Graphical AbstractShows the hypothesis regarding cardiac wasting associated dysfunction, and associated implications for clinical practice and future research development.Open in new tabDownload slide

BACKGROUND:National heart failure guidelines recommend quadruple therapy with renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors for patients with heart failure with reduced ejection fraction (HFrEF), most of whom also receive loop diuretics. However, the guidelines are less clear about the safe approaches to discontinuing older drugs whose decreasing or residual benefit is less well understood. The objective of this study was to examine whether digoxin can be safely discontinued in patients with HFrEF receiving beta-blockers. METHODS:In OPTIMIZE-HF, of 2477 patients with HFrEF (EF ≤45%) receiving beta-blockers and digoxin, digoxin was discontinued in 450 patients. We assembled a propensity score-matched cohort of 433 pairs of patients in which digoxin continuation vs. discontinuation groups were balanced on 51 baseline characteristics. Using the same approach, from 992 patients not on beta-blockers, we assembled a matched cohort of 198 pairs of patients also balanced on 51 baseline characteristics. Hazard ratios (HRs) and 95% CIs for 1-year outcomes were estimated. RESULTS:Among patients receiving beta-blockers, digoxin discontinuation had no association with the combined endpoint of heart failure readmission or death (HR, 1.01; 95% CI, 0.85-1.19), heart failure readmission (HR, 1.03; 95% CI, 0.85-1.25) or death (HR, 0.91; 95% CI, 0.72-1.14). Respective HRs (95% CIs) among patients not receiving beta-blockers were 1.60 (1.25-2.04), 1.62 (1.18-2.22) and 1.43 (1.08-1.89). CONCLUSIONS:Digoxin can be discontinued without increasing the risk of adverse outcomes in patients with HFrEF receiving beta-blockers. Future studies need to examine the residual benefit of older heart failure drugs to ensure their safe discontinuation in patients with HFrEF receiving newer guideline-directed medical therapy.

Background: Cardiac troponin I (cTnI) above the 99th percentile is associated with an increased risk of major adverse events. Patients with detectable cTnI below the 99th percentile are a heterogeneous group with a less well-defined risk profile. The purpose of this study is to investigate the prognostic relevance of detectable cTnI below the 99th percentile in patients undergoing coronary angiography. Methods: The study included 14,776 consecutive patients (mean age of 65.4 +/- 12.7 years, 71.3 % male) from the Essen Coronary Artery Disease (ECAD) registry. Patients with cTnI levels above the 99th percentile and patients with ST-segment elevation acute myocardial infarction were excluded. All-cause mortality was defined as the primary endpoint. Results: Detectable cTnI below the 99th percentile was present in 2811 (19.0 %) patients, while 11,965 (81.0 %) patients were below detection limit of the employed assay. The mean follow-up was 4.25 +/- 3.76 years. All-cause mortality was 20.8 % for patients with detectable cTnI below the 99th percentile and 15.0 % for those without detectable cTnI. In a multivariable Cox regression analysis, detectable cTnI was independently associated with all-cause mortality with a hazard ratio of 1.60 (95 % CI 1.45-1.76; p < 0.001). There was a stepwise relationship with increasing all-cause mortality and tertiles of detectable cTnI levels with hazard ratios of 1.63 (95 % CI 1.39-1.90) for the first tertile to 2.02 (95 % CI 1.74-2.35) for the third tertile. Conclusions: Detectable cTnI below the 99th percentile is an independent predictor of mortality in patients undergoing coronary angiography with the risk of death growing progressively with increasing troponin levels.

Patients with cancer face a significant risk of cardiovascular death, regardless of time since cancer diagnosis. Elderly patients are particularly more susceptible as cancer-associated cardiac complications present in advanced stage cancer. These patients may often present with symptoms observed in chronic heart failure (HF). Cardiac wasting, commonly observed in these patients, is a multifaceted syndrome characterized by systemic metabolic alterations and inflammatory processes that specifically affect cardiac function and structure. Experimental and clinical studies have demonstrated that cancer-associated cardiac wasting is linked with cardiac atrophy and altered cardiac morphology, which impairs cardiac function, particularly pertaining to the left ventricle. Therefore, this review aims to present a summary of epidemiologic data and pathophysiological mechanisms of cardiac wasting due to cancer, and future directions in this field.

