher all-cause mortality in an unadjusted analysis (hazard ratio [HR], 1.63; 95% CI, 1.06 to 2.52; P<0.03). However, this association was not significant after adjustment for baseline characteristics in the full cohort (N=112; HR, 0.99; 95% CI 0.5 to 1.97; P=0.98) or propensity-matched cohort (N=70; HR, 0.94; 95% CI 0.48 to 1.85; P=0.86).

Conclusions— In this single-center retrospective study, there were no mortality differences between chronic intravenous dobutamine or milrinone in patients with stage D heart failure being discharged from the hospital. The high mortality in this group selected for inotrope dependence warrants careful consideration of all options and priorities for further care.

Methods and Results— Frozen surgical myectomy specimens from 47 patients with HCM were examined and genotyped for mutations involving 8 myofilament-encoding genes. Myofilament protein levels were quantified by Western blotting with localization graded from immunohistochemical staining of tissue sections. Overall, 25 of 47 (53%) patients had myofilament-HCM, including 12 with MYBPC3-HCM and 9 with MYH7-HCM. As compared with healthy heart tissue, levels of myofilament proteins were increased in patients manifesting a mutation in either gene. Patients with a frameshift mutation predicted to truncate MYBPC3 exhibited marked disturbances in protein localization as compared with missense mutations in either MYBPC3 or MYH7.

Conclusions— In this first expression study in human HCM tissue, increased myofilament protein levels in patients with either MYBPC3- or MYH7-mediated HCM suggest a poison peptide mechanism. Specifically, the mechanism of dysfunction may vary according to the genetic subgroup suggested by a distinctly abnormal distribution of myofilament proteins in patients manifesting a truncation mutation in MYBPC3.

Methods and Results— Papillary muscle strips from TG rabbits expressing 40% (TG40) and 15% -MHC (TG15) and from nontransgenic (NTG) controls expressing 100% β-MHC (NTG40 and NTG15) were demembranated and calcium activated. Myofilament tension and calcium sensitivity were similar in TGs and respective NTGs. Force-clamp measurements revealed 50% higher power production in TG40 versus NTG40 (P<0.001) and 20% higher power in TG15 versus NTG15 (P<0.05). A characteristic of acto-myosin crossbridge kinetics, the "dip" frequency, was significantly higher in TG40 versus NTG40 (0.70±0.04 versus 0.39±0.09 Hz, P<0.01) but not in TG15 versus NTG15. The calculated crossbridge time-on was also significantly shorter in TG40 (102.3±14.2 ms) versus NTG40 (175.7±19.7 ms) but not in TG15 versus NTG15.

Conclusions— The incorporation of 40% -MHC leads to greater myofilament power production and more rapid crossbridge cycling, which facilitate ejection and relengthening during short cycle intervals, and thus protect against tachycardia-induced cardiomyopathy. Our results suggest, however, that, even when compared with the virtual absence of -MHC in the failing heart, the 5% to 7% -MHC content of the normal human heart has little if any functional significance.

Methods and Results— In patients with chronic heart failure treated with angiotensin-converting enzyme inhibition, cardiac oxidative capacity, measured in saponin-permeabilized fibers, was 25% lower, and proliferator-activated receptor- coactivator-1 protein content was 34% lower compared with nonfailing controls. In a rat model of myocardial infarction, angiotensin-converting enzyme inhibition therapy was only partially able to protect cardiac mitochondrial function and transcription cascade. Expression of proliferator-activated receptor- coactivator-1 and its transcription cascade were evaluated after a 48-hour exposure of cultured adult rat ventricular myocytes to endothelin-1, angiotensin II, aldosterone, phenylephrine, or isoprenaline. Endothelin-1 (–30%) and, to a lesser degree, angiotensin II (–20%) decreased proliferator-activated receptor- coactivator-1 mRNA content, whereas other hormones had no effect (phenylephrine) or even increased it (aldosterone, isoprenaline).

Conclusions— Taken together, these results show that, despite angiotensin-converting enzyme inhibition treatment, oxidative capacity is reduced in human and experimental heart failure and that endothelin-1 and angiotensin II could be involved in the downregulation of the mitochondrial transcription cascade.

