Lifestyle Walking Intervention for Patients With Heart Failure With Reduced Ejection Fraction: The WATCHFUL Trial.

BACKGROUND: Physical activity is pivotal in managing heart failure with reduced ejection fraction, and walking integrated into daily life is an especially suitable form of physical activity. This study aimed to determine whether a 6-month lifestyle walking intervention combining self-monitoring and regular telephone counseling improves functional capacity assessed by the 6-minute walk test (6MWT) in patients with stable heart failure with reduced ejection fraction compared with usual care. METHODS: The WATCHFUL trial (Pedometer-Based Walking Intervention in Patients With Chronic Heart Failure With Reduced Ejection Fraction) was a 6-month multicenter, parallel-group randomized controlled trial recruiting patients with heart failure with reduced ejection fraction from 6 cardiovascular centers in the Czech Republic. Eligible participants were ≥18 years of age, had left ventricular ejection fraction <40%, and had New York Heart Association class II or III symptoms on guidelines-recommended medication. Individuals exceeding 450 meters on the baseline 6MWT were excluded. Patients in the intervention group were equipped with a Garmin vívofit activity tracker and received monthly telephone counseling from research nurses who encouraged them to use behavior change techniques such as self-monitoring, goal-setting, and action planning to increase their daily step count. The patients in the control group continued usual care. The primary outcome was the between-group difference in the distance walked during the 6MWT at 6 months. Secondary outcomes included daily step count and minutes of moderate to vigorous physical activity as measured by the hip-worn Actigraph wGT3X-BT accelerometer, NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity C-reactive protein biomarkers, ejection fraction, anthropometric measures, depression score, self-efficacy, quality of life, and survival risk score. The primary analysis was conducted by intention to treat. RESULTS: Of 218 screened patients, 202 were randomized (mean age, 65 years; 22.8% female; 90.6% New York Heart Association class II; median left ventricular ejection fraction, 32.5%; median 6MWT, 385 meters; average 5071 steps/day; average 10.9 minutes of moderate to vigorous physical activity per day). At 6 months, no between-group differences were detected in the 6MWT (mean 7.4 meters [95% CI, -8.0 to 22.7]; P=0.345, n=186). The intervention group increased their average daily step count by 1420 (95% CI, 749 to 2091) and daily minutes of moderate to vigorous physical activity by 8.2 (95% CI, 3.0 to 13.3) over the control group. No between-group differences were detected for any other secondary outcomes. CONCLUSIONS: Whereas the lifestyle intervention in patients with heart failure with reduced ejection fraction improved daily steps by about 25%, it failed to demonstrate a corresponding improvement in functional capacity. Further research is needed to understand the lack of association between increased physical activity and functional outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03041610.

Statistical analysis plan for a randomized controlled trial examining pedometer-based walking intervention in patients with heart failure with reduced ejection fraction: the WATCHFUL trial.

BACKGROUND: Physical activity is an effective management strategy for heart failure with reduced ejection fraction, but patients' compliance is challenging. Walking is a suitable form of physical activity due to its convenience and sustainability, and it can potentially improve functional capacity in heart failure patients. OBJECTIVES: The WATCHFUL trial aims to determine whether a pedometer-based walking intervention combined with face-to-face sessions and regular telephone contact improves functional capacity in heart failure patients. METHODS: The WATCHFUL trial is a 6-month multicenter, parallel-group, randomized, controlled, superiority trial with a 6-month follow-up. A total of 202 patients were recruited for the trial. The primary analysis will evaluate the change in distance walked during the 6-min walk test from baseline to 6 months based on the intention-to-treat population; the analysis will be performed using a linear mixed-effect model adjusted for baseline values. Missing data will be imputed using multiple imputations, and the impact of missing data will be assessed using a sensitivity analysis. Adverse events are monitored and recorded throughout the trial period. DISCUSSION: The trial has been designed as a pragmatic trial with a scalable intervention that could be easily translated into routine clinical care. The trial has been affected by the COVID-19 pandemic, which slowed patients' recruitment and impacted their physical activity patterns. CONCLUSIONS: The present publication provides details of the planned statistical analyses for the WATCHFUL trial to reduce the risks of reporting bias and erroneous data-driven results. TRIAL REGISTRATION: ClinicalTrials.gov (identifier: NCT03041610, registered: 3/2/2017).

Oxidative Stress in Takotsubo Syndrome-Is It Essential for an Acute Attack? Indirect Evidences Support Multisite Impact Including the Calcium Overload-Energy Failure Hypothesis.

Indirect evidences in reviews and case reports on Takotsubo syndrome (TTS) support the fact that the existence of oxidative stress (OS) might be its common feature in the pre-acute stage. The sources of OS are exogenous (environmental factors including pharmacological and toxic influences) and endogenous, the combination of both may be present, and they are being discussed in detail. OS is associated with several pathological conditions representing TTS comorbidities and triggers. The dominant source of OS electrones are mitochondria. Our analysis of drug therapy related to acute TTS shows many interactions, e.g., cytostatics and glucocorticoids with mitochondrial cytochrome P450 and other enzymes important for OS. One of the most frequently discussed mechanisms in TTS is the effect of catecholamines on myocardium. Yet, their metabolic influence is neglected. OS is associated with the oxidation of catecholamines leading to the synthesis of their oxidized forms - aminochromes. Under pathological conditions, this pathway may dominate. There are evidences of interference between OS, catecholamine/aminochrome effects, their metabolism and antioxidant protection. The OS offensive may cause fast depletion of antioxidant protection including the homocystein-methionine system, whose activity decreases with age. The alteration of effector subcellular structures (mitochondria, sarco/endoplasmic reticulum) and subsequent changes in cellular energetics and calcium turnover may also occur and lead to the disruption of cellular function, including neurons and cardiomyocytes. On the organ level (nervous system and heart), neurocardiogenic stunning may occur. The effects of OS correspond to the effect of high doses of catecholamines in the experiment. Intensive OS might represent "conditio sine qua non" for this acute clinical condition. TTS might be significantly more complex pathology than currently perceived so far.

Prognostic value of oxidative stress in patients with acute myocardial infarction complicated by cardiogenic shock: A prospective cohort study.

INTRODUCTION: Cardiogenic shock is a frequent complication of acute myocardial infarction. Similar to ischemia/reperfusion injury, excessive production of reactive oxygen species can be expected in those who experience cardiogenic shock. The aims of this study were to describe the extent and time course of oxidative stress and evaluate the prognostic value of oxidative stress markers in patients who experienced ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock. METHODS: Plasma/serum levels of selected biomarkers of oxidative stress (oxidised guanine species (OGS), malondialdehyde, and glutathione peroxidase 3) and markers, which simultaneously reflect severe cellular damage (ferric ion reducing antioxidant power (FRAP), Cu/Zn-superoxide dismutase (SOD), and glutathione) were measured seven times per week in a prospective cohort of 82 patients with STEMI complicated by cardiogenic shock. RESULTS: We found elevated OGS levels in patients who died during three months, which persisted significantly increased the next 12 h compared to surviving patients. A similar time course pattern also exhibited concentrations of FRAP and SOD. The other markers did not change significantly and did not show differences between surviving and non-surviving patients during the monitored period. In addition, a strong relationship between OGS, FRAP, and SOD levels (on admission and 12 h after admission) and 3-month mortality was found. CONCLUSION: Levels of OGS, FRAP, and SOD within 12 h after hospital admission were revealed as early predictors of the adverse development of STEMI complicated by cardiogenic shock.

Prognostic value of high-sensitivity cardiac troponin I in heart failure patients with mid-range and reduced ejection fraction.

BACKGROUND: The identification of high-risk heart failure (HF) patients makes it possible to intensify their treatment. Our aim was to determine the prognostic value of a newly developed, high-sensitivity troponin I assay (Atellica®, Siemens Healthcare Diagnostics) for patients with HF with reduced ejection fraction (HFrEF; LVEF < 40%) and HF with mid-range EF (HFmrEF) (LVEF 40%-49%). METHODS AND RESULTS: A total of 520 patients with HFrEF and HFmrEF were enrolled in this study. Two-year all-cause mortality, heart transplantation, and/or left ventricular assist device implantation were defined as the primary endpoints (EP). A logistic regression analysis was used for the identification of predictors and development of multivariable models. The EP occurred in 14% of the patients, and these patients had higher NT-proBNP (1,950 vs. 518 ng/l; p < 0.001) and hs-cTnI (34 vs. 17 ng/l, p < 0.001) levels. C-statistics demonstrated that the optimal cut-off value for the hs-cTnI level was 17 ng/l (AUC 0.658, p < 0.001). Described by the AUC, the discriminatory power of the multivariable model (NYHA > II, NT-proBNP, hs-cTnI and urea) was 0.823 (p < 0.001). Including heart failure hospitalization as the component of the combined secondary endpoint leads to a diminished predictive power of increased hs-cTnI. CONCLUSION: hs-cTnI levels ≥ 17 ng/l represent an independent increased risk of an adverse prognosis for patients with HFrEF and HFmrEF. Determining a patient's hs-cTnI level adds prognostic value to NT-proBNP and clinical parameters.

Differences in risk profiles and long-term outcomes in acute heart failure patients with preserved and reduced left ventricular ejection fraction in the Czech Republic: The AHEAD registry sub-analysis.

BACKGROUND: The latest European heart failure guidelines define patients as those with reduced (HFrEF), mid-range, and preserved (HFpEF) left ventricular ejection fraction (LVEF; <40%, 40%-49%, and ≥50%, respectively). We investigated the causes of rehospitalizations/deaths in our institution's heart failure patients and focused on differences in the clinical presentation, risk profile, and long-term outcomes between the HFrEF and HFpEF groups in a real-life scenario. METHODS AND RESULTS: We followed 1274 patients discharged from heart failure hospitalization in 2 centres. The mean patient age was 75.9 years, and men and women were represented equally. During the minimal follow-up of 2 years, 57% of patients were hospitalised for any cause, 24.9% for decompensated heart failure, and 43.3% for any cardiovascular cause. A total of 36.1% of patients died, either with prior (11.8%) or without prior (24.3%) heart failure rehospitalization. Heart failure was also the most frequent cause of cardiovascular hospitalization, followed by gastrointestinal problems, infections, and tumours for noncardiovascular hospitalizations. Patients with HFrEF had different baseline characteristics and risk profiles, experienced more hospitalizations for acute heart failure (28.6% vs 20.2%, P=0.012), and had higher cardiovascular mortality (82.4% vs 63.5%, P<0.001) when compared with HFpEF patients. Overall mortality and rehospitalization rates were similar. CONCLUSION: Within 2 years, half of the patients died and/or were hospitalised for acute decompensation of heart failure, and only one-third of the patients survived without any hospitalization. HFrEF and HFpEF patients were confirmed to be different entities with diverse characteristics, risk profiles, and cardiovascular event rates.

The detrimental effect of COVID-19 nationwide quarantine on accelerometer-assessed physical activity of heart failure patients.

AIMS: A reduction of habitual physical activity due to prolonged COVID-19 quarantine can have serious consequences for patients with cardiovascular diseases, such as heart failure. This study aimed to explore the effect of COVID-19 nationwide quarantine on accelerometer-assessed physical activity of heart failure patients. METHODS AND RESULTS: We analysed the daily number of steps in 26 heart failure patients during a 6-week period that included 3 weeks immediately preceding the onset of the quarantine and the first 3 weeks of the quarantine. The daily number of steps was assessed using a wrist-worn accelerometer worn by the patients as part of an ongoing randomized controlled trial. Multilevel modelling was used to explore the effect of the quarantine on the daily step count adjusted for weather conditions. As compared with the 3 weeks before the onset of the quarantine, the step count was significantly lower during each of the first 3 weeks of the quarantine (P < 0.05). When the daily step count was averaged across the 3 weeks before and during the quarantine, the decrease amounted to 1134 (SE 189) steps per day (P < 0.001), which translated to a 16.2% decrease. CONCLUSIONS: The introduction of the nationwide quarantine due to COVID-19 had a detrimental effect on the level of habitual physical activity in heart failure patients, leading to an abrupt decrease of daily step count that lasted for at least the 3-week study period. Staying active and maintaining sufficient levels of physical activity during the COVID-19 pandemic are essential despite the unfavourable circumstances of quarantine.

Delayed-type Hypersensitivity to Metals in Newly Diagnosed Patients with Nonischemic Dilated Cardiomyopathy.

The causes of nonischemic dilated cardiomyopathy are classified as genetic or nongenetic, but environmental factors such as metal pollutants may interact with genetic susceptibility. The presence of metal particles has been detected in the myocardium, including in those patients with dilated cardiomyopathy. It is also known that hypersensitivity reactions can induce inflammation in tissue. The present study aimed to verify if metal-induced delayed-type hypersensitivity is present in patients with nonischemic dilated cardiomyopathy. The patient group consisted of 30 patients with newly diagnosed dilated cardiomyopathy; the control group comprised 41 healthy subjects. All patients and control subjects provided blood samples for lymphocyte transformation testing (MELISA®) to assess possible hypersensitivity to seven common metals. Specific exposure to metals was based on interview data. Results showed that exposure to cadmium and lead (p = 0.0002), aluminum (p = 0.0006), nickel (p = 0.0012), and chromium (p = 0.0065) was more often reported by patients than controls. The patients also had significantly more frequent hypersensitivity reactions to mercury (26.7% vs. 7.3%, p = 0.014624), nickel (40% vs. 12.2%, p = 0.02341), and silver (20% vs. 4.8%, p = 0.025468) than the control group. Patients with dilated cardiomyopathy had greater exposure to certain metals compared with healthy controls. Hypersensitivity to metals was more frequent in patients with dilated cardiomyopathy, suggesting a possible association that warrants further investigation.