BACKGROUND:With the advent of novel chemotherapy, survival of patients with cancer has improved. However, people with cancer have an increased risk of heart failure (HF). Conversely, HF-related mortality may undermine survival among people with cancer. We aim to analyze the trends of mortality in people with HF and cancer in the adult US population. METHODS:We conducted an examination of death certificates sourced from the CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research) database, from the years 1999 to 2020. Mortality in adults with HF and cancer was assessed. Age-adjusted mortality rates (AAMRs) per 100,000 persons and annual percent change were reported. RESULTS:Between 1999 and 2020, 621,783 deaths occurred from HF in people with cancer. The AAMR declined from 16.4 in 1999 to 11.9 in 2017, after which an increase to 14.5 was observed in 2020. Men had consistently higher overall AAMR as compared to women (men = 18.1 vs women = 9.9). Similar AAMR was observed between non-Hispanic (NH) Blacks/African Americans (13.9) and NH Whites (13.3), with lower in American Indian/Alaska Native (9.6) and Hispanics (7.4). Asian/Pacific Islanders reported the lowest AAMR (5.7). The Midwestern region reported the highest AAMR (14.8). We observed the highest AAMR amongst the older population (61.4). CONCLUSION:The mortality rates of people with HF and cancer are increasing in the adult U.S. POPULATION:This underscores the need for increased screening, aggressive management, and subsequent surveillance of people at risk or with manifested HF in people with cancer.

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. We investigated whether GH resistance is associated with changes in left ventricular (LV) mass (cardiac wasting) in patients with cancer. We measured plasma IGF-I, GH, and GHBP in 159 women and 148 men with cancer (83

AIMS:Traditional cardiovascular (CV) biomarkers (high-sensitivity troponinT [hsTnT] and N-terminal pro-B-type natriuretic peptide [NT-proBNP]) are important to monitor cancer patients' cardiac function and to assess prognosis. Newer CV biomarkers (mid-regional pro-adrenomedullin [MR-proADM], C-terminal pro-arginine vasopressin [copeptin], and mid-regional pro-atrial natriuretic peptide [MR-proANP]) might outperform traditional biomarkers. METHODS AND RESULTS:Overall, 442 hospitalized cancer patients without significant CV disease or current infection were enrolled (61 ± 15 years, 52% male, advanced cancer stage: 85%) and concentrations of CV biomarkers were analysed. Differences in echocardiographic, clinical, laboratory parameters were assessed. Patients were followed for up to 69 months for all-cause mortality. In univariable analyses, MR-proADM, hsTnT, copeptin, MR-proANP, and NT-proBNP predicted all-cause mortality. In multivariable analyses (adjusted for sex, age, Eastern Cooperative Oncology Group performance status, estimated glomerular filtration rate [eGFR], C-reactive protein, anti-cancer therapy, reason for hospitalization, cancer stage and type), only MR-proADM remained an independent predictor of mortality (MR-proADM per 1 ln: hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.47-3.50], p < 0.001). MR-proADM had the highest area under the curve (AUC) using receiver operating characteristic analysis (AUC [95% CI] 0.74 [0.69-0.79]; hsTnT: AUC 0.69; copeptin: AUC 0.66; MR-proANP: AUC 0.63; NT-proBNP: AUC 0.62). Optimal cut-point for mortality prediction with MR-proADM was 0.94 nmol/L (HR 2.43 [95% CI 1.92-3.06], p < 0.001). Patients with MR-proADM >0.94 nmol/L were older, more often had cancer stage IV, showed reduced performance status, eGFR, haemoglobin, diastolic left ventricular function, and elevated systolic pulmonary artery pressure. CONCLUSION:MR-proADM is an independent predictor of mortality in advanced stage, hospitalized cancer patients without significant CV disease or current infection. The optimal MR-proADM cut-point for mortality prediction was 0.94 nmol/L with hazards for mortality being approximately 2.5 times higher. There was a continuous increase in mortality risk with stepwise increase of MR-proADM concentrations. Elevated concentrations of MR-proADM were also associated with reduced performance status and mildly reduced left ventricular diastolic function as well as higher age and more often cancer stage IV.

