Abnormal left ventricular ejection fraction response to mental stress and exercise in cardiomyopathy

Cardiac resynchronization therapy (CRT) improves LV structure, function, and clinical outcomes in New York Heart Association class III/IV heart failure with prolonged QRS. It is not known whether patients with New York Heart Association class I/II systolic heart failure exhibit left ventricular (LV) reverse remodeling with CRT or whether reverse remodeling is modified by the cause of heart failure. Six hundred ten patients with New York Heart Association class I/II heart failure, QRS duration > or =120 ms, LV end-diastolic dimension > or =55 mm, and LV ejection fraction < or =40% were randomized to active therapy (CRT on; n=419) or control (CRT off; n=191) for 12 months. Doppler echocardiograms were recorded at baseline, before hospital discharge, and at 6 and 12 months. When CRT was turned on initially, immediate changes occurred in LV volumes and ejection fraction; however, these changes did not correlate with the long-term changes (12 months) in LV end-systolic (r=0.11, P=0.31) or end-diastolic (r=0.10, P=0.38) volume indexes or LV ejection fraction (r=0.07, P=0.72). LV end-diastolic and end-systolic volume indexes decreased in patients with CRT turned on (both P<0.001 compared with CRT off), whereas LV ejection fraction in CRT-on patients increased (P<0.0001 compared with CRT off) from baseline through 12 months. LV mass, mitral regurgitation, and LV diastolic function did not change in either group by 12 months; however, there was a 3-fold greater reduction in LV end-diastolic and end-systolic volume indexes and a 3-fold greater increase in LV ejection fraction in patients with nonischemic causes of heart failure. CRT in patients with New York Heart Association I/II resulted in major structural and functional reverse remodeling at 1 year, with the greatest changes occurring in patients with a nonischemic cause of heart failure. CRT may interrupt the natural disease progression in these patients. Clinical Trial Registration- Clinicaltrials.gov Identifier: NCT00271154.

Impact of a New Conduction Defect After Transcatheter Aortic Valve Implantation on Left Ventricular Function

The effects of sacubitril/valsartan (angiotensin receptor-neprilysin inhibitor [ARNI]) on myocardial tissue in heart failure (HF) with left ventricular ejection fraction (LVEF) <50% remain unclear. Sixty-four HF outpatients with LVEF <50% were randomized to ARNI (switching from an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker [ACEi/ARB] to ARNI) or control (continuing with ACEi/ARB). Left ventricular (LV) structure and myocardial tissue, including changes in LV extracellular volume fraction (ECV), were evaluated before and after the 9-month program using cardiac magnetic resonance imaging. The primary endpoint was changes in ECV. Secondary endpoints were changes in LVEF, LV volume and mass, and extra- and intracellular mass. Fifty-nine patients completed the 9-month intervention. ARNI decreased systolic blood pressure from the first month. The ARNI group showed significant reductions in LV volume, LV mass, and extra- and intracellular mass from baseline to 9 months, but there was no change in LVEF, or in ECV (31.6±5.0% vs. 31.9±5.0%, respectively; P=0.795). In the control group, there was no change in systolic blood pressure, LV volume, LV mass, ECV, or extra- and intracellular mass. There was no significant difference in the change in ECV between the ARNI and control groups (0.3±5.1% vs. 1.2±4.1%, respectively; P=0.461), whereas the change in extracellular mass was greater in the ARNI group (P=0.025). ARNI reduced LV volume and mass, resulting from decreases in both extra- and intracellular mass, without changing ECV. This suggests ARNI has potential to improve LV tissue characteristics in HF patients with LVEF <50%.

