Several studies suggest that psychological factors are associated with negative outcomes and in particular higher mortality rates among heart failure (HF) patients. We aimed to evaluate the effect sizes of depression and anxiety on all-cause mortality in HF patients. We conducted a systematic review according to the PRISMA methodology. We searched for studies on depression or anxiety effects on all-cause mortality among HF patients published up to June 2015. A number of 26 and 6 articles met inclusion criteria for depression (total 80,627 patients) and anxiety (total 17,214 patients), respectively. The effect estimates were pooled using random-effect meta-analysis. Depression has significant and moderately heterogeneous effect on all-cause mortality (HR = 1.57; 95 %CI 1.30–1.89, p < 0.001); adjustment for confounders led to a similar effect estimate (HR = 1.40; 95 %CI 1.22–1.60; p < 0.001). Larger studies and higher study prevalence of depression were associated with smaller effect size. The effect of anxiety on mortality outcome was small and not conclusive given the low number of studies (n = 6) (HR = 1.02; 95 % CI 1.00–1.04, p < 0.05). This systematic review and meta-analysis suggests that depression is an important and independent predictor of all-cause mortality among HF patients, while anxiety does not appear to have a strong effect. Further research is recommended toward the detection and treatment of depression.
Hospitalization for worsening chronic heart failure results in high post-discharge mortality, morbidity, and cost. However, thorough characterization, soon after discharge of patients with early post-discharge events has not been previously performed. The objectives of this study were to describe the baseline, in-hospital, and post-discharge clinical, laboratory, and neurohormonal profiles of patients hospitalized for worsening heart failure with reduced ejection fraction (EF) who die or are re-admitted for cardiovascular (CV) causes within 90 days of initial hospitalization. Retrospective analysis of 4,133 patients hospitalized for worsening heart failure with EF ≤40% in the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial, which randomized patients to tolvaptan or placebo, both in addition to standard therapy. Clinical and laboratory parameters were obtained within 48 h of admission, during hospitalization, and post-discharge weeks 1, 4, 8, and every 8 weeks thereafter for a median of 9.9 months. Patients with events within 90 days were compared with those with later/no events. All-cause mortality (ACM) and CV re-hospitalization were independently adjudicated. Within 90 days of admission, 395 patients (9.6%) died and 801 patients (19.4%) were re-hospitalized for CV causes. Significant baseline and longitudinal differences were seen between groups with early versus later (>90 days) or no events at 12 months post-randomization. Post-discharge outcomes were similar in the tolvaptan and placebo groups. Patients with early post-discharge events experienced clinically significant worsening in signs and symptoms, laboratory values, and neurohormonal parameters soon after discharge. Identifying these abnormalities may facilitate efforts to reduce post-discharge mortality and re-hospitalization.
Although treatment for heart failure induced by cancer therapy has improved in recent years, the prevalence of cardiomyopathy due to antineoplastic therapy remains significant worldwide. In addition to traditional mediators of myocardial damage, such as reactive oxygen species, new pathways and target cells should be considered responsible for the impairment of cardiac function during anticancer treatment. Accordingly, there is a need to develop novel therapeutic strategies to protect the heart from pharmacologic injury, and improve clinical outcomes in cancer patients. The development of novel protective therapies requires testing putative therapeutic strategies in appropriate animal models of chemotherapy-induced cardiomyopathy. This Position Paper of the Working Group on Drug Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology aims to: (1) define the distinctive etiopatogenetic features of cardiac toxicity induced by cancer therapy in humans, which include new aspects of mitochondrial function and oxidative stress, neuregulin-1 modulation through the ErbB receptor family, angiogenesis inhibition, and cardiac stem cell depletion and/or dysfunction; (2) review the new, more promising therapeutic strategies for cardioprotection, aimed to increase the survival of patients with severe antineoplastic-induced cardiotoxicity; (3) recommend the distinctive pathological features of cardiotoxicity induced by cancer therapy in humans that should be present in animal models used to identify or to test new cardioprotective therapies.