Pulmonary hypertension (PH) associated with left heart failure (LHF) (PH-LHF) is one of the most common causes of PH. It directly contributes to symptoms and reduced functional capacity and negatively affects right heart function, ultimately leading to a poor prognosis. There are no specific treatments for PH-LHF, despite the high number of drugs tested so far. This scientific document addresses the main knowledge gaps in PH-LHF with emphasis on pathophysiology and clinical trials. Key identified issues include better understanding of the role of pulmonary venous versus arteriolar remodelling, multidimensional phenotyping to recognize patient subgroups positioned to respond to different therapies, and conduct of rigorous pre-clinical studies combining small and large animal models. Advancements in these areas are expected to better inform the design of clinical trials and extend treatment options beyond those effective in pulmonary arterial hypertension. Enrichment strategies, endpoint assessments, and thorough haemodynamic studies, both at rest and during exercise, are proposed to play primary roles to optimize early-stage development of candidate therapies for PH-LHF.

Heart failure with preserved ejection fraction (HFpEF) represents a highly heterogeneous clinical syndrome affected in its development and progression by many comorbidities. The left ventricular diastolic dysfunction may be a manifestation of various combinations of cardiovascular, metabolic, pulmonary, renal, and geriatric conditions. Thus, in addition to treatment with sodium-glucose cotransporter 2 inhibitors in all patients, the most effective method of improving clinical outcomes may be therapy tailored to each patient's clinical profile. To better outline a phenotype-based approach for the treatment of HFpEF, in this joint position paper, the Heart Failure Association of the European Society of Cardiology, the European Heart Rhythm Association and the European Hypertension Society, have developed an algorithm to identify the most common HFpEF phenotypes and identify the evidence-based treatment strategy for each, while taking into account the complexities of multiple comorbidities and polypharmacy.

Introduction Cancer-associated cardiac wasting has been investigated in rodent models with cachexia and in autopsies so far. Little is known as to the translational evidence for cardiac wasting in patients with active malignancy. Hypothesis Different cardiac morphologic and functional abnormalities, compatible with cardiac wasting, are manifest in patients with advanced cancer and between different cancer types. This may also be associated with relevant clinical and prognostic findings. Methods Three-hundred patients with active cancer, without known significant cardiovascular disease or infection, were recruited in a prospective, observational study. Sixty healthy subjects and 60 chronic heart failure patients with reduced ejection fraction (<40%), of comparable age and sex were also included in the study as controls. Left ventricular (LV) mass was assessed by transthoracic echocardiography at baseline and at follow-up (after 122±71 days). Self-reported outcomes at baseline were also evaluated in cancer patients. Results LV mass in cancer patients was lower than in healthy subjects and heart failure patients (177±47g vs 203±64g vs 300±71g; p<0.001). Cachectic cancer patients presented with particularly low LV mass in comparison to non-cachectic cancer patients (153±42g vs 187±45g; p<0.001). Compared to healthy controls, LV mass was reduced in a similar extent in cancer patients that were anti-cancer therapy naïve, had non-cardiotoxic agents before, or previous cardiotoxic agents (176±48g vs 179±45g vs 177±47g; p>0.05). Mean LV mass had declined by 9.3±12.8% (p<0.001) in 90 cancer patients who received a second echocardiogram. In cancer patients with a decline in LV mass during follow-up, resting heart rate increased (p=0.001) and stroke volume decreased (p<0.001) over time. During an average 16 month-follow-up, 149 patients died (1-year all-cause mortality 43%; 95% confidence interval, 37 to 49%). LV mass and LV mass adjusted for height predicted all-cause mortality (both p<0.05). Adjustment of LV mass for body surface area was not a prognostic marker. Maximum handgrip strength, six-minute walking distance, and stair-climbing power, Eastern Co-operative of Oncology Group (ECOG) performance status scale and Karnofsky performance status, were significantly impaired in patients with prognostically relevant cardiac wasting (all p<0.05). Conclusion Patients with advanced cancer independent of prior systemic cardiotoxic anti-cancer therapy show reduced LV mass. Low LV mass is associated with increased all-cause mortality in cancer and poor functional status. Prognostic and clinical impact of cardiac wasting in cancer patients is less evident when adjustment for body surface area is used. Other echocardiographic alterations are observed when LV mass loss is present. This represents a novel form of cardiac wasting-associated cardiomyopathy in cancer.