Methods and Results— Cardiac-restricted MT1-MMPexp was constructed in mice using the full-length human MT1-MMP gene ligated to the myosin heavy chain promoter, which yielded approximately a 200% increase in MT1-MMP when compared with age/strain-matched wild-type (WT) mice. Left ventricular (LV) function and geometry was assessed by echocardiography in 3-month ("young") WT (n=32) and MT1-MMPexp (n=20) mice and compared with 14-month ("middle-aged") WT (n=58) and MT1-MMPexp (n=35) mice. LV end-diastolic volume was similar between the WT and MT1-MMPexp young groups, as was LV ejection fraction. In the middle-aged WT mice, LV end-diastolic volume and ejection fraction was similar to young WT mice. However, in the MT1-MMPexp middle-aged mice, LV end-diastolic volume was 43% higher and LV ejection fraction 40% lower (both P<0.05). Moreover, in the middle-aged MT1-MMPexp mice, myocardial fibrillar collagen increased by nearly 2-fold and was associated with 3-fold increase in the processing of the profibrotic molecule, latency-associated transforming growth factor binding protein. In a second study, 14-day survival after myocardial infarction was significantly lower in middle-aged MT1-MMPexp mice.

Conclusions— Persistently increased myocardial MT1-MMP expression, in and of itself, caused LV remodeling, myocardial fibrosis, dysfunction, and reduced survival after myocardial injury. These findings suggest that MT1-MMP plays a mechanistic role in adverse remodeling within the myocardium.

Methods and Results— Humoral vascular changes, including endothelial complement staining, were present in bm12 heart grafts, explanted 50 days after transplantation. Alloantibody was not detectable, but long-lasting autoantibody responses developed in C57BL/6 recipients from the third week after transplantation. No autoantibody was generated if donor CD4 T cells were depleted before heart graft retrieval or in recipients that lacked B-cell major histocompatibility complex class II expression, indicating that humoral autoimmunity is a consequence of donor CD4 T-cell allorecognition of the major histocompatibility complex class II complex on recipient autoreactive B cells. An effector role for autoantibody in graft rejection was confirmed by abrogation of humoral vascular rejection, and attenuation of vasculopathy, in B-cell deficient recipients and by development of vascular obliteration and accelerated rejection in recipients primed for autoantibody before transplantation.

Conclusions— Passenger CD4 T cells within heart transplants can contribute to allograft vasculopathy by providing help to recipient B cells for autoantibody generation.

Methods and Results— We used the US Census 2000 database to derive a composite SE score for the block group of residence for all patients who underwent their first heart transplant at Children’s Hospital Boston between 1991 and 2005 (n=135). Cox proportional hazards models were used to determine the risk of graft failure (death or retransplant) in the lowest tertile SE group (low SE group) compared with the remaining 2 of 3 patients (controls). The 2 groups were similar with respect to age, gender, diagnosis, and year of transplant. White race was less frequent in low SE group (64% versus 90%, P=0.001). Graft failure occurred in 46 transplant recipients (40 deaths, 6 retransplant). Low SE group (hazard ratio 2.4, 95% CI 1.3 to 4.3) and nonwhite race (hazard ratio 2.7, 95% CI 1.4 to 5.2) were both associated with higher risk of graft failure. In a multivariable model controlling for diagnosis and pretransplant support, race, and low SE position (hazard ratio 2.0, 95% CI 1.0 to 3.7, P=0.04) remained associated with graft failure. Low SE position group had a higher incidence rate of graft rejection and was at a higher risk of late rejection.

Conclusion— Low SE position may be an independent risk factor for graft failure in pediatric heart transplant recipients.

Methods and Results— We applied pacemaker fluctuations by adjusting heart rate (by 30 bpm) or atrioventricular delay (between optimal and nonoptimal values) or both, with period of 60 s in 19 heart failure patients (age 73±11, EF 29±12%). The changes in cardiac output, by either heart rate or atrioventricular delay or both, were made either as a step ("square wave") or more gradually ("sine wave"). We obtained changes in cardiac output sufficient to engender comparable oscillations in et-CO₂ (P=NS) in all 19 patients either by manipulation of heart rate (14), or by atrioventricular delay (2) or both (3). The square wave produced 191% larger and 250% more sudden changes in blood pressure than the sine wave alternations (22.4±11.7 versus 13.6±4.5 mm Hg, P<0.01 and 19.8±10.0 versus 7.9±3.2 mm Hg over 5 s, P<0.01), but peak-to-trough et-CO₂ elicited was only 45% higher (0.45±0.18 versus0.31±0.13 kPa, P=0.01).

Conclusion— This study shows that cardiac output is the key to dynamically manipulating the respiratory system with pacing sequences. When manipulating respiration by this route, a sine wave pattern may be preferable to a square wave, because it minimizes sudden blood pressure fluctuations.

