A probabilistic decision support tool for prediction and management of rainfall-related poor water quality events for a drinking water treatment plant.

A data-driven Bayesian Network (BN) model was developed for a large Australian drinking water treatment plant, whose raw water comes from a river into which a number of upstream dams outflow water and smaller tributaries flow. During wet weather events, the spatial distribution of rainfall has a crucial role on the incoming raw water quality, as runoff from specific sub-catchments usually causes significant turbidity and conductivity issues, as opposed to larger dam outflows which have typically better water quality. The BN relies on a conceptual model developed following expert consultation, as well as a combination of different types (e.g. water quality, flow, rainfall) and amount (e.g. high-frequency, daily, scarce depending on variable) of historical data. The validated model proved to have acceptable accuracy in predicting the probability of different incoming raw water quality ranges, and can be used to assess different scenarios (e.g. timing, flow) of dam water releases, for the purpose of achieving dilution of the tributary's poor-quality water and mitigate related drinking water treatment challenges.

Chlorophyll and phycocyanin in-situ fluorescence in mixed cyanobacterial species assemblages: Effects of morphology, cell size and growth phase.

Cyanobacteria harmful blooms can represent a major risk for public health due to potential release of toxins and other noxious compounds in the water. A continuous and high-resolution monitoring of the cyanobacteria population is required due to their rapid dynamics, which has been increasingly done using in-situ fluorescence of phycocyanin (f-PC) and chlorophyll a (f-Chl a). Appropriate in-situ fluorometers calibration is essential because f-PC and f-Chl a are affected by biotic and abiotic factors, including species composition. Measurement of f-PC and f-Chl a in mixed species assemblages during different growth phases - representative of most field conditions - has received little attention. We hypothesized that f-PC and f-Chl a of mixed assemblages of cyanobacteria may be accurately estimated if taxa composition and fluorescence characteristics are known. We also hypothesized that species with different morphologies would have different fluorescence per unit cell and biomass. We tested these hypotheses in a controlled culture experiment in which photosynthetic pigment fluorescence, chemical pigment extraction, optical density and microscopic enumeration of four common cyanobacteria species (Aphanocapsa sp, Microcystis aeruginosa, Dolichospermum circinale and Raphidiopsis raciborskii) were quantified. Both monocultures and mixed cultures were monitored from exponential to late stationary growth phases. The sum of fluorescence of individual species calculated for mixed samples was not significantly different than measured fluorescence of mixed cultures. Estimated and measured f-PC and f-Chl a of mixed cultures had higher correlations and smaller absolute median errors when estimations were based on fluorescence per biomass instead of fluorescence per cell. Largest errors were overestimations of measured fluorescence for species with different morphologies. Fluorescence per cell was significantly different among most species, while fluorescence per unit biomass was not, indicating that conversion of fluorescence to biomass reduces species-specific bias. This study presents new information on the effect of species composition on cyanobacteria fluorescence. Best practices of deployment and operation of fluorometers, and data-driven models supporting in-situ fluorometers calibration are discussed as suitable solutions to minimize taxa-specific bias in fluorescence estimates.

Light-induced fluorescence quenching leads to errors in sensor measurements of phytoplankton chlorophyll and phycocyanin.

Optical sensors for fluorescence of chlorophyll a (f-Chl a) and phycocyanin (f-PC) are increasingly used as a proxy for biomass of algae and cyanobacteria, respectively. They provide measurements at high-frequency and modest cost. These sensors require site-specific calibration due to a range of interferences. Light intensity affects the fluorescence yield of cyanobacteria and algae through light harvesting regulation mechanisms, but is often neglected as a potential source of error for in-situ f-Chl a and f-PC measurements. We hypothesised that diel light variations would induce significant f-Chl a and f-PC suppression when compared to dark periods. We tested this hypothesis in a controlled experiment using three commercial fluorescence probes which continuously measured f-Chl a and f-PC from a culture of the cyanobacterium Dolichospermum variabilis as well as f-Chl a from a culture of the green alga Ankistrodesmus gracilis in a simulated natural light regime. Under light, all devices showed a significant (p<0.01) suppression of f-Chl a and f-PC compared to measurements in the dark. f-Chl a decreased by up to 79% and f-PC by up to 59% at maximum irradiance compared to dark-adapted periods. Suppression levels were higher during the second phase of the diel cycle (declining light), indicating that quenching is dependent on previous light exposure. Diel variations in light intensity must be considered as a significant source of bias for fluorescence probes used for algal monitoring. This is of high relevance as most monitoring activities take place during daytime and hence f-Chl a and f-PC are likely to be systematically underestimated under bright conditions. Compensation models, design modifications to fluorometers and sampling design are discussed as suitable alternatives to overcome light-induced fluorescence quenching.

