Redfield, Margaret M.

Background : Dyssynchrony indexes derived from time to peak systolic velocity and time to peak strain have been reported to predict left ventricular reverse remodeling (RR) after cardiac resynchronization therapy (CRT). The predictive characteristics of these indices have not been validated in a variety of clinical settings. Our objective was to determine the predictive value of strain and tissue velocity derived dyssynchrony indices for RR or clinical response to CRT in a prospective single-center CRT registry. Methods : Prospective registry of all heart failure patients (pts) undergoing CRT with echo before and 3 and 6 months after CRT. Color -coded tissue Doppler imaging in 12 segments was used to calculate the standard deviation of time to peak strain (Tϵ-SD) and time to peak systolic velocity (Tv-SD). RR was defined as a decrease in end systolic volume (ESV; biplane Simpson’s method) ≥15%. Indices were assessed with receiver-operating characteristics (ROC) analysis and the area under the curve (AUC) calculated in all pts and excluding those with atrial fibrillation at implant. Results : To date, of the first 87 patients, 4 died (classified as non-responder); 83 pts had 3 and 59 pts had 6 month echocardiography follow-up. Tϵ-SD (93%) and Tv-SD (98%) were feasible in most pts. RR occurred in 42 pts (51%) at 3 month and 32 patients (54%) at 6 month follow-up. See table . Tϵ-SD was superior to Tv-SD for prediction of RR in all pts and in those without atrial fibrillation. Findings were similar regardless of ischemic (68% of patients) or non-ischemic etiology. Neither baseline Tϵ-SD nor Tv-SD correlated with the improvement in clinical response measured by the change in six minute walk distance or peak VO 2 at 3 or 6 month after CRT (data not shown). Conclusions : In this single center experience, mechanical dyssynchrony measured by strain imaging but not tissue velocity imaging was predictive of RR. Neither index predicted clinical response.

Background: Effect of CRT on the timing of regional myocardial strain is not fully described. We aimed to explore the effect of CRT on the timing of regional myocardial strain using speckle tracking echocardiography (STE). Methods: STE and tissue Doppler imaging were performed in 91 patients before and 6 month after CRT. Time to peak longitudinal strain (Tϵ) from the onset of QRS was measured in 16 segments from three apical views. Time to peak systolic tissue velocity (Tv) was also measured in 12 basal and mid segments. Reverse remodeling was defined as 10% reduction in end-systolic volume. Results: At baseline, Tϵ and Tv demonstrated specific pattern with earlier septal and delayed lateral contraction (Figure ). Tϵ in responders showed significantly earlier timing in mid inferoseptal (p=0.003) and anteroseptal segments (base, P=0.005, mid P=0.007) than in nonresponders, whereas the timing of free wall did not differ between responders and non-responders. After CRT, Tϵ in earlier segments (inferoseptal, anteroseptal and inferior wall) prolonged significantly (p<0.001), whereas other segments did not change timing. Accordingly, SD of Tϵ in 12 segments reduced after CRT (110±46 ms vs. 81±36 ms, p<0.001). Tv did not change in all segments and SD of Tv did not improve after CRT (43±16 vs. 46±16 ms, p=0.20). Conclusions: Simultaneous electrical activation of LV free wall and septum with CRT achieves mechanical synchronization by delaying the timing of earlier contracting segment rather than directly shortening the timing in lateral wall. This could be explained by the increased wall stress on the septum as it contracts simultaneously with the opposing LV free wall. Figure. Change in Regional Timing in Strain and Peak Velocity

Background: Cardiac resynchronization therapy (CRT) improves global systolic function in left ventricle. However, the impact of CRT on regional myocardial function is less clear. The aim of this study, therefore, is to evaluate regional changes in myocardial strain after CRT. Methods: Speckle tracking echocardiography (STE) was performed in 91 patients before and 6 month after CRT. Peak longitudinal strain was measured in 18 segments at base, mid and apex in three apical views. Left ventricular end-systolic volume (ESV) was measured by biplane Simpson’s method and reverse remodeling was defined as 10 % reduction in ESV at 6 month after CRT. Results: Peak strain improved in basal and mid segments of medial walls (basal inferoseptal, anteroseptal and inferior segments, p<0.05, mid inferoseptal and inferior segments: p<0.01) in entire group after CRT, with a greater degree of improvement in CRT responders than in nonresponders (Figure ). There was no significant improvement in free wall strain, with significant reduction in basal inferolateral segment after CRT (P=0.047) in entire group. Nonresponders had significant reduction in strain at the mid anterolateral segment (P=0.004) (Figure ). Strain of the apical segments also did not improve. Conclusions: CRT induces reverse remodeling by enhancing regional myocardial function in the septum, but suppresses the function in the free wall. Lack of reverse remodeling after CRT was characterized by the reduced function in lateral segments without improvement in septal function..