Purpose: In-hospital improvement of left ventricular (LV) systolic function is frequently observed in acute decompensated heart failure (ADHF) patients presented with high systolic blood pressure (SBP) on admission. However, determinants of improved LV systolic function in patients with ADHF remain unclear. Methods: We examined 214 consecutive patients admitted by ADHF with SBP > 140 mmHg, impaired LV systolic function, defined as LV ejection fraction (EF) < 50% or fractional shortning < 26%, but no acute coronary syndrome. Patients were divided into 2 groups according to the presence or absence of improved LV systolic function, defined as normalized predischarge LV systolic function. Results: Improved LV systolic function was observed in 54 patients and length of hospital stay was comparable between two groups. Patients with improved LV systolic function had lower BNP level, smaller LV systolic and diastolic diameters at admission, higher baseline and % increase of LV systolic function than those without. ROC curves showed that smaller LV systolic diameter (LVSD) at admission was superior to other variables for predicting improved LV systolic function (AUC: 0.80) (Figure). Multivariate logistic regression analysis showed that smaller LVSD (<46mm) was the strongest independent determinant for improvement of LV systolic function (OR: 6.51, 95% CI: 1.60-26.34, p=0.0086) among variables including lower BNP level (OR: 2.09, 95% CI: 1.01-4.30), no history of coronary artery disease (OR: 2.37, 95% CI: 1.12-5.01), and LV diastolic diameter at admission (p = 0.98). ![Figure][1] Figure 1 Conclusions: Smaller LVSD at admission was the strongest determinant for in-hospital improvement of LV systolic function in patients with ADHF with high blood pressure and impaired LV systolic function. [1]: pending:yes

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Is the measurement of left ventricular ejection fraction the proper end point for cell therapy trials? An analysis of the effect of bone marrow mononuclear stem cell administration on left ventricular ejection fraction after ST-segment elevation myocardial infarction when evaluated by cardiac magnetic resonance imaging

Abstract #4102 Background&amp;#x2028; Dose-Dense (dd) doxorubicin-cyclophosphamide (AC)-paclitaxel (P) is superior to q3w AC-P. Both are associated with a &amp;lt;1% incidence of congestive heart failure (CHF). The advent of targeted therapies potentially raises the risks of cardiac toxicity. We have, therefore, conducted 3 sequential safety studies using ddAC → P, one of which included bevacizumab (B) concurrently with ddAC. Here we report the cardiac safety of ddAC alone or with B.&amp;#x2028; Methods&amp;#x2028; Patients with HER2-positive breast cancer were treated on successive trials of ddAC → P and trastuzumab (T) (left ventricular ejection fraction (LVEF) &amp;gt; 55%) and ddAC → PT-lapatinib (LVEF &amp;gt; 50%). Patients with HER2-normal breast cancer were treated with B-ddAC → B-nanoparticle albumin-bound-P (LVEF &amp;gt; 50%). In all 3 trials LVEF was measured by MUGA scan at enrolment and at month 2 following completion of ddAC x 4. Prospective cardiac safety assessments before and after q 2 week AC x 4 were aggregated to determine the acute risks of cardiac dysfunction.&amp;#x2028; Results&amp;#x2028; From Jan '05 to May '08 236 pts were enrolled in 3 trials. Median age was 47yrs (range 27-75). Median LVEF pre-ddAC was 68% (range 52-82%). LVEF post-ddAC is available in 233 pts (99%) (1 pt withdrew consent, 1 progressive disease, 1 died from viral pneumonia). Median LVEF was unchanged at 68% (range 47-81%). No pt developed symptomatic CHF. Two pts had asymptomatic LVEF decline &amp;gt;15%: 1 pt (post B-ddAC) had decline from 71 to 53%, which improved to 64% in 4 wks and 1 pt (post ddAC) had decline 68% to 47%, which improved to 64% in 4 wks. No other pt had asymptomatic LVEF decline below 50%. Five of six pts with LVEF declines of 10-15% had improvement in LVEFs and continued treatment while 1 withdrew consent. Post-ddAC LVEF was similar whether or not pts received B.&amp;#x2028; &amp;#x2028; Conclusions&amp;#x2028; Previously reported high rates of asymptomatic LVEF post q3w AC leading to pt dropout were not seen in these studies of ddAC or B-ddAC. Post-ddAC LVEFs were similar with or without concurrent bevacizumab. Dose-dense AC is safe and not associated with frequent acute changes in LVEF regardless of the concurrent use of B. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4102.