A systematic literature review of forecasting and predictive models for cyanobacteria blooms in freshwater lakes.

Cyanobacteria harmful blooms (CyanoHABs) in lakes and reservoirs represent a major risk for water authorities globally due to their toxicity and economic impacts. Anticipating bloom occurrence and understanding the main drivers of CyanoHABs are needed to optimize water resources management. An extensive review of the application of CyanoHABs forecasting and predictive models was performed, and a summary of the current state of knowledge, limitations and research opportunities on this topic is provided through analysis of case studies. Two modelling approaches were used to achieve CyanoHABs anticipation; process-based (PB) and data-driven (DD) models. The objective of the model was a determining factor for the choice of modelling approach. PB models were more frequently used to predict future scenarios whereas DD models were employed for short-term forecasts. Each modelling approach presented multiple variations that may be applied for more specific, targeted purposes. Most models reviewed were site-specific. The monitoring methodologies, including data frequency, uncertainty and precision, were identified as a major limitation to improve model performance. A lack of standardization of both model output and performance metrics was observed. CyanoHAB modelling is an interdisciplinary topic and communication between disciplines should be improved to facilitate model comparisons. These shortcomings can hinder the adoption of modelling tools by practitioners. We suggest that water managers should focus on generalising models for lakes with similar characteristics and where possible use high frequency monitoring for model development and validation.

Cardiac contractility modulation improves long-term survival and hospitalizations in heart failure with reduced ejection fraction.

AIMS: Cardiac contractility modulation (CCM) improves symptoms and exercise tolerance and reduces heart failure (HF) hospitalizations over 6-month follow-up in patients with New York Heart Association (NYHA) class III or IV symptoms, QRS < 130 ms and 25% ≤ left ventricular ejection fraction (LVEF) ≤ 45% (FIX-HF-5C study). The current prospective registry study (CCM-REG) aimed to assess the longer-term impact of CCM on hospitalizations and mortality in real-world experience in this same population. METHODS AND RESULTS: A total of 140 patients with 25% ≤ LVEF ≤ 45% receiving CCM therapy (CCM-REG25-45 ) for clinical indications were included. Cardiovascular and HF hospitalizations, Minnesota Living with Heart Failure Questionnaire (MLHFQ) and NYHA class were assessed over 2 years. Mortality was tracked through 3 years and compared with predictions by the Seattle Heart Failure Model (SHFM). A separate analysis was performed on patients with 35% ≤ LVEF ≤ 45% (CCM-REG35-45 ) and 25% ≤ LVEF < 35% (CCM-REG25-34 ). Hospitalizations decreased by 75% (from 1.2/patient-year the year before, to 0.35/patient-year during the 2 years following CCM, P < 0.0001) in CCM-REG25-45 and by a similar amount in CCM-REG35-45 (P < 0.0001) and CCM-REG25-34 . MLHFQ and NYHA class improved in all three cohorts, with progressive improvements over time (P < 0.002). Three-year survival in CCM-REG25-45 (82.8%) and CCM-REG24-34 (79.4%) were similar to those predicted by SHFM (76.7%, P = 0.16; 78.0%, P = 0.81, respectively) and was better than predicted in CCM-REG35-45 (88.0% vs. 74.7%, P = 0.046). CONCLUSION: In real-world experience, CCM produces results similar to those of previous studies in subjects with 25% ≤ LVEF ≤ 45% and QRS < 130 ms; cardiovascular and HF hospitalizations are reduced and MLHFQ and NYHA class are improved. Overall mortality was comparable to that predicted by the SHFM but was lower than predicted in patients with 35% ≤ LVEF ≤ 45%.

Cardiac contractility modulation treatment in patients with symptomatic heart failure despite optimal medical therapy and cardiac resynchronization therapy (CRT).