BACKGROUND:Body wasting in patients with cancer can affect the heart. OBJECTIVES:The frequency, extent, and clinical and prognostic importance of cardiac wasting in cancer patients is unknown. METHODS:This study prospectively enrolled 300 patients with mostly advanced, active cancer but without significant cardiovascular disease or infection. These patients were compared with 60 healthy control subjects and 60 patients with chronic heart failure (ejection fraction <40%) of similar age and sex distribution. RESULTS:Cancer patients presented with lower left ventricular (LV) mass than healthy control subjects or heart failure patients (assessed by transthoracic echocardiography: 177 ± 47 g vs 203 ± 64 g vs 300 ± 71 g, respectively; P < 0.001). LV mass was lowest in cancer patients with cachexia (153 ± 42 g; P < 0.001). Importantly, the presence of low LV mass was independent of previous cardiotoxic anticancer therapy. In 90 cancer patients with a second echocardiogram after 122 ± 71 days, LV mass had declined by 9.3% ± 1.4% (P < 0.001). In cancer patients with cardiac wasting during follow-up, stroke volume decreased (P < 0.001) and resting heart rate increased over time (P = 0.001). During follow-up of on average 16 months, 149 patients died (1-year all-cause mortality 43%; 95% CI: 37%-49%). LV mass and LV mass adjusted for height squared were independent prognostic markers (both P < 0.05). Adjustment of LV mass for body surface area masked the observed survival impact. LV mass below the prognostically relevant cutpoints in cancer was associated with reduced overall functional status and lower physical performance. CONCLUSIONS:Low LV mass is associated with poor functional status and increased all-cause mortality in cancer. These findings provide clinical evidence of cardiac wasting-associated cardiomyopathy in cancer.

In recent years cardio-oncology has substantially gained in relevance and interest. For this reason, cardio-oncological guidelines were compiled for the first time by the European Society of Cardiology (ESC) in cooperation with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). These European guidelines provide very detailed recommendations on the prevention and management of cancer treatment-related cardiac dysfunction and on other frequently asked questions in cardio-oncology. Nowadays, due to the longer survival of cancer patients and better chances of being cured, cardiac function is becoming increasingly more important and in individual cases can determine the prognosis. This comment provides a brief review of the most important points in the new European guidelines on cardio-oncology taking the current situation in Germany into account.

The registry data presented by Mahmood et al.9 demonstrate that CAR T-cell recipients experience severe cardiac events (SCEs) at significant rates. In these patients, cardiovascular risk factors and cardiovascular disease [atrial fibrillation and heart failure including a decline in left ventricular ejection fraction (LVEF)] were significantly more frequent. CAR T-cell infusion exerts direct and indirect effects on the cardiovascular system (via cytokines, activated monocytes/macrophages, and/or directly from T cells). SCEs presented as heart failure, cardiogenic shock, and myocardial infarction, together with increased biomarkers. SCEs in turn were associated with overall and non-relapse mortality.