Methods and Results— Eighty patients with chronic HF and 20 healthy controls were evaluated consecutively, but the required quality for procedures was only reached by 71 patients with HF and 19 healthy controls. Each subject underwent pulmonary function measurements, including lung diffusion for carbon monoxide and membrane diffusion capacity, and maximal cardiopulmonary exercise test. Plasma SPB was measured by immunoblotting. In patients with HF, SPB values were higher (4.5 [11.1] versus 1.6 [2.9], P=0.0006, median and 25th to 75th interquartile), whereas lung diffusion for carbon monoxide (19.7±4.5 versus 24.6±6.8 mL/mm Hg per min, P<0.0001, mean±SD) and membrane diffusion capacity (28.9±7.4 versus 38.7±14.8, P<0.0001) were lower. Peak oxygen consumption and ventilation/carbon dioxide production slope were 16.2±4.3 versus 26.8±6.2 mL/kg per min (P<0.0001) and 29.7±5.9 and 24.5±3.2 (P<0.0001) in HF and controls, respectively. In the HF population, univariate analysis showed a significant relationship between plasma SPB and lung diffusion for carbon monoxide, membrane diffusion capacity, peak oxygen consumption, and ventilation/carbon dioxide production slope (P<0.0001 for all). On multivariable logistic regression analysis, membrane diffusion capacity (β, –0.54; SE, 0.018; P<0.0001), peak oxygen consumption (β, –0.53; SE, 0.036; P=0.004), and ventilation/carbon dioxide production slope (β, 0.25; SE, 0.026; P=0.034) were independently associated with SPB.

Conclusion— Circulating plasma SPB levels are related to alveolar gas diffusion, overall exercise performance, and efficiency of ventilation showing a link between alveolar-capillary barrier damage, gas exchange abnormalities, and exercise performance in HF.

Methods and Results— Patients were randomized to PAC or CLIN during hospitalization with chronic heart failure and mean left ventricular ejection fraction 20%, and at least 1 symptom and 1 sign of congestion. MR and mitral flow patterns, measured blinded to therapy and timepoint, were available at baseline and discharge in 133 patients, and at 3 months in 104 patients. Changes in MR and related transmitral flow patterns were compared between PAC and CLIN patients. Jugular venous pressure, edema, and weights decreased similarly during therapy in the hospital for both groups. In PAC but not in CLIN patients, MR jet area, MR/left atrial area ratio, and E velocity were each significantly reduced and deceleration time increased by discharge. By 3 months, patients had clinical evidence of increased jugular venous pressure, edema, and weight since discharge, reaching significance in the PAC arm, and the change in MR was no longer different between the 2 groups, although the change in E velocity remained greater in PAC patients.

Conclusions— During hospitalization, therapy guided by PAC to reduce left-sided pressures improved MR and related filling patterns more than therapy guided clinically by evidence of systemic venous congestion. This early reduction did not translate into improved outcomes out of the hospital, where volume status reverted toward baseline.

Methods and Results— Twenty-nine patients (63±12 years old) with New York Heart Association class II-III heart failure underwent serial measurements of left ventricular volumes using 3-dimensional echocardiography and blood pressures by sphygmomanometry at baseline, 2 weeks, 2, 6, and 12 months after initiation of carvedilol. From these parameters, left ventricular contractility (indexed by the end-systolic pressure-volume ratio), total peripheral resistance, and effective arterial elastance (E_a) were derived. Overall, EF increased by 7-percentage points after 6 months of therapy (from 25±9 to 32±9, P<0.0001). This change was due to an increase in stroke volume (P<0.001) with no significant change in end-diastolic volume (P=0.15). The EF change correlated with increased contractility, decreased HR and decreased total peripheral resistance (P<0.003 in each case). In those patients whose EF increased at least 5 points, 60% of the increase was due to HR reduction, 30% was due to increased contractility, and <20% was due to the decrease in total peripheral resistance.

Conclusions— Decreased HR, improved chamber contractility and afterload reduction each contributed significantly to improved EF with carvedilol.