BACKGROUND: A significant proportion of patients receiving CRT are non-responders. We evaluated the efficacy of Cardiac Contractility Modulation in subjects with reduced LVEF who, despite cardiac resynchronization therapy (CRT), continued to experience clinically significant symptoms. METHODS: This was a multi-center, open label, treatment-only, feasibility study of 17 CRT non-responders who received CCM therapy. Changes in NYHA class, ejection fraction (EF), Minnesota Living with Heart Failure Questionnaire (MLWHFQ) score, and exercise tolerance (6 minute walk test; 6MWT and peak VO2) were analyzed over 6 months. Mortality and hospitalization rates were determined. RESULTS: Patients (82% male) were 69.4 ±â€¯9.6 years of age with baseline EF = 22.8 ±â€¯6.5%. Among primary endpoints, peak VO2 increased 1.1 ±â€¯1.6 ml/kg/min (p = 0.03) and MLWHFQ improved (-16 ±â€¯16 points; p < 0.01). Mean NYHA class improved (-0.33 ±â€¯0.49; p = 0.02), 6MWT increased (52 ±â€¯60 m; p < 0.01), while EF trended up (2.9 ±â€¯5.8%; p = 0.08) at 6 months. During the 6-month follow-up period, there were 18 hospitalizations in 9 subjects and 2 patients died. CONCLUSIONS: Patients with heart failure and reduced ejection fraction who remain moderately to severely symptomatic despite use of CRT, may benefit from CCM therapy with improvement in quality of life and exercise tolerance. A larger prospective study in this population is warranted.

Cardiac Contractility Modulation: A Technical Guide for Device Implantation.

This article provides a technical description of common implant practice for delivery of cardiac contractility modulation (CCM) therapy to heart failure patients. As of September 2016, the authors of this article collectively have been involved with more than 400 system implantations in five medical centers, beginning with the advent of CCM therapy approximately 12 years ago. CCM therapy has been evaluated in a variety of studies, and was shown to be safe and effective and of benefit to patient quality of life and exercise capacity. As the use of CCM therapy continuously expands among medical centers in Europe, this article describes the technical and practical aspects of the implant procedure, and additional special technical cases based on our cumulative experience.

Cardiac contractility modulation in heart failure patients: Randomized comparison of signal delivery through one vs. two ventricular leads.

BACKGROUND: Cardiac contractility modulation (CCM) is an electrical stimulation treatment for symptomatic heart failure (HF) patients. The procedure involves implantation of two ventricular leads for delivery of CCM impulses. The purpose of this study is to compare the efficacy and safety of CCM when the signal is delivered through one vs. two ventricular leads. METHODS: This prospective blinded randomized trial enrolled 48 patients. Eligible subjects had symptoms despite optimal HF medications, left ventricular ejection fraction <40% and peakVO2≥9ml O2/kg/min. All patients received a CCM system with two ventricular leads, and were randomized to CCM active through both or just one ventricular lead; 25 patients were randomized to receive signal delivery through two leads (Group A) and 23 patients to signal delivery through one lead (Group B). The study compared the mean changes from baseline to 6 months follow-up in peakVO2, New York Heart Association (NYHA) classification, and quality of life (by MLWHFQ). RESULTS: Following 6 months, similar and significant (p<0.05) improvements from baseline in NYHA (-0.7±0.5 vs. -0.9±0.7) and MLWHFQ (-14±20 vs. -16±22) were observed in Group A and in Group B. PeakVO2 showed improvement trends in both groups (0.34±1.52 vs. 0.10±2.21ml/kg/min; p=ns). No patient died. Serious adverse event rates (20 events in 10 subjects) were not different between groups. No statistically significant difference was found in any of the study endpoints. CONCLUSIONS: The efficacy and safety of CCM in this study were similar when the signal was delivered through either one or two ventricular leads. These results support the potential use of a single ventricular lead for delivery of CCM.

Improvement of long-term survival by cardiac contractility modulation in heart failure patients: A case-control study.