BackgroundAdenosine or regadenoson vasodilator stress cardiovascular magnetic resonance (CMR) is an effective non-invasive strategy for evaluating symptomatic coronary artery disease. Vasodilator injection typically precedes ventricular functional sequences to efficiently reduce overall scanning times, though the effects of vasodilators on CMR-derived ventricular volumes and function are unknown.MethodsWe prospectively enrolled 25 healthy subjects to undergo consecutive adenosine and regadenoson administration. Short axis CINE datasets were obtained on a 1.5 T scanner following adenosine (140mcg/kg/min IV for 6 min) and regadenoson (0.4 mg IV over 10 s) at baseline, immediately following administration, at 5 min intervals up to 15 min. Hemodynamic response, bi-ventricular volumes and ejection fractions were determined at each time point.ResultsPeak heart rate was observed early following administration of both adenosine and regadenoson. Heart rate returned to baseline by 10 min post-adenosine while remaining elevated at 15 min post-regadenoson (p = 0.0015). Left ventricular (LV) ejection fraction (LVEF) increased immediately following both vasodilators (p < 0.0001 for both) and returned to baseline following adenosine by 10 min (p = 0.8397). Conversely, LVEF following regadenoson remained increased at 10 min (p = 0.003) and 15 min (p = 0.0015) with a mean LVEF increase at 15 min of 4.2 ± 1.3%. Regadenoson resulted in a similar magnitude reduction in both LV end-diastolic volume index (LVEDVi) and LV end-systolic volume index (LVESVi) at 15 min whereas LVESVi resolved at 15 min following adenosine and LVEDVi remained below baseline values (p = 0.52).ConclusionsRegadenoson and adenosine have significant and prolonged impact on ventricular volumes and LVEF. In patients undergoing vasodilator stress CMR where ventricular volumes and LVEF are critical components to patient care, ventricular functional sequences should be performed prior to vasodilator use or consider the use of aminophylline in the setting of regadenoson. Additionally, heart rate resolution itself is not an effective surrogate for return of ventricular volumes and LVEF to baseline.

Cardiac magnetic resonance (CMR) has been recognized as the gold standard for the evaluation of left ventricular (LV) function. Cardiac gated PET allows the simultaneous assessment of LV function with the evaluation of myocardial perfusion and metabolism. But the correlations between PET and CMR remain controversial. We conducted a systematic electronic search of PubMed, Embase and the Cochrane Library . Forest plot, spearman correlation analysis and Bland-Altman analysis were used to evaluate the correlations between PET and CMR. Pooled analysis of 13 studies showed that PET underestimated left ventricular end-diastolic volumes (LVEDV) [mean difference (MD), -15.30; 95% confidence interval (CI), -23.10 to -7.50; P < 0.001] and left ventricular end-systolic volumes (LVESV) (MD, -6.20; 95% CI, -12.58 to 0.17; P = 0.06) but not left ventricular ejection fraction (LVEF) (MD, -0.35; 95% CI, -1.75 to 1.06; P = 0.63). Overall, there were very good correlations between PET and CMR measurements for LVEDV ( r , 0.897), LVESV ( r , 0.924) and LVEF ( r , 0.898). Subgroup analysis indicated that LVEDV ≥180 ml and LVEF <40% reduced the accuracy of PET, especially the measurement of LVEF ( r , LVEDV ≥180 vs . r , LVEDV < 180 : 0.821 vs. 0.944; r , LVEF < 40% vs . r , LVEF ≥40% : 0.784 vs. 0.901). Correlations between PET and CMR measurements of LVEDV, LVESV and LVEF were excellent, but these two methods could not be used interchangeably for accurate measurements of LV volume and LVEF in patients with significantly increased LV volume and decreased LVEF.

There is an important need for better biomarkers to predict left ventricular (LV) remodelling in dilated cardiomyopathy (DCM). We undertook a comprehensive assessment of cardiac structure and myocardial composition to determine predictors of remodelling. Prospective study of patients with recent-onset DCM with cardiovascular magnetic resonance (CMR) assessment of ventricular structure and function, extracellular volume (T1 mapping), myocardial strain, myocardial scar (late gadolinium enhancement) and contractile reserve (dobutamine stress). Regression analyses were used to evaluate predictors of change in LV ejection fraction (LVEF) over 12 months. We evaluated 56 participants (34 DCM patients, median LVEF 43%; 22 controls). Absolute LV contractile reserve predicted change in LVEF (1% increase associated with 0.4% increase in LVEF at 12 months, P=0.02). Baseline myocardial strain (P=0.39 global longitudinal strain), interstitial myocardial fibrosis (P=0.41), replacement myocardial fibrosis (P=0.25), and right ventricular contractile reserve (P=0.17) were not associated with LV reverse remodelling. There was a poor correlation between contractile reserve and either LV extracellular volume fraction (r=-0.22, P=0.23) or baseline LVEF (r=0.07, P=0.62). Men were more likely to experience adverse LV remodelling (P=0.01) but age (P=0.88) and disease-modifying heart failure medication (beta-blocker, P=0.28; angiotensin-converting enzyme inhibitor, P=0.92) did not predict follow-up LVEF. Substantial recovery of LV function occurs within 12 months in most patients with recent-onset DCM. Women had the greatest improvement in LVEF. A low LV contractile reserve measured by dobutamine stress CMR appears to identify patients whose LVEF is less likely to recover.