Methods and Results— We retrospectively analyzed the records of all orthotopic heart transplant patients who had ICD implantation between January 1995 and December 2005 at 5 heart transplant centers. Thirty-six patients were considered high risk for sudden cardiac death. The mean age at orthotopic heart transplant was 44±14 years, the majority being male (n=29). The mean age at ICD implantation was 52±14 years, whereas the average time from orthotopic heart transplant to ICD implant was 8 years ±6 years. The main indications for ICD implantation were severe allograft vasculopathy (n=12), unexplained syncope (n=9), history of cardiac arrest (n=8), and severe left ventricular dysfunction (n=7). Twenty-two shocks were delivered to 10 patients (28%), of whom 8 (80%) received 12 appropriate shocks for either rapid ventricular tachycardia or ventricular fibrillation. The shocks were effective in terminating the ventricular arrhythmias in all cases. Three (8%) patients received 10 inappropriate shocks. Underlying allograft vasculopathy was present in 100% (8 of 8) of patients who received appropriate ICD therapy.

Conclusions— Use of ICDs after heart transplantation may be appropriate in selected high-risk patients. Further studies are needed to establish an appropriate prevention strategy in this population.

Methods and Results— Women aged 48 to 83 (n=36873) and men aged 45 to 79 (n=43487) self-reported height, weight, and WC. HF hospitalization or death (n=382 women, 718 men) between January 1, 1998, and December 31, 2004, was determined through administrative registers. Hazard ratios, from Cox proportional-hazards models, for an interquartile range higher BMI were 1.39 (95% CI, 1.15 to 1.68) at age 60 and 1.13 (95% CI, 1.02 to 1.27) at 75 in women. In men, hazard ratios were 1.54 (95% CI, 1.37 to 1.73) at 60 and 1.25 (95% CI, 1.16 to 1.35) at 75. A 10-cm higher WC was associated with 15% (95% CI, 2% to 31%) and 18% (95% CI, 4% to 33%) higher HF rates among women with BMI 25 and 30 kg/m², respectively; hazard ratios for 1 kg/m² higher BMI were 1.00 (95% CI, 0.96 to 1.04) and 1.01 (95% CI, 0.98 to 1.04) for WC 70 and 100 cm, respectively. In men, a 10-cm higher WC was associated with 16% and 18% higher rates for BMI 25 and 30 kg/m², respectively; a 1 kg/m² higher BMI was associated with 4% higher HF rates regardless of WC.

Conclusions— Strength of the association between BMI and HF events declined with age. In women, higher WC was associated with HF at all levels of BMI. Both BMI and WC were predictors among men.

Methods and Results— In the 8290, Prevention of Events with Angiotensin-Converting Enzyme Inhibition patients without preexisting HF, new-onset HF hospitalizations, and fatal HF were assessed over a median follow-up of 4.8 years. Covariates were evaluated and maintained in the Cox regression multivariable model using backward selection if P<0.05. A risk score was developed and converted to an integer-based scoring system. Among the Prevention of Events with Angiotensin-Converting Enzyme Inhibition population (age, 64±8; female, 18%; prior myocardial infarction, 55%), there were 268 cases of fatal and nonfatal HF. Twelve characteristics were associated with increased risk of HF along with several baseline medications, including older age, history of hypertension, and diabetes. Randomization to trandolapril independently reduced the risk of HF. There was no interaction between trandolapril treatment and other risk factors for HF. The risk score (range, 0 to 21) demonstrated excellent discriminatory power (c-statistic 0.80). Risk of HF ranged from 1.75% in patients with a risk score of 0% to 33% in patients with risk score ≥16.

Conclusion— Among patients with stable coronary artery disease and preserved ejection fraction, traditional and newer factors were independently associated with increased risk of HF. Trandolopril decreased the risk of HF in these patients with preserved ejection fraction.

Methods and results— Leukocyte counts were measured in 16 940 men from the general population (mean age 44 years) without history of myocardial infarction or stroke. Incidence of hospitalizations due to HF (primary diagnosis) was monitored over 23 years of follow-up, in relation to quartiles of leukocytes. Subjects with myocardial infarction during follow-up were censored in the main analysis. During the follow-up, 436 men were hospitalized due to HF. Incidence of HF hospitalizations was increased in men with high leukocyte counts. After adjustments for confounding factors, the adjusted hazards ratio (HR, 95% CI) for HF hospitalization was 1.00 (reference), 1.26 (0.93 to 1.7), 1.24 (0.91 to 1.7), and 1.73 (1.3 to 2.3), respectively, for men with leukocytes in the 1st, 2nd, 3rd, and 4th (highest) quartiles (trend, P<0.001). This relationship was consistent in smokers and nonsmokers and in men with and without hypertension, respectively.

Conclusion— High leukocyte counts in middle-aged men were associated with increased long-term incidence of HF hospitalizations.