INTRODUCTION: Cardiac contractility modulation (CCM) has been shown to be effective in improving symptoms and cardiac function in heart failure (HF). However, there is limited data on the role of CCM on long-term survival, which was explored in the present study. METHODOLOGY: Forty-one consecutive HF patients with left ventricular ejection fraction (EF) <40% received CCM and were followed for approximately 6 years. They were compared with another 41 HF patients who were enrolled into the HF registry in the same period, and had similar age, gender, EF and etiology of HF. The primary end-point was all cause-mortality. This was stratified by EF. Secondary end-points included HF hospitalization, cardiovascular death, and the composite outcome of death or heart failure hospitalization. RESULTS: The CCM and control groups were well balanced for demographic data, medications and baseline left ventricular EF (27 ± 6 vs 27 ± 7%, p=NS). The mean follow-up duration was 75 ± 19 months in the CCM group and 69 ± 17 months in the control group. All-cause mortality was lower in the CCM group than the control group (39% vs. 71%, respectively; Log-rank χ(2)=11.23, p=0.001). Of note, the improvement of all-cause mortality is more dramatic in patients with EF ≥ 25-40% (36% vs. 80%, Log-rank χ(2)=15.8, p<0.001) than those with EF<25% (50% vs. 56%, p=NS), CCM vs. control respectively. Similar results were shown for the benefit of CCM in the secondary endpoints of cardiovascular death, and the composite outcome of death or heart failure hospitalization. The occurrence of HF hospitalization showed no significant difference between CCM and control groups in the whole cohort (41% vs. 49%, p=NS), but was significantly lower with CCM in subjects with EF ≥ 25-40% at baseline (36% vs. 64%, Log-rank χ(2)=7.79, p=0.005). CONCLUSION: CCM resulted in significant improvement of long-term survival, in particular in those with EF ≥ 25-40%. A reduction in heart failure hospitalizations was also seen in this group of patients with less severely reduced EF.

A randomized comparison of 5 versus 12 hours per day of cardiac contractility modulation treatment for heart failure patients: A preliminary report.

BACKGROUND: Cardiac contractility modulation (CCM) signals are non-excitatory electrical signals delivered during the absolute refractory period intended to improve contraction and cardiac function. Clinical trials have shown that CCM treatment significantly improves exercise tolerance and quality of life in symptomatic heart failure patients. Studies with CCM therapy typically include CCM delivery for 3, 5 or 7 h per day, although other configurations are also commonly used. Each has been associated with improved outcomes in heart failure, but it is not clear whether different application durations are associated with the various degrees of benefit. The purpose of the current pilot evaluation study was to evaluate the quality of life, exercise tolerance, and cardiac function, over a 6-month period when CCM was delivered for 5 h/day vs. 12 h/day. Increasing the daily CCM therapy duration is safe and as good as the standard CCM periods of application per day. METHODS: This single center pilot evaluation study involved 19 medically refractory symptomatic patients with heart failure and reduced left ventricular function who underwent implantation of an Optimizer™ system (Impulse Dynamics, Orangeburg, NY, USA). Patients were randomized into one of two treatment groups; 5 h/day CCM treatment or 12 h/day CCM treatment. Subjects and evaluating physicians were blinded to the study group. Subjects returned to the hospital after 12 and 24 weeks. Efficacy evaluations included changes from baseline to 24 weeks in Minnesota Living With Heart Failure Questionnaire score (MLWHFQ), maximal oxygen consumption in the cardio-pulmonary stress test (peak VO2), New York Heart Association classification (NYHA), 6-min walk distance (6MWD), and ejection fraction (EF). RESULTS: At the end of 24 weeks, clinical improvement was observed in the entire cohort in all efficacy measures (mean change from baseline of -17.1 in MLWHFQ, -0.86 in NYHA, and improvement trend of 1.48 mL O2/kg/min in peak VO2, 31.3 m in 6MWD, and 2.25% in EF). There were no significant differences, either clinically or statistically, between the groups receiving CCM for 5 h/day vs. 12 h/day. Three subjects were voluntarily withdrawn before completing the study. One subject died from pneumonia after 125 days, and 6 serious adverse events were reported, none of which was classified as related to either the device or the procedure. CONCLUSIONS: Together with previously reported experience with CCM, delivery of CCM therapy is equally safe and appears similarly effective over the range of shorter (5 h) to longer (12 h) daily periods of application. Given the small sample size, further studies are warranted.

Efficacy and survival in patients with cardiac contractility modulation: long-term single center experience in 81 patients.