Introduction: Maintaining cancer patients′ exercise capacity and therefore patients′ self-determined life is of huge importance, but little is known about major determinants. We sought to identify determinants of exercise capacity in patients with a broad spectrum of cancer types, who were already receiving cancer treatment or about to commence such therapy. Methods: Exercise capacity was assessed in 253 consecutive patients mostly suffering from advanced cancer using the 6-minute walk test (6-MWT). All patients underwent echocardiography, physical examination, resting electrocardiogram (ECG), hand grip strength (HGS) measurement, and laboratory assessments. Results: Patients were divided into two groups according to the median distance in the 6-MWT (459 meters). Patients with lower exercise capacity were older, had significantly lower HGS and haemoglobin and higher values of high sensitive (hs) Troponin T and NT-proBNP (all p <0.05). Whilst the co-morbidity burden was significantly higher in this group, no differences were detected for sex, body mass index, tumour type, or cachexia (all p > 0.2). Using multivariable logistic regression, we found that the presence of anaemia (odds ratio (OR) 6.172, 95% confidence interval (CI) 1.401-27.201, p=0.016) as well as an increase in hs Troponin T (OR 3.077, 95% CI 1.202-5.301, p=0.019) remained independent predictors of impaired exercise capacity. Increasing HGS was associated with a reduced risk of a lower exercise capacity (OR 0.896, 95% CI 0.813 - 0.987, p=0.026). Conclusions: Screening patients for elevated hs troponin levels as well as reduced HGS may help to identify patients at risk of lower exercise capacity during cancer treatment.

AbstractBackgroundMaintaining the ability to perform self‐care is a critical goal in patients with cancer. We assessed whether the patient‐reported ability to walk 4 m and wash oneself predict survival in patients with pre‐terminal cancer.MethodsWe performed a prospective observational study on 169 consecutive hospitalized patients with cancer (52% female, 64 ± 12 years) and an estimated 1–12 months prognosis at an academic, inpatient palliative care unit. Patients answered functional questions for ‘today’, ‘last week’, and ‘last month’, performed patient‐reported outcomes (PROs), and physical function assessments.ResultsNinety‐two (54%) patients reported the ability to independently walk 4 m and 100 (59%) to wash ‘today’. The median number of days patients reported the ability to walk 4 m and wash were 6 (IQR 0–7) and 7 (0–7) days (‘last week’); and 27 (5–30) and 26 (10–30) days (‘last month’). In the last week, 32% of patients were unable to walk 4 m on every day and 10% could walk on 1–3 days; 30% were unable to wash on every day and 10% could wash on 1–3 days. In the last months, 14% of patients were unable to walk 4 m on every day and 10% could only walk on 1–10 days; 12% were unable to wash on every day and 11% could wash on 1–10 days. In patients who could walk ‘today’ average 4 m gait speed was 0.78 ± 0.28 m/s. Patients who reported impaired walking and washing experienced more symptoms (dyspnoea, exertion, and oedema) and decreased physical function (higher Eastern Cooperative Oncology Group Performance Status, and lower Karnofsky Performance Status and hand‐grip strength [unable vs. able to walk ‘today’: 205 ± 87 vs. 252 ± 78 Newton, P = 0.001; unable vs. able to wash ‘today’: 204 ± 86 vs. 250 ± 80 Newton, P = 0.001]). During the 27 months of observation, 152 (90%) patients died (median survival 46 days). In multivariable Cox proportional hazards regression analyses, all tested parameters were independent predictors of survival: walking 4 m ‘today’ (HR 0.63, P = 0.015), ‘last week’ (per 1 day: HR 0.93, P = 0.011), ‘last month’ (per 1 day: HR 0.98, P = 0.012), 4 m gait speed (per 1 m/s: HR 0.45, P = 0.002), and washing ‘today’ (HR 0.67, P = 0.024), ‘last week (per 1 day HR 0.94, p=0.019), and ‘last month’ (per 1 day HR 0.99, P = 0.040). Patients unable to walk and wash experienced the shortest survival and most reduced functional status.ConclusionsIn patients with pre‐terminal cancer, the self‐reported ability to walk 4 m and wash were independent predictors of survival and associated with decreased functional status.