The aim of this study is to perform a systematic review of the costing methodological approaches adopted by published cost-of-illness (COI) studies. A systematic review was performed to identify cost-of-illness studies of heart failure published between January 2003 and September 2015 via computerized databases such as Pubmed, Wiley Online, Science Direct, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL). Costs reported in the original studies were converted to 2014 international dollars (Int$). Thirty five out of 4972 studies met the inclusion criteria. Nineteen out of the 35 studies reported the costs as annual cost per patient, ranging from Int$ 908.00 to Int$ 84,434.00, while nine studies reported costs as per hospitalization, ranging from Int$ 3780.00 to Int$ 34,233.00. Cost of heart failure increased as condition of heart failure worsened from New York Heart Association (NYHA) class I to NYHA class IV. Hospitalization cost was found to be the main cost driver to the total health care cost. The annual cost of heart failure ranges from Int$ 908 to Int$ 40,971 per patient. The reported cost estimates were inconsistent across the COI studies, mainly due to the variation in term of methodological approaches such as disease definition, epidemiological approach of study, study perspective, cost disaggregation, estimation of resource utilization, valuation of unit cost components, and data sources used. Such variation will affect the reliability, consistency, validity, and relevance of the cost estimates across studies.
A large body of evidence exists indicating that autonomic imbalance is characteristic of heart failure, with several parameters of autonomic function associated with adverse clinical outcomes. The aim of this systematic review and meta-analysis was to investigate the effects of exercise training on parameters of autonomic function in patients with heart failure and where possible quantify the size of the effect. We conducted database searches (PubMed, EMBASE and Cochrane Trials Register to 31 March 2017) for exercise-based rehabilitation trials in heart failure; using search terms, exercise training, autonomic function, heart rate recovery, heart rate variability and muscle sympathetic nerve activity. Pooled data indicated a statistically significant increase in heart rate recovery at 1 min (HRR1) in exercise compared to control groups, mean difference 5.90 bpm (95%CI 5.12, 6.69; p < 0.00001). Pooled data also indicated that exercise training improved the short-term heart rate variability (HRV) parameters of root mean square of successive differences between normal heart beats (RMSSD (ms)) [mean difference 10.44 (95%CI 0.60, 20.28, p = 0.04)] and high-frequency normalised units (HFnu) [mean difference 7.72 (95%CI 3.32, 12.12, p = 0.0006), which are predominantly reflective of parasympathetic activity. Analyses also indicated a statistically significant decrease in muscle sympathetic nerve activity (MSNA) bursts/minute (mean difference − 11.09 (95%CI − 16.18, − 6.00; p < 0.0001) and MSNA bursts/100 heart beats (mean difference − 15.44 (95%CI − 20.95, −9.92; p < 0.00001) in exercise groups compared to controls. With improvements in HRR, HRV and MSNA, exercise training appears to facilitate an improvement in parasympathetic tone and reduction in sympathetic activity.
Cardiovascular magnetic resonance (CMR) is a versatile imaging modality that enables aetiological assessment and provides additional information to that of standard echocardiography in a significant proportion of patients with heart failure. In addition to highly accurate and reproducible assessment of ventricular volumes and replacement fibrosis, multiparametric mapping techniques have rapidly evolved to further expand the diagnostic and prognostic applications in various conditions ranging from acute inflammatory and ischaemic cardiomyopathy, to cardiac involvement in systemic diseases such as sarcoidosis and iron overload cardiomyopathy. In this review, we discuss the established role of T2* imaging and rapidly evolving clinical applications of myocardial T2 mapping as quantitative adjuncts to established qualitative imaging techniques.