AIMS: To analyze long-term efficacy and survival in patients with chronic heart failure treated with cardiac contractility modulation. METHODS: 81 patients implanted with a CCM device between 2004 and 2012 were included in this retrospective analysis. Changes in NYHA class, ejection fraction (EF), Minnesota Living with Heart Failure Questionnaire, NT-proBNP and peak VO2 were analyzed during a mean follow up of 34.2 ± 28 months (6-123 months). Observed mortality rate was compared with that predicted by the MAGGIC Score. RESULTS: Patients were 61 ± 12 years old with EF 23 ± 7%. Heart failure was due to ischemic (n=48, 59.3%) or idiopathic dilated (n=33, 40.7%) cardiomyopathy. EF increased from 23.1 ± 7.9 to 29.4 ± 8.6% (p<0.05), mean NT-proBNP decreased from 4395 ± 3818 to 2762 ± 3490 ng/l (p<0.05) and mean peak VO2 increased from 13.9 ± 3.3 to 14.6 ± 3.5 ml/kg/min (p=0.1). The overall clinical responder rate (at least 1 class improvement of NYHA within 6 months or last follow-up) was 74.1%. 21 (25.9%) patients died during follow up, 11 (52.4%) due to cardiac conditions and 10 (47.6%) due to non-cardiac conditions. Mortality rates at 1 and 3 years were 5.2% and 29.5% compared to mortality rates estimated from the MAGGIC risk score of 18.4% (p<0.001) and 40% (p=ns), respectively. Log-Rank analysis of all events through 3 years of follow-up, however, was significantly less than predicted (p=0.022). CONCLUSIONS: CCM therapy improved quality of life, exercise capacity, NYHA class, EF and NT-proBNP levels during long-term follow up. Mortality rates appeared to be lower than estimated from the MAGGIC score.

Long term impact of cardiac contractility modulation on QRS duration.

BACKGROUND AND PURPOSE: Cardiac contractility modulation (CCM) is an implantable device treatment for heart failure with reduced ejection fraction. CCM therapy improves patient functional status but its effect on intra-ventricular conduction remains unknown. METHODS: 70 patients treated with CCM between 12/2002 and 5/2013 had 12-vector-ECG recordings made at baseline and final follow-up visits. QRS complex duration was measured at each time point. RESULTS: Mean follow-up was 2.8 years. Mean QRS duration was unchanged from baseline (112.0 ms) to last follow up (112.9 ms, p=n.s.). These results are strikingly different from comparative published data of several studies with heart failure patients without CCM, consistently indicating an increase in QRS duration (6.0-23.4 ms) over a similar time period. CONCLUSIONS: CCM prevents chronic ventricular depolarization delay that occurs in heart failure and that is associated with poorer outcomes. This supports the safety of long-term CCM therapy and suggests a possible long-term benefit in maintaining QRS duration.

Cardiac contractility modulation electrical signals normalize activity, expression, and phosphorylation of the Na+-Ca2+ exchanger in heart failure.

BACKGROUND: Expression and phosphorylation of the cardiac Na(+)-Ca(2+) exchanger-1 (NCX-1) are up-regulated in heart failure (HF). We examined the effects of chronic cardiac contractility modulation (CCM) therapy on the expression and phosphorylation of NCX-1 and its regulators GATA-4 and FOG-2 in HF dogs. METHODS AND RESULTS: Studies were performed in LV tissue from 7 CCM-treated HF dogs, 7 untreated HF dogs, and 6 normal (NL) dogs. mRNA expression of NCX-1, GATA-4, and FOG-2 was measured using reverse transcriptase polymerase chain reaction, and protein level was determined by Western blotting. Phosphorylated NCX-1 (P-NCX) was determined using a phosphoprotein enrichment kit. Compared with NL dogs, NCX-1 mRNA and protein expression and GATA-4 mRNA and protein expression increased in untreated HF dogs, whereas FOG-2 expression decreased. Compared with NL dogs, the level of P-NCX-1 normalized to total NCX-1 increased in untreated HF dogs (0.80+/-0.10 vs 0.37+/-0.04; P < .05). CCM therapy normalized NCX-1 expression, GATA-4, and FOG-2 expression, and the ratio of P-NCX-1 to total NCX-1 (0.62+/-0.10). CONCLUSION: Chronic monotherapy with CCM restores expression and phosphorylation of NCX-1. These findings are consistent with previous observations of improved LV function and normalized sarcoplasmic reticulum calcium cycling in the left ventricles of HF dogs treated with CCM therapy.

Ca(2+)-binding proteins in dogs with heart failure: effects of cardiac contractility modulation electrical signals.