Previous studies demonstrated transcatheter aortic valve replacement (TAVR) with an earlier generation balloon-expandable valve to be noninferior to surgical aortic valve replacement (SAVR) for death and disabling stroke in intermediate-risk patients with symptomatic, severe aortic stenosis at 5 years. However, limited long-term data are available with the more contemporary SAPIEN 3 (S3) bioprosthesis.The aim of this study was to compare 5-year risk-adjusted outcomes in intermediate-risk patients undergoing S3 TAVR vs SAVR.Propensity score matching was performed to account for baseline differences in intermediate-risk patients undergoing S3 TAVR in the PARTNER 2 (Placement of Aortic Transcatheter Valves) S3 single-arm study and SAVR in the PARTNER 2A randomized clinical trial. The primary composite endpoint consisted of 5-year all-cause death and disabling stroke.A total of 783 matched pairs of intermediate-risk patients with severe aortic stenosis were studied. There were no differences in the primary endpoint between S3 TAVR and SAVR at 5 years (40.2% vs 42.7%; HR: 0.87; 95% CI: 0.74-1.03; P = 0.10). The incidence of mild or greater paravalvular regurgitation was more common after S3 TAVR. There were no differences in structural valve deterioration–related stage 2 and 3 hemodynamic valve deterioration or bioprosthetic valve failure.In this propensity-matched analysis of intermediate-risk patients, 5-year rates of death and disabling stroke were similar between S3 TAVR and SAVR. Rates of structural valve deterioration–related hemodynamic valve deterioration were similar, but paravalvular regurgitation was more common after S3 TAVR. Longer-term follow-up is needed to further evaluate differences in late adverse clinical events and bioprosthetic valve durability. (PII S3i [PARTNER II Trial: Placement of Aortic Transcatheter Valves II – S3 Intermediate], NCT03222128; PII A (PARTNER II Trial: Placement of Aortic Transcatheter Valves II – XT Intermediate and High Risk], NCT01314313)

AbstractBackgroundHand grip strength (HGS) is a widely used functional test for the assessment of strength and functional status in patients with cancer, in particular with cancer cachexia. The aim was to prospectively evaluate the prognostic value of HGS in patients with mostly advanced cancer with and without cachexia and to establish reference values for a European‐based population.MethodsIn this prospective study, 333 patients with cancer (85% stage III/IV) and 65 healthy controls of similar age and sex were enrolled. None of the study participants had significant cardiovascular disease or active infection at baseline. Repetitive HGS assessment was performed using a hand dynamometer to measure the maximal HGS (kilograms). Presence of cancer cachexia was defined when patients had ≥5% weight loss within 6 months or when body mass index was <20.0 kg/m2 with ≥2% weight loss (Fearon's criteria). Cox proportional hazard analyses were performed to assess the relationship of maximal HGS to all‐cause mortality and to determine cut‐offs for HGS with the best predictive power. We also assessed associations with additional relevant clinical and functional outcome measures at baseline, including anthropometric measures, physical function (Karnofsky Performance Status and Eastern Cooperative of Oncology Group), physical activity (4‐m gait speed test and 6‐min walk test), patient‐reported outcomes (EQ‐5D‐5L and Visual Analogue Scale appetite/pain) and nutrition status (Mini Nutritional Assessment).ResultsThe mean age was 60 ± 14 years; 163 (51%) were female, and 148 (44%) had cachexia at baseline. Patients with cancer showed 18% lower HGS than healthy controls (31.2 ± 11.9 vs. 37.9 ± 11.6 kg, P < 0.001). Patients with cancer cachexia had 16% lower HGS than those without cachexia (28.3 ± 10.1 vs. 33.6 ± 12.3 kg, P < 0.001). Patients with cancer were followed for a mean of 17 months (range 6–50), and 182 (55%) patients died during follow‐up (2‐year mortality rate 53%) (95% confidence interval 48–59%). Reduced maximal HGS was associated with increased mortality (per −5 kg; hazard ratio [HR] 1.19; 1.10–1.28; P < 0.0001; independently of age, sex, cancer stage, cancer entity and presence of cachexia). HGS was also a predictor of mortality in patients with cachexia (per −5 kg; HR 1.20; 1.08–1.33; P = 0.001) and without cachexia (per −5 kg; HR 1.18; 1.04–1.34; P = 0.010). The cut‐off for maximal HGS with the best predictive power for poor survival was <25.1 kg for females (sensitivity 54%, specificity 63%) and <40.2 kg for males (sensitivity 69%, specificity 68%).ConclusionsReduced maximal HGS was associated with higher all‐cause mortality, reduced overall functional status and decreased physical performance in patients with mostly advanced cancer. Similar results were found for patients with and without cancer cachexia.