Impact of empagliflozin on insulin needs in patients with heart failure and diabetes: An EMPEROR-Pooled analysis.

AIM: To assess the effect of empagliflozin on patients with comorbid heart failure (HF) and diabetes with or without baseline insulin, and to study the impact of empagliflozin on insulin requirements over time. MATERIALS AND METHODS: We performed a post-hoc analysis of pooled patient-level data from two cardiovascular outcomes trials of empagliflozin in HF (EMPEROR-Reduced and EMPEROR-Preserved trials). We undertook a subgroup analysis stratified by baseline insulin use, including all patients with diabetes. The studied endpoints included the primary composite endpoint of first hospitalization for HF or cardiovascular death, rate of decline of estimated glomerular filtration rate, composite renal outcome and rates of sustained insulin initiation. RESULTS: Among 4794 patients with diabetes, 1333 (658 in empagliflozin, 675 in placebo) were using insulin at baseline. The treatment effect of empagliflozin on the primary endpoint was consistent irrespective of insulin use [no insulin, hazard ratio 0.74, 95% confidence interval (CI) 0.63-0.86; using insulin, hazard ratio 0.81, 95% CI 0.66-1.00, pinteraction = .49], as was the effect on the rate of decline of the estimated glomerular filtration rate (pinteraction = .75). There was no effect of empagliflozin on the composite renal outcome in patients using or not using insulin (pinteraction = .30). Among patients not using insulin at baseline, those randomized to empagliflozin initiated insulin less frequently throughout the follow-up period compared with those receiving placebo (2.6% vs. 3.8%, odds ratio 0.66, 95% CI 0.50-0.88). CONCLUSIONS: Empagliflozin exerts a consistent benefit on cardiovascular outcomes and renal function decline, irrespective of baseline insulin use, and reduces the need for sustained insulin initiation in patients with HF and diabetes.

Leveraging electronic health records to streamline the conduct of cardiovascular clinical trials.

Conventional randomized controlled trials (RCTs) can be expensive, time intensive, and complex to conduct. Trial recruitment, participation, and data collection can burden participants and research personnel. In the past two decades, there have been rapid technological advances and an exponential growth in digitized healthcare data. Embedding RCTs, including cardiovascular outcome trials, into electronic health record systems or registries may streamline screening, consent, randomization, follow-up visits, and outcome adjudication. Moreover, wearable sensors (i.e. health and fitness trackers) provide an opportunity to collect data on cardiovascular health and risk factors in unprecedented detail and scale, while growing internet connectivity supports the collection of patient-reported outcomes. There is a pressing need to develop robust mechanisms that facilitate data capture from diverse databases and guidance to standardize data definitions. Importantly, the data collection infrastructure should be reusable to support multiple cardiovascular RCTs over time. Systems, processes, and policies will need to have sufficient flexibility to allow interoperability between different sources of data acquisition. Clinical research guidelines, ethics oversight, and regulatory requirements also need to evolve. This review highlights recent progress towards the use of routinely generated data to conduct RCTs and discusses potential solutions for ongoing barriers. There is a particular focus on methods to utilize routinely generated data for trials while complying with regional data protection laws. The discussion is supported with examples of cardiovascular outcome trials that have successfully leveraged the electronic health record, web-enabled devices or administrative databases to conduct randomized trials.

Association of Hospital Procedural Volume With Outcomes of Left Ventricular Assist Device Placement.