Methods and Results— Intracellular Ca²⁺ transients were measured using confocal microscopy in whole rat hearts from age-matched Wistar-Kyoto control rats and spontaneously hypertensive rats at 23 months of age. Basal Ca²⁺ transients in myocytes in spontaneously hypertensive rats were smaller in amplitude and longer in duration than Wistar-Kyoto control rats. There was also greater variability in transient characteristics associated with duration between myocytes of CHF than Wistar-Kyoto controls. Approximately 21% of CHF myocytes demonstrated spontaneous Ca²⁺ waves compared with very little of this activity in Wistar-Kyoto control rats. A separate population of spontaneously hypertensive rat myocytes showed Ca²⁺ waves that were triggered during pacing and were absent at rest (triggered waves). Rapid pacing protocols caused Ca²⁺ alternans to develop at slower heart rates in CHF.

Conclusions— Epicardial cells demonstrate both serious defects and greater cell-to-cell variability in Ca²⁺ cycling in CHF. The defects in Ca²⁺ cycling include both spontaneous and triggered waves of Ca²⁺ release, which promote triggered activity. The slowing of Ca²⁺ repriming in the sarcoplasmic reticulum is probably responsible for the increased vulnerability to Ca²⁺ alternans in CHF. Our results suggest that defective Ca²⁺ cycling could contribute both to reduced cardiac output in CHF and to the establishment of repolarization gradients, thus creating the substrate for reentrant arrhythmias.

Methods and Results— In pigs with a MI induced by ligation of the left circumflex coronary artery, β-blocker therapy (bisoprolol, MI+β) was initiated on the first day after MI. Remote left ventricular subendocardial biopsies were taken 3 weeks after sham or MI surgery. Isometric force was measured in single permeabilized cardiomyocytes. Maximal force (F_max) was lower, whereas Ca²⁺ sensitivity was higher in untreated MI compared with sham (both P<0.05). The difference in Ca²⁺ sensitivity was abolished by treatment of cells with the β-adrenergic kinase, protein kinase A. β-blocker therapy partially reversed F_max and Ca²⁺ sensitivity to sham values and significantly reduced passive force. Despite the lower myofilament Ca²⁺ sensitivity in MI+β compared with untreated myocardium, the protein kinase A induced reduction in Ca²⁺ sensitivity was largest in cardiomyocytes from myocardium treated with β-blockers. Phosphorylation of β-adrenergic target proteins (myosin binding protein C and troponin I) did not differ among groups, whereas myosin light chain 2 phosphorylation was reduced in MI, which coincided with increased expression of protein phosphatase 1. β-blockade fully restored the latter alterations and significantly reduced expression of protein phosphatase 2a.

Conclusions— β-blockade reversed myofilament dysfunction and enhanced myofilament responsiveness to protein kinase A in remote myocardium after MI. These effects likely contribute to the beneficial effects of β-blockade on global left ventricular function after MI.

Methods and Results— Adult male Sprague-Dawley rats were subjected to left anterior descending coronary artery ligation (myocardial infarction). One week post-myocardial infarction, left ventricular fractional shortening was significantly reduced to 22±1% in CHF animals versus 38±1% for sham-operated controls (P<0.001). Serum T₃ concentration was also significantly reduced (80±3 versus 103±6 ng/dL; P<0.001), in CHF animals versus Shams. At 9 weeks post-myocardial infarction, systolic function (+dP/dt max) was significantly attenuated in CHF animals (4773±259 versus 6310±267 mmHg/s; P<0.001) as well as diastolic function measured by half time to relaxation (15.9±1.2 versus 11.1±0.3 ms; P<0.001). -myosin heavy chain expression was also significantly reduced by 77% (P<0.001), and β-myosin heavy chain expression was increased by 21%. Continuous T₃ replacement was initiated 1 week post-myocardial infarction with osmotic mini-pumps (6 µg/kg/d), which returned serum T₃ concentrations to levels similar to Sham controls while resting conscious heart rate, arterial blood pressure and the incidence of arrhythmias were not different. At 9 weeks, systolic function was significantly improved by T₃ replacement (6279±347 mmHg/s; P<0.05) and a trend toward improved diastolic function (12.3±0.6 ms) was noted. T₃ replacement in CHF animals also significantly increased - and reduced β-MHC expression, (P<0.05).

Conclusions— These data indicate that T₃ replacement to euthyroid levels improves systolic function and tends to improve diastolic function, potentially through changes in myocardial gene expression.