BACKGROUND: In dogs with heart failure (HF), chronic therapy with cardiac contractility modulation (CCM) electrical signals delivered to left ventricular (LV) muscle during the absolute refractory period improves LV function. This study examined the effects of CCM therapy on the expression of calcium (Ca(2+))-binding proteins (CBPs) in dogs with HF. METHODS AND RESULTS: Studies were performed in LV tissue from seven CCM-treated HF dogs, seven untreated HF dogs, and six normal (NL) dogs. mRNA expression of S100A1, sorcin, presenillin-1 (PS1), PS2, histidine-rich Ca(2+)-binding protein (HRC), and 18S ribosomal RNA (18S), a housekeeping gene, was measured using RT-PCR. Protein levels of CBPs and calsequestrin (CSQ) were determined by Western blotting. No difference was observed in the expression of 18S and CSQ among study groups. Compared with NL, the expression of S100A1, sorcin, and HRC was decreased, whereas the expression of PS2 was increased in untreated HF dogs. CCM therapy normalized the expression of S100A1, sorcin, and PS2 but not of HRC. No change was seen in the expression of PS1 among study groups. CONCLUSION: CCM therapy restores LV expression of S100A1, PS2, and sorcin. Normalization of CBPs may partly contribute to improved LV function in HF following CCM therapy.

Effects of chronic therapy with cardiac contractility modulation electrical signals on cytoskeletal proteins and matrix metalloproteinases in dogs with heart failure.

OBJECTIVES: Therapy with cardiac contractility modulation (CCM) electrical signals delivered to left ventricular (LV) muscle during the absolute refractory period improves LV systolic and diastolic function in dogs with heart failure (HF). This study examined the effects of CCM therapy on mRNA and protein expression of cytoskeletal proteins, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) in the LV myocardium of dogs with HF. METHODS: HF was produced in 14 dogs by coronary microembolizations. Dogs were randomized to 3 months of CCM therapy (n = 7) or to sham-operated controls (n = 7). LV tissue from 6 normal (NL) dogs was used for comparison. mRNA expression was measured using reverse-transcriptase polymerase chain reaction and protein expression using Western blots. RESULTS: Compared with NL dogs, controls showed upregulation of mRNA and protein expression of the cytoskeletal proteins tubulin and fibronectin and MMP-1, MMP-2 and MMP-9, and downregulation of the cytoskeletal protein titin. Normalized expression of all these genes and proteins was seen after CCM therapy. No differences in expression of TIMP-1 and TIMP-2 were observed among groups. CONCLUSIONS: CCM therapy normalizes expression of key cytoskeletal proteins and MMPs and may partly explain the improvement in LV function seen in HF following CCM therapy.

Therapy with cardiac contractility modulation electrical signals improves left ventricular function and remodeling in dogs with chronic heart failure.

OBJECTIVES: This study examined the effects of long-term delivery of cardiac contractility modulation (CCM) electric signals on left ventricular (LV) function and global, cellular, and molecular remodeling in dogs with chronic heart failure (HF). BACKGROUND: Acute studies in dogs with experimentally induced HF showed that CCM signals applied to the failing myocardium during the absolute refractory period improved LV function without increasing myocardial oxygen consumption. METHODS: In one study, dogs with intracoronary microembolization-induced HF were randomized to 3 months of active CCM monotherapy or to a sham-operated control group. In another study, 19 HF dogs were randomized to 3 months chronic monotherapy with extended release metoprolol succinate (MET-ER), MET-ER with CCM, or no therapy at all (control group). RESULTS: In CCM-only treated dogs, LV ejection fraction (EF) increased (27 +/- 1% vs. 33 +/- 1%, p < 0.0001) compared with a decrease in sham-operated control animals (27 +/- 1% vs. 23 +/- 1%, p < 0.001). The increase in EF seen with CCM-treated dogs was accompanied by reduced LV volumes, improved myocardial structure, reversal of the maladaptive fetal gene program, and an improvement in sarcoplasmic reticulum calcium cycling proteins. Dogs treated with a combination of MET-ER and CCM showed a greater increase in LV EF and a greater reversal of LV global, structural, and biochemical remodeling compared with dogs treated with MET-ER alone. CONCLUSIONS: In dogs with HF, long-term CCM therapy improves LV systolic function. The improvements are additive to those seen with beta-blockers. These findings are further strengthened by the concomitant benefits of CCM therapy on LV global, cellular, and biochemical remodeling.