BACKGROUND: With the advancement in device technology, the use of durable left ventricular assist devices (LVADs) has increased significantly in recent years. However, there is a dearth of evidence to conclude whether patients who undergo LVAD implantation at high-volume centers have better clinical outcomes than those receiving care at low- or medium-volume centers. METHODS: We analyzed the hospitalizations using the Nationwide Readmission Database for the year 2019 for new LVAD implantation. Baseline comorbidities and hospital characteristics were compared among low- (1-5 procedures/year), medium- (6-16 procedures/year) and high-volume (17-72 procedures/year) hospitals. The volume/outcome relationship was analyzed using the annualized hospital volume as a categorical variable (tertiles) as well as a continuous variable. Multilevel mixed-effect logistic regression and negative binomial regression models were used to determine the association of hospital volume and outcomes, with tertile 1 (low-volume hospitals) as the reference category. RESULTS: A total of 1533 new LVAD procedures were included in the analysis. The inpatient mortality rate was lower in the high-volume centers compared with the low-volume centers (9.04% vs 18.49%, aOR 0.41, CI0.21-0.80; P = 0.009). There was a trend toward lower mortality rates in medium-volume centers compared with low-volume centers; however, it did not reach statistical significance (13.27% vs 18.49%, aOR 0.57, CI0.27-1.23; P = 0.153). Similar results were seen for major adverse events (composite of stroke/transient ischemic attack and in-hospital mortality). There was no significant difference in bleeding/transfusion, acute kidney injury, vascular complications, pericardial effusion/hemopericardium/tamponade, length of stay, cost, or 30-day readmission rates between medium- and high-volume centers compared to low-volume centers. CONCLUSION: Our findings indicate lower inpatient mortality rates in high-volume LVAD implantation centers and a trend toward lower mortality rates in medium-volume LVAD implantation centers compared to lower-volume centers.

Role of Cardiac Contractility Modulation in Heart Failure With a Higher Ejection Fraction.

Cardiac contractility modulation (also known as CCM) is a novel device therapy that delivers nonexcitatory electric stimulation to cardiac myocytes during the absolute refractory period, and it has been shown to improve functional status and clinical outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF). CCM therapy is currently recommended for a subset of patients with advanced HFrEF who are not candidates for cardiac resynchronization therapy. A growing body of evidence demonstrates the benefit of CCM therapy in patients with HFrEF and with ejection fraction at the upper end of the spectrum and in patients with HF and with mildly reduced ejection fraction (HFmrEF). Experimental studies have also observed reversal of pathological biomolecular intracellular changes with CCM therapy in HF with preserved ejection fraction (HFpEF), indicating the potential for clinically meaningful benefits of CCM therapy in these patients. In this review, we sought to discuss the basis of CCM therapy and its potential for management of patients with HF with higher ejection fractions.

Multi-lead atrioventricular sequential pacing: A promising alternative to conventional temporary pacing techniques.

Temporary right ventricular pacing in unstable bradycardia and cardiovascular interventions is associated with atrioventricular dyssynchrony and reduced cardiac output. Currently, sequential atrioventricular pacing options are limited andnot routinely used. Herein, we discuss a novel, first in-human technique of temporary atrioventricular sequential pacing and how it compares to existing modalities of atrioventricular pacing.

Association between high vancomycin minimum inhibitory concentration and clinical outcomes in patients with methicillin-resistant Staphylococcus aureus bacteraemia - A retrospective cohort study.

The purpose of this study is to determine the role of high (≥ 1.5 mg/L) vancomycin minimum inhibitory concentration (VMIC) in predicting clinical outcomes in patients with methicillin-resistant Staphylococcus aureus bacteraemia (MRSAB). A retrospective study was conducted at Mayo Clinic, Minnesota. Patients ≥ 18 years with a 3-month follow-up were included. Outcomes were defined as 30-day all-cause in-hospital mortality, median duration of bacteraemia, metastatic infectious complications, and relapse of MRSAB. A total of 475 patients with MRSAB were identified, and 93 (19.6%) of them had high VMIC isolates. Sixty-four percent of patients were male with a mean age of 69.0 years. Active solid organ malignancy and skin and soft tissue infection as source of MRSAB were associated with high VMIC, while septic arthritis as a complication was significantly associated with low VMIC on multivariate analysis. Eighty-one (17.1%) patients died within 30 days of hospitalization, with no significant difference in mortality rates between the two groups. In-hospital mortality, median duration of bacteraemia, and metastatic infectious complications were not significantly associated with high VMIC MRSAB.

Using Arterial Recoil for Large Bore Access Closure After Impella Assist Device Removal.