Iron deficiency or overload poses an increasingly complex issue in cardiovascular disease, especially heart failure. The potential benefits and side effects of iron supplementation are still a matter of concern, even though current guidelines suggest therapeutic management of iron deficiency. In this review, we sought to examine the iron metabolism and to identify the rationale behind iron supplementation and iron chelation. Cardiovascular disease is increasingly linked with iron dysmetabolism, with an increased proportion of heart failure patients being affected by decreased plasma iron levels and in turn, by the decreased quality of life. Multiple studies have concluded on a benefit of iron administration, even if just for symptomatic relief. However, new studies field evidence for negative effects of dysregulated non-bound iron and its reactive oxygen species production, with concern to heart diseases. The molecular targets of iron usage, such as the mitochondria, are prone to deleterious effects of the polyvalent metal, added by the scarcely described processes of iron elimination. Iron supplementation and iron chelation show promise of therapeutic benefit in heart failure, with the extent and mechanisms of both prospects not being entirely understood. It may be that a state of decreased systemic and increased mitochondrial iron levels proves to be a useful frame for future advancements in understanding the interconnection of heart failure and iron metabolism.
Heart failure with preserved ejection fraction (HFpEF) is a common disorder generating high mortality and important morbidity prevalence, with a very limited medical treatment available. Studies have shown that the pathophysiological hallmark of this condition is an elevated left intra-atrial pressure (LAP), exertional dyspnea being its clinical manifestation. The increasing pressure from LA is not based on volume overload (such as in heart failure with reduced ejection fraction) but on a diastolic left ventricular (LV) dysfunction combined with an inter-atrial dyssynchrony mimicking a pseudo-pacemaker syndrome. In this review, we aimed to summarize current knowledge and discuss future directions of the newest interventional percutaneous therapies of HFpEF. Novel interventional approaches developed to counter these mechanisms are as follows: LA decompression (inter-atrial shunt devices), enhancement of LV compliance (LV expanders), and inter-atrial resynchronization therapy (LA permanent pacing). To date, inter-atrial shunt devices (IASD) are the most studied, being the only devices currently tested in a phase 3 trial. Recent data showed that IASD are feasible, safe, and have a short-term clinical benefit in HFpEF patients. LV expanders and LA pacing therapy present with a smaller clinical benefit compared with IASD, but they are safe, without any major adverse outcomes currently noted. With further development and improvement of these mechanism-specific devices, it will be interesting to determine in the future whether a complex intervention of multiple HFpEF device implantation will be safe and have further benefits in HFpEF patients.
The efficacy and safety of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure (HF) are controversial. To explore the role of MRAs in HF patients with an ejection fraction of no more than 45%, we conducted a network meta-analysis of randomized controlled trials (RCTs). We systematically searched PubMed, Embase, the Cochrane Library, and Clinicaltrials. RCTs involving the efficacy and/or safety of the use of MRAs in patients with HF were included. Outputs are presented as the surface under the cumulative ranking area (SUCRA) probabilities. Thirteen RCTs involving a total of 13,597 participants were included. Finerenone 10 mg was associated with the lowest probability of achieving at cardiovascular mortality (SUCRA, 5.0%), followed by finerenone 7.5 mg (SUCRA, 31.6%). In reducing N-terminal pro-B-type natriuretic peptide, finerenone 15 mg and finerenone 7.5 mg ranked the best and second best (SUCRA 68.1% and 63.8%, respectively), followed by finerenone 10 mg (SUCRA 59.2%). Spironolactone and canrenone have a higher risk of hyperkalemia and renal deterioration. Regarding the prevention of worsening renal function, finerenone 7.5 mg (SUCRA 14.3%) was the best treatment, followed by finerenone 2.5 mg (SUCRA 16.3%) and finerenone 10 mg (SUCRA 25.6%). Compared with spironolactone and eplerenone, finerenone 10 mg was associated with low risk in the occurrence of cardiovascular mortality, hospitalization, and adverse events (P < 0.01). This network meta-analysis is the first to find that finerenone 7.5–10 mg has the highest probability of being the optimal alternative among MRAs in the treatment of HF patients with an ejection fraction of no more than 45%.
Pathological cardiac remodeling is induced through multiple mechanisms that include neurohumoral and biomechanical stress resulting in transcriptional alterations that ultimately become maladaptive and lead to the development of heart failure (HF). Although cardiac transcriptional remodeling is mediated by the activation of numerous signaling pathways that converge on a limited number of transcription factors (TFs) that promote hypertrophy (pro-hypertrophic TFs), the current therapeutic approach to prevent HF utilizes pharmacological inhibitors that largely target specific receptors that are activated in response to pathological stimuli. Thus, there is limited efficacy with the current pharmacological approaches to inhibit transcriptional remodeling associated with the development of HF. Recent evidence suggests that these pro-hypertrophic TFs co-localize at enhancers to cooperatively activate transcription associated with pathological cardiac remodeling. In disease states, including cancer and HF, evidence suggests that the general transcriptional machinery is disproportionately bound at enhancers. Therefore, pharmacological inhibition of transcriptional machinery that integrates pro-hypertrophic TFs may represent a promising alternative therapeutic approach to limit pathological remodeling associated with the development of HF.
Heart failure (HF) is mainly caused by left ventricular (LV) impairment of function, hence detailed assessment of its structure and function is a clinical priority. The frequent involvement of the left atrium (LA) and the right ventricle (RV) in the overall cardiac performance has recently gained significant interest with specific markers predicting exercise intolerance and prognosis being proposed. The LA and RV are not anatomically separated from the LV, while the LA controls the inlet the RV shares the interventricular septum with the LV. Likewise, the function of the two chambers is not entirely independent from that of the LV, with the LA enlarging to accommodate any rise in filling pressures, which could get transferred to the RV via the pulmonary circulation. In the absence of pulmonary disease, LA and RV function may become impaired in patients with moderate-severe LV disease and raised filling pressures. These changes can often occur irrespective of the severity of systolic dysfunction, thus highlighting the important need for critical assessment of the function of the two chambers. This review evaluates the pivotal role of the left atrium and right ventricle in the management of HF patients based on the available evidence.
Acute heart failure hospitalizations complicated by diuretic resistance are associated with worse outcomes. Yet, quantification of the frequency and accompanying risk from loop diuretic resistance is limited by the absence of a comprehensive definition with universal clinical application. Herein, we outline limitations of the current metrics used to identify and define diuretic resistance. We discuss the best available methods to identify and prognosticate outcomes in diuretic resistance. We propose a mechanism-based classification system of diuretic resistance by anatomical location as follows: pre-nephron resistance, pre-loop of Henle resistance, loop of Henle resistance, and post-loop of Henle resistance. Within this paradigm, we compare and contrast historical beliefs of resistance mechanisms with current literature specific to patients with heart failure. We recommend a treatment pathway to restore diuretic efficacy with a literature review of the various combination diuretic strategies and ongoing clinical trials that may impact current best practices.
The study tests the hypothesis that in patients admitted with acutely decompensated heart failure (ADHF), achievement of adequate body hydration status with intensive medical therapy, modulated by combined bioelectrical vectorial impedance analysis (BIVA) and B-type natriuretic peptide (BNP) measurement, may contribute to optimize the timing of patient’s discharge and to improve clinical outcomes. Three hundred patients admitted for ADHF underwent serial BIVA and BNP measurement. Therapy was titrated to reach a BNP value of 250 pg/ml). Worsening of renal function (WRF) was evaluated during hospitalization. Death and rehospitalization were monitored with a 6-month follow-up. BNP value on discharge of ≤250 pg/ml led to a 25% event rate within 6 months (Group A: 17.4%; Group B: 21%, Chi2; n.s.), whereas a value >250 pg/ml (Group C) was associated with a far higher percentage (37%). At discharge, body hydration was 73.8 ± 3.2% in the total population and 73.2 ± 2.1, 73.5 ± 2.8, 74.1 ± 3.6% in the three groups, respectively. WRF was observed in 22.3% of the total. WRF occurred in 22% in Group A, 32% in Group B, and 20% in Group C (P = n.s.). Our study confirms the hypothesis that combined BNP/BIVA sequential measurements help to achieve adequate fluid balance status in patients with ADHF and can be used to