To study how sepsis affects hemodynamic responses to catecholamines and fluids, either Escherichia coli-infected (septic, n = 8) or sterile (controls, n = 6) fibrin clots were implanted intraperitoneally into 2-yr-old beagles. Hemodynamics were measured at each of four doses of dopamine (0, 5, 10, and 20 micrograms.kg-1.min-1) and norepinephrine (0, 10, 20, and 40 micrograms.min-1), before and after infusion of fluid (Ringer 40 ml.kg-1). Septic animals had lower mean arterial pressure (MAP, P = 0.04), stroke volume index (SVI, P = 0.0001), and left ventricular (LV) ejection fraction (LVEF) (P = 0.0001) than controls. During this time, increasing doses of dopamine and norepinephrine produced corresponding increases (P < 0.001) in LVEF, SVI, and MAP. However, during sepsis, the ability of dopamine to increase MAP diminished, while its ability to increase LVEF and SVI was maintained. Conversely, the ability of norepinephrine to increase LVEF and SVI diminished, but its ability to increase MAP was maintained. During sepsis, fluids alone increased (P < 0.05) MAP, LVEF, SVI, and cardiac index (CI). Fluids with catecholamines also significantly increased (P < 0.05) MAP with only minimal increases in LVEF, SVI, and CI. These data demonstrate that during sepsis without catecholamines, fluids improve cardiac performance and systemic pressures, but with catecholamines, fluids have minimal effects on cardiac performance and augment MAP. Furthermore, during sepsis dopamine is more effective than norepinephrine in increasing LV performance, but norepinephrine is more effective than dopamine in increasing systemic pressures.

Transthyretin amyloid cardiomyopathy (ATTR-CM) has a specific pathophysiology, with myocardial stiffening and systolic dysfunction only in advanced stages. We aimed to investigate the response to cardiac resynchronization therapy (CRT) in ATTR-CM compared with heart failure. In this multicenter, observational study, patients with ATTR-CM receiving CRT (n=101) were matched to patients without amyloid cardiomyopathy by sex, age, and implantation type (CRT with versus without defibrillator versus conduction system pacing, upgrade versus first implant). We evaluated changes in QRS duration and echocardiographic parameters following CRT implantation and at the most recent available assessments. The study end points were all-cause death alone or combined with heart failure hospitalization. Patients with ATTR-CM (median age, 76 [interquartile range, 72-83] years, 98% men, left ventricular (LV) ejection fraction 30% [26-33]) showed greater QRS shortening after CRT implantation (P=0.012), but not after a median of around 1 year (P=0.152). There were no significant differences in the absolute LV ejection fraction changes immediately after implantation (+7 [+2/+10] versus +3 [0/+9] units; P=0.124), or to the last echo (P=0.796), which was performed after 1.3 years in patients with ATTR-CM and 2.9 years in patients without amyloid cardiomyopathy. Patients with ATTR-CM had a shorter survival than controls (P<0.001 for both end points). Patients with ATTR-CM experiencing an early improvement in LV ejection fraction had a longer survival (log-rank, 4.3; P=0.038). Following CRT implantation, patients with ATTR-CM show QRS narrowing and improvement in LV ejection fraction, not different from patients without amyloid cardiomyopathy. Early favorable LV remodeling seems to be associated with a lower risk of all-cause death.

Introduction: Interleukin-33 (IL-33) is a potent mediator of injury-induced local inflammation. Soluble ST2 (sST2), a decoy receptor of IL-33, is a prognostic serum biomarker for heart failure (HF). Here, we evaluated the impact of tozorakimab, an IL-33-neutralizing monoclonal antibody, on sST2-related secondary cardiac endpoints. Methods: FRONTIER-1 was a 24-week phase 2B study (NCT04170543) in patients with diabetic kidney disease (DKD). Key cardiac exclusion criteria were: 1) NYHA Class 3/4; 2) Left ventricular ejection fraction (LVEF) &lt; 40%; 3) B-type natriuretic peptide (BNP) &gt; 200 pg/mL. Local echocardiography (LVEF) was performed at Screening and Week 24. For exploratory analysis, echocardiography recordings were evaluated by a core laboratory. Throughout the study, BNP and sST2 were assessed and adverse events (AE) recorded. Safety and tolerability were evaluated for all dosed participants (Safety Analysis Population, SAP). Results: 573 participants were included in the SAP (139 = placebo / 434 = tozorakimab). Baseline characteristics were balanced across treatment groups. Tozorakimab was generally well tolerated and the incidences of AE, serious AE (SAEs), discontinuations, and death were similar to placebo. In the placebo group, cardiac disorder AE were reported in 6.5%, and SAE in 2.2%. Decline in LVEF of &gt; 10% was seen in 5 participants (4.3%). None developed BNP &gt; 200 pg/mL or clinical signs of HF. 1 participant (0.7%) presented with clinical symptoms of HF (SAE) without significant changes in LVEF or BNP. On tozorakimab, cardiac disorder AE/SAE were less frequent (3.7%/1.8%). Decline in LVEF of &gt; 10% was observed in 31 participants (8.3%), with 3 showing BNP elevation to 200–308 pg/mL. Two of these participants (0.5%) developed clinical signs of HF with LVEF 55%/30% and BNP &lt; 200 pg/mL. No further AE related to HF were reported for tozorakimab. Central analysis of LVEF revealed a substantial variability of site-based measurements indicating LVEF reductions &gt; 10 % in 2 (3.7%) participants on placebo and 6 (2.9%) on tozorakimab. Furthermore, central exploratory analysis demonstrated a slight increase in LVEF from baseline (1.62%, 95% CI: 0.22, 3.03) and a reduction in average E/e' (-0.47, 95% CI: -0.93, -0.01) for tozorakimab, but not placebo. Trends in BNP and sST2 over time were comparable. Conclusion: This study suggests a favorable cardiac safety profile for tozorakimab in patients with DKD. IL-33 inhibition did not elevate serum sST2 significantly.

Comparison of ambulatory left ventricular ejection fraction and blood pressure in systemic hypertension in patients with and without increased left ventricular mass

The purpose of this study was to determine the impact of the left ventricular (LV) segmental wall motion abnormalities detected by equilibrium radionuclide angiography (ERNA) on the improvement in LV and right ventricular (RV) function during biventricular (BIV) stimulation. We studied 28 patients in NYHA functional classes III or IV and QRS duration > 150 ms on resting electrocardiogram. ERNA was performed before and during BIV stimulation at a 6-month follow-up. A significant shortening of QRS duration was observed during BIV stimulation (165 +/- 5 ms before vs 133 +/- 6 ms during, P < 0.01). Wall motion abnormalities (WMA) were observed in 16 patients (10 with nonischemic cardiomyopathies). In this group, LV and RV ejection fractions (EF) did not increase during BIV stimulation (LVEF = 22 +/- 2% vs 20 +/- 1.6%, ns; RVEF = 34 +/- 3% vs 37 +/- 3.8%, ns). Significant increases in RVEF (23 +/- 3.2% --> 38 +/- 2.9%, P = 0.001) and LVEF (20 +/- 2.5% --> 30 +/- 3%, P = 0.01) were observed in the group of patients without segmental WMA and with global hypokinesia (GH). In this group, a significant decrease in the dispersion in the phase of RV contraction was observed (SD = 39 +/- 5 vs 26 +/- 2 ms; P < 0.01). WMA predicted an increase in LVEF, in contrast to a baseline 6-minute-walk test, maximal oxygen consumption and LVEF, or amount of QRS shortening. BIV stimulation increased in LV and RV EF in patients with ventricular dyssynchrony in absence of segmental WMA. ERNA was reliable in the selection of candidates for CRT.