The use of Impella assist device for high-risk percutaneous coronary interventions and cardiogenic shock has increased in the last decade and requires a large bore arterial access (LBA). However, LBA closure following Impella removal is associated with significant complications. Herein, we describe the safety and efficacy of a novel method of LBA closure using arterial recoil following Impella removal. We performed a retrospective review of electronic medical records of patients who underwent LBA closure using this method from July 1, 2018 to June 30, 2022. The procedure involves controlled downsizing of the arterial sheath from 12 French (Fr) to 6 Fr catheters with intermittent compression to allow patent hemostasis facilitated by arterial recoil. Baseline characteristics and outcomes including closure success, immediate/delayed bleeding, and access site complications were included. Of 103 patients with Impella placement, 20 (19%) underwent LBA closure with this method. Patients were predominantly male (80%) and White (55%) with a mean age of 65 ± 16 years. After downsizing of the femoral sheath to 6 Fr, 14 patients underwent manual compression, 3 patients had a 6 Fr catheter left in place to maintain access, and 3 patients underwent placement of a Perclose or Vascade device. Successful LBA closure was performed in all patients with no immediate or delayed bleeding complications. Five patients (25%) died inpatient; the deaths were unrelated to complications of Impella removal. In conclusion, LBA closure post-Impella removal with this novel method was safe and effective. Further prospective studies are needed to ascertain its comparative efficacy.

Critical re-evaluation of the identification of iron deficiency states and effective iron repletion strategies in patients with chronic heart failure.

According to current guidelines, iron deficiency is defined by a serum ferritin level <100 ng/ml or a transferrin saturation (TSAT) <20% if the serum ferritin level is 100-299 µg/L. These criteria were developed to encourage the use of intravenous iron as an adjunct to erythropoiesis-stimulating agents in the treatment of renal anaemia. However, in patients with heart failure, these criteria are not supported by any pathophysiological or clinical evidence that they identify an absolute or functional iron deficiency state. A low baseline TSAT-but not serum ferritin level-appears to be a reliable indicator of the effect of intravenous iron to reduce major heart failure events. In randomized controlled trials, intravenous iron decreased the risk of cardiovascular death or total heart failure hospitalization in patients with a TSAT <20% (risk ratio 0.67 [0.49-0.92]) but not in patients with a TSAT ≥20% (risk ratio 0.99 [0.74-1.30]), with the magnitude of the risk reduction being proportional to the severity of hypoferraemia. Patients who were enrolled in clinical trials solely because they had a serum ferritin level <100 µg/L showed no significant benefit on heart failure outcomes, and it is noteworthy that serum ferritin levels of 20-300 µg/L lie entirely within the range of normal values for healthy adults. Current guidelines reflect the eligibility criteria of clinical trials, which inadvertently adopted unvalidated criteria to define iron deficiency. Reliance on these guidelines would lead to the treatment of many patients who are not iron deficient (serum ferritin level <100 µg/L but normal TSAT) and ignores the possibility of iron deficiency in patients with a low TSAT but with serum ferritin level of >300 µg/L. Importantly, analyses of benefit based on trial eligibility-driven guidelines substantially underestimate the magnitude of heart-failure-event risk reduction with intravenous iron in patients who are truly iron deficient. Based on all available data, we recommend a new mechanism-based and trial-tested approach that reflects the totality of evidence more faithfully than the historical process adopted by clinical investigators and by the guidelines. Until additional evidence is forthcoming, an iron deficiency state in patients with heart failure should be defined by a TSAT <20% (as long as the serum ferritin level is <400 µg/L), and furthermore, the use of a serum ferritin level <100 µg/L alone as a diagnostic criterion should be discarded.

Use of natriuretic peptides and echocardiography for diagnosing heart failure.

AIMS: International guidelines have recommended the use of echocardiography and natriuretic peptides (NP) testing in the diagnostic evaluation of heart failure (HF) for more than 10 years. However, real-world utilization of these diagnostic tests in the US is not known. We sought to assess contemporary trends in echocardiography and NP testing for diagnosing HF in the US. METHODS AND RESULTS: The TriNetX data were queried for the total number of first HF diagnoses in adults aged >18 years in the US from 2016 to 2019 with exclusions applied. NP testing and echocardiography any time before through 1 year following the index diagnosis were assessed. Temporal trends significance was evaluated using Cochran-Armitage trend tests. A total of 124 126 patients were included. Mean age was 68 ± 13 years, 53% were male, and 71% were White. Overall, 61 023 (49%) incident diagnoses were made in the outpatient and 63 103 (51%) in the inpatient setting with a significantly increasing trend toward inpatient diagnoses (p < 0.001). Of all incident HF diagnoses, 70 612 (57%) underwent echocardiography, 67 991 (55%) underwent NP testing, and 31 206 (25%) did not undergo either diagnostic test. There were increasing trends in the proportion of patients diagnosed in the inpatient versus outpatient setting that underwent echocardiography, NP testing, and either diagnostic test (p < 0.001 for all). CONCLUSIONS: We found low rates of echocardiography and NP testing in those with HF, with more of such testing performed amongst inpatient diagnoses. We also found increasing rates of inpatient HF diagnoses, indicating lost opportunities for earlier treatment initiation and better outcomes.