Background: Chronic renal insufficiency (CRI) is a strong predictor of increased mortality in the presence of heart failure (HF) and its prevalence has been increasing in the US. In addition, CRI is a major contributing factor to the progression of HF as it is associated with chronic volume overload, accelerated atherosclerosis and hypertension (HTN). The first aim of the current study was to evaluate the prevalence of CRI in an adult general population. The second aim was to address whether calculated glomerular filtration rate (cGFR) adds value to the cardiac biomarkers BNP and NT-proBNP in detecting early cardiac structural and functional impairments in the general population. Methods: From 1997 to 1999 medical history, physical examination, echocardiography, BNP (Biosite) and NT-proBNP (Roche) and serum creatinine (SCr) were obtained in 1,982 randomly selected residents of Olmsted County, MN >= 45 years (range 45 – 96 years). GFR was calculated using the Cockroft Gault equation. CRI was defined as a GFR < 60 ml/min. Cardiac structure and function were evaluated by in-depth echocardiographic examination. Results: The prevalence of cardiovascular co-morbidities was coronary atherosclerosis 12%, HTN 29.5% and diabetes mellitus 7.5%. The prevalence of CRI was 22.8% when cGFR was used for its detection. Importantly, by Chi-Square model, cGFR significantly increased the ability of BNP in detecting left ventricular hypertrophy (LVH) (p=0.004), increased relative wall thickness (p=0.0036), diastolic dysfunction (DDF) (p=0.0001) and HTN (p=0.0002). Similarly, when combined with NT-proBNP, cGFR increased the predictive power of detecting DDF (p=0.0001) and HTN (p=0.0366). Conclusion: This study reports a higher than predicted prevalence of CRI in this general US population equal to 23% and closely associated with the prevalence of HTN (29.5%). Importantly, this study also demonstrates that cGFR has additive predictive power when used in combination with two cardiac biomarkers of cardiac dysfunction and remodeling, BNP and NT-proBNP. These studies underscore the increasing burden of CRI in the general population and the utility of assessing cardiorenal function by combining renal and cardiac biomarkers in assessment of cardiac structure and function.

Introduction: Mortality among patients with heart failure (HF) is high. Though individual biomarkers have been studied to determine their value in risk prediction, the role of a multimarker strategy in predicting mortality above established risk indicators requires evaluation in a relevant cohort using robust analytical methods. Objective: To determine whether adding C-reactive protein (CRP), B-type natriuretic peptide (BNP), and troponin T (TnT) to established risk indicators improved HF mortality risk prediction. Methods: Olmsted County residents presenting with HF from July 2004 to September 2007 were prospectively recruited to undergo biomarker measurement. We investigated whether addition of CRP, BNP, and TnT to a model including established risk indicators improved 6-month mortality risk prediction using multiple methods ( c statistic, net reclassification index, integrated discrimination improvement). Results: Of 566 participants (mean age 77±13 years, 48% male), 87(15%) patients died after 6 months follow-up. Patients with CRP (<12.1mg/L), BNP (<341pg/mL), and TnT (≥0.01ng/mL) below the median (n=112) had the lowest mortality (3%), those with one or two biomarkers above the median had intermediate mortality, and those with all biomarkers above the median (n=105) had markedly increased 6-month mortality (33%). After adjustment for other predictors, higher CRP, BNP, and TnT were each associated with increased mortality, with odds ratios (95% confidence intervals) of 1.66(1.24 –2.24), 2.06(1.42–3.07), and 1.45(1.12–1.87), respectively. While adding CRP, BNP, and TnT individually to the model improved mortality risk prediction, the combination of two or more biomarkers offered greater incremental benefit. Using all biomarkers resulted in an increase in the c statistic from 0.747 to 0.832 (p<0.001), a net reclassification index of 0.33 (p<0.001), and a 100% relative improvement in risk discrimination (integrated discrimination improvement 0.097, p<0.001). Conclusions: The combined use of CRP, BNP, and TnT markedly improved the prediction of 6-month mortality in HF beyond established risk indicators. Implementation of a multimarker strategy including CRP, BNP, and TnT for risk prediction in HF should be considered. This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).

Background Patients with heart failure and preserved ejection fraction (HFpEF) have diastolic dysfunction, but are traditionally considered to have normal left ventricular (LV) systolic function. However, ventricular remodeling can result in preservation of EF despite abnormal myocardial contractility. Methods We performed echo-Doppler characterization of LV chamber and myocardial systolic properties in a population-based study, comparing patients with HFpEF (N=244) to healthy controls (CON, N=617), and hypertensives without HF (HTN, N=719), then examined long term outcome. Results All subjects had a normal EF (>50%). However, systolic chamber function, measured by wall stress-corrected endocardial fractional shortening (sc-eFS), was impaired in HFpEF (96±12%) compared to both CON (100±8%, p<0.0001) and HTN (108±11%, p<0.0001). Myocardial contractility, assessed by wall stress-corrected midwall shortening (sc-mFS), was also reduced in HFpEF (91±13%) compared to CON (100±10%, p<0.0001) and HTN (105±12%, p<0.0001). HTN had increased sc-eFS and sc-mFS compared with both HFpEF and CON (p<0.0001). In HFpEF, impaired sc-mFS was associated with increased mortality, independent of age (Figure ), while EF and sc- eFS were not. Conclusions Despite preservation of EF, unselected HFpEF patients from the community have significantly impaired systolic chamber function and depressed myocardial contractility. Abnormal myocardial contractility in HFpEF is associated with increased mortality. These data suggest that myocardial systolic dysfunction contributes to the pathophysiology of HFpEF and may represent a potential therapeutic target.

Introduction: Left atrial structure and function (LA) is affected by the presence of heart failure (HF), but the specific impact of HF subtype is poorly characterized. Hypothesis: HF-induced LA remodeling differs between patients with preserved (pEF) or reduced ejection fraction (rEF). Methods: 198 consecutive HF patients referred to Mayo Clinic (51% HFpEF, NYHA 3.1±0.7, 66±13 years, 39% females) and 40 HF-free controls of similar age and gender underwent right heart catheterization (LA pressures), echocardiography (LA volumes) and follow-up. Results: Compared with controls, HF patients had larger atria and more impaired LA reservoir and contractile function (total and active LAEF, all p<0.001). At identical mean LA pressure (20 vs 20 mmHg, p=0.9), HFrEF patients had larger LA volumes (LAVI 50 vs 41 ml/m 2 p<0.001), but HFpEF patients had higher LA peak (V-wave) and lower LA minimal pressures, with higher LA stiffness (0.79 vs 0.48 mmHg.ml -1 , p<0.001, Fig-A) and LA pressure pulsatility (19 vs 13 mmHg, p<0.001). Despite smaller LA size, better LA function (total LAEF 39 vs 35 %, p=0.04, active LAEF 30 vs 22 %, p<0.001) and less mitral regurgitation (grade 1.8 vs 2.5, p<0.001), HFpEF patients had more atrial fibrillation (42 vs 26%, p=0.02). After a median follow-up 350 days, 31 HFpEF and 28 HFrEF patients died. LA function was associated with mortality in HFpEF, but not in HFrEF (Fig-B). Conclusions: HFrEF is characterized by greater eccentric LA remodeling, but HFpEF is associated with increased LA stiffening and greater LA pressure pulsatility which may contribute to greater burden of atrial fibrillation. The observation that LA function is more closely linked to outcome in HFpEF supports the goal to maintain or improve LA function in HFpEF.

P46 While heart failure (HF), an emerging epidemic, complicates myocardial infarction (MI), little is known on the predictors of HF post-MI, in particular the impact of reperfusion therapy. This population-based study was undertaken to examine the association between clinical characteristics and post-MI HF between 1979 and 1994. Hospitalized incident MIs were validated using enzymes, chest pain, and Minnesota coding of the ECG. Framingham criteria were used to ascertain both in- and outpatient HF. Proportional hazard regression was used to identify predictors of CHF. In the study period, 1657 patients (pts.) (mean age 67.2 ± 13.9 years, 43% women) had an incident MI. History of diabetes, hypertension and prior HF was found in 19%, 54% and 11% of pts respectively. After 5 years, 43% of pts had experienced HF. Factors independently associated with HF were (see table). There was a 2% decline per year in occurrence of HF. Adding reperfusion therapy in the model attenuated the association between year and HF (adjusted RR for reperfusion 0.67, 95% CI 0.53, 0.84, p=0.006; adjusted for year 0.99; 95% CI 0.97, 1.01, p=0.37). Thus, while remaining frequent post-MI CHF has declined over time. Reperfusion therapy accounted for most of the effect of year. Table 1.

Background: Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with important regional differences. We investigated these differences in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF), the largest and most inclusive global HFpEF trial. Methods: We studied differences in clinical characteristics, outcomes, and treatment effects of sacubitril/valsartan in 4796 patients with HFpEF from the PARAGON-HF trial, grouped according to geographic region. Results: Regional differences in patient characteristics and comorbidities were observed: patients from Western Europe were oldest (mean 75±7 years) with the highest prevalence of atrial fibrillation/flutter (36%); Central/Eastern European patients were youngest (mean 71±8 years) with the highest prevalence of coronary artery disease (50%); North American patients had the highest prevalence of obesity (65%) and diabetes (49%); Latin American patients were younger (73±9 years) and had a high prevalence of obesity (53%); and Asia-Pacific patients had a high prevalence of diabetes (44%), despite a low prevalence of obesity (26%). Rates of the primary composite end point of total hospitalizations for HF and death from cardiovascular causes were lower in patients from Central Europe (9 per 100 patient-years) and highest in patients from North America (28 per 100 patient-years), which was primarily driven by a greater number of total hospitalizations for HF. The effect of treatment with sacubitril-valsartan was not modified by region (interaction P >0.05). Conclusions: Among patients with HFpEF recruited worldwide in PARAGON-HF, there were important regional differences in clinical characteristics and outcomes, which may have implications for the design of future clinical trials. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711.