Trends in sleep apnea and heart failure related mortality in the United States from 1999 to 2019.

National estimates of deaths related to both heart failure (HF) and sleep apnea (SA) are not known. We evaluated the trends in HF and SA related mortality using the CDC-WONDER database in adults aged ≥25 years in the US. All deaths related to HF and SA as contributing or underlying causes of death were queried. Between 1999 and 2019, there were a total of 6,484,486 deaths related to HF, 204,824 deaths related to SA, and 53,957 deaths related to both. There was a statistically significant increase in the age-adjusted mortality rate (AAMR) for both SA-related (average annual percent change [AAPC] 8.2%) and combined HF and SA- related (AAPC 10.1 %) deaths. Men had consistently higher AAMRs compared with women, and both groups had a similar increasing trend in AAMR. Non-Hispanic (NH) Black individuals had the highest HF and SA-related AAMR, followed by NH White and Hispanic/Latino individuals. Adults aged >75 years consistently had the highest AAMR with the steepest increase (AAPC 11.1%). In conclusion, HF and SA-related mortality has significantly risen over the past two decades with the elderly, men, and NH Black at disproportionately higher risk.

Racial and ethnic disparities in cardiovascular disease - analysis across major US national databases.

BACKGROUND: There are several studies that have analyzed disparities in cardiovascular disease (CVD) health using a variety of different administrative databases; however, a unified analysis of major databases does not exist. In this analysis of multiple publicly available datasets, we sought to examine racial and ethnic disparities in different aspects of CVD, CVD-related risk factors, CVD-related morbidity and mortality, and CVD trainee representation in the US. METHODS: We used National Health and Nutrition Examination Survey, National Ambulatory Medical Care Survey, National Inpatient Sample, Centers for Disease Control and Prevention Wide-Ranging OnLine Data for Epidemiologic Research, United Network for Organ Sharing, and American Commission for Graduate Medical Education data to evaluate CVD-related disparities among Non-Hispanic (NH) White, NH Black and Hispanic populations. RESULTS: The prevalence of most CVDs and associated risk factors was higher in NH Black adults compared to NH White adults, except for dyslipidemia and ischemic heart disease (IHD). Statins were underutilized in IHD in NH Black and Hispanic patients. Hospitalizations for HF and stroke were higher among Black patients compared to White patients. All-cause, CVD, heart failure, acute myocardial infarction, IHD, diabetes mellitus, hypertension and cerebrovascular disease related mortality was highest in NH Black or African American individuals. The number of NH Black and Hispanic trainees in adult general CVD fellowship programs was disproportionately lower than NH White trainees. CONCLUSION: Racial disparities are pervasive across the spectrum of CVDs with NH Black adults at a significant disadvantage compared to NH White adults for most CVDs.

Association of an impaired GH-IGF-I axis with cardiac wasting in patients with advanced cancer.

BACKGROUND: Growth hormone (GH) resistance is characterized by high GH levels but low levels of insulin-like growth factor-I (IGF-I) and growth hormone binding protein (GHBP) and, for patients with chronic disease, is associated with the development of cachexia. OBJECTIVES: We investigated whether GH resistance is associated with changes in left ventricular (LV) mass (cardiac wasting) in patients with cancer. METHODS: We measured plasma IGF-I, GH, and GHBP in 159 women and 148 men with cancer (83% stage III/IV). Patients were grouped by tertile of echocardiographic LVmass/height2 (women, < 50, 50-61, > 61 g/m2; men, < 60, 60-74, > 74 g/m2) and by presence of wasting syndrome with unintentional weight loss (BMI < 24 kg/m2 and weight loss ≥ 5% in the prior 12 months). Repeat echocardiograms were obtained usually within 3-6 months for 85 patients. RESULTS: Patients in the lowest LVmass/height2 tertile had higher plasma GH (median (IQR) for 1st, 2nd, and 3rd tertile women, 1.8 (0.9-4.2), 0.8 (0.2-2.2), 0.5 (0.3-1.6) ng/mL, p = 0.029; men, 2.1 (0.8-3.2), 0.6 (0.1-1.7), 0.7 (0.2-1.9) ng/mL, p = 0.003). Among women, lower LVmass was associated with higher plasma IGF-I (68 (48-116), 72 (48-95), 49 (35-76) ng/mL, p = 0.007), whereas such association did not exist for men. Patients with lower LVmass had lower log IGF-I/GH ratio (women, 1.60 ± 0.09, 2.02 ± 0.09, 1.88 ± 0.09, p = 0.004; men, 1.64 ± 0.09, 2.14 ± 0.11, 2.04 ± 0.11, p = 0.002). GHBP was not associated with LVmass. Patients with wasting syndrome with unintentional weight loss had higher plasma GH and GHBP, lower log IGF-I/GH ratio, and similar IGF-I. Overall, GHBP correlated inversely with log IGF-I/GH ratio (women, r = - 0.591, p < 0.001; men, r = - 0.575, p < 0.001). Additionally, higher baseline IGF-I was associated with a decline in LVmass during follow-up (r = - 0.318, p = 0.003). CONCLUSION: In advanced cancer, reduced LVmass is associated with increased plasma GH and reduced IGF-I/GH ratio, suggesting increasing GH resistance, especially for patients with wasting syndrome with unintentional weight loss. Higher baseline IGF-I was associated with a decrease in relative LVmass during follow-up.

SGLT-2 Inhibitors in Heart Failure: A Review of Current Evidence.

Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are the latest addition to guideline-directed medical therapy in heart failure (HF) with reduced ejection fraction with recent trials suggesting a significant reduction in adverse cardiovascular outcomes in patients with HF with mildly reduced and preserved ejection fraction. SGLT-2 inhibitors have evolved as metabolic drugs due to their multi-system effects and are indicated for the management of HF across the ejection fraction spectrum, type 2 diabetes, and chronic kidney disease. There is ongoing research to explore the mechanistic effects of SGLT-2 inhibitors in HF and to evaluate their use in worsening HF and after myocardial infarction. This review focuses on the evidence for SGLT-2 inhibitors from type 2 diabetes cardiovascular outcome and primary HF trials and discusses ongoing research related to their use in cardiovascular disease.

Acute Left Ventricular Assist Device Failure From Outflow Graft Dissection Flap Successfully Treated With Stent Placement.

Outflow graft obstruction (OGO) is a potentially fatal complication of left ventricular assist device (LVAD) implantation. Common causes include graft kinking, luminal stenosis, and graft thrombosis. We describe a case of a 51-year-old female who presented with acute LVAD failure and cardiogenic shock. Initial imaging revealed OGO without luminal stenosis following which she was she was empirically treated for graft thrombosis with anticoagulation and catheter-based thrombolytic therapy with no success. Further imaging in the catheterization laboratory revealed a potential neointimal flap dissection acting as a one-way valve. A stent was successfully placed across the outflow graft with immediate resolution of cardiogenic shock. The case emphasizes the importance of including neointimal flap as a differential for OGO in acute LVAD failure, especially in cases where thrombolytic therapy fails to correct hemodynamic compromise.

Frailty and Its Implications in Heart Failure with Reduced Ejection Fraction: Impact on Prognosis and Treatment.

Frailty affects half of all patients with heart failure with reduced ejection fraction (HFrEF) and carries a ∼2-fold increased risk of mortality. The relationship between frailty and HFrEF is bidirectional, with one condition exacerbating the other. Paradoxical to their higher clinical risk, frail patients with HFrEF are more often under-treated due to concerns over medication-related adverse clinical events. However, current evidence suggests consistent safety of HF medical therapies among older frail patients with HFrEF. A multidisciplinary effort is necessary for the appropriate management of these high-risk patients which focuses on the optimization of known beneficial therapies with a goal-directed effort toward improving quality of life.

Frailty and heart failure: State-of-the-art review.

At least half of all patients with heart failure (HF) are affected by frailty, a syndrome that limits an individual ability to recover from acute stressors. While frailty affects up to 90% of patients with HF with preserved ejection fraction, it is also seen in ~30-60% of patients with HF with reduced ejection fraction, with ~26% higher prevalence in women compared with men. The relationship between frailty and HF is bidirectional, with both conditions exacerbating the other. Frailty is further complicated by a higher prevalence of sarcopenia (by ~20%) in HF patients compared with patients without HF, which negatively affects outcomes. Several frailty assessment methods have been employed historically including the Fried frailty phenotype and Rockwood Clinical Frailty Scale to classify HF patients based on the severity of frailty; however, a validated HF-specific frailty assessment tool does not currently exist. Frailty in HF is associated with a poor prognosis with a 1.5-fold to 2-fold higher risk of all-cause death and hospitalizations compared to non-frail patients. Frailty is also highly prevalent in patients with worsening HF, affecting >50% of patients hospitalized for HF. Such patients with multiple readmissions for decompensated HF have markedly poor outcomes compared to younger, non-frail cohorts, and it is hypothesized that it may be due to major physical and functional limitations that limit recovery from an acute episode of worsening HF, a care aspect that has not been addressed in HF guidelines. Frail patients are thought to confer less benefit from therapeutic interventions due to an increased risk of perceived harm, resulting in lower adherence to HF interventions, which may worsen outcomes. Multiple studies report that <40% of frail patients are on guideline-directed medical therapy for HF, of which most are on suboptimal doses of these medications. There is a lack of evidence generated from randomized trials in this incredibly vulnerable population, and most current practice is governed by post hoc analyses of trials, observational registry-based data and providers' clinical judgement. The current body of evidence suggests that the treatment effect of most guideline-based interventions, including medications, cardiac rehabilitation and device therapy, is consistent across all age groups and frailty subgroups and, in some cases, may be amplified in the older, more frail population. In this review, we discuss the characteristics, assessment tools, impact on prognosis and impact on therapeutic interventions of frailty in patients with HF.

Ventilatory Failure And Pulmonary Embolism In Covid-19 Requiring Enhanced Venous Drainage For Extracorporeal Membrane Oxygenation.

COVID-19 infection manifests as a spectrum of respiratory and vascular complications, including acute respiratory distress syndrome (ARDS) and pulmonary embolism. Herein, we describe a case of a healthy young male who presented with ARDS refractory to mechanical ventilation and concomitant bilateral pulmonary emboli managed with extracorporeal membrane oxygenation (ECMO) and embolectomy. The embolectomy and initial veno-venous ECMO configuration failed to correct the patient's hypoxemia despite maximal flows. This was thought to be due to a high-output state secondary to vasodilatory shock preventing adequate drainage from the existing single drainage ECMO cannulation, following which a second venous cannula was placed to form a unique veno-veno-venous ECMO circuit that resolved the persistent hypoxemia. The case underscores the importance of identifying embolic events and vasodilatory shock in COVID-19 patients, both of which need to be addressed simultaneously to avoid worsening right ventricular failure (via both mechanical and hypoxia-driven pathways) and the resulting veno-arterial ECMO along with its associated complications.

Temporal Trends and Outcomes of Implantable Cardioverter Defibrillators in Heart Failure and Chronic Kidney Disease in the United States.

Chronic kidney disease (CKD) and hemodialysis increase the risk of sudden cardiac death (SCD) in heart failure (HF); however, national trends in utilization and outcomes of implantable cardioverter-defibrillator (ICD) in this population remain unknown. We sought to evaluate the utilization and outcomes of ICD therapy in HF patients with CKD and end-stage renal disease (ESRD) using the National Inpatient Sample from 2009 to 2018. Hospitalizations with a discharge diagnosis of systolic HF and ICD implantation were identified and stratified by stages of kidney disease. A total of 281,219 systolic HF hospitalizations who underwent ICD implantation were included. A significant decrease in inpatient ICD implantation was observed over the past decade (3.7% in 2009 to 1.1% in 2018) regardless of renal impairment. In-hospital mortality was highest in ESRD, followed by CKD compared with patients with no CKD. Length of hospital stay and hospitalization costs were also significantly higher in patients with CKD and ESRD. The overall utilization of inpatient ICD implantation has decreased in systolic HF patients and inpatient ICD placement in CKD is associated with an increased risk of mortality and adverse clinical outcomes. This indicates that patients with renal impairment and HF represent a sicker cohort than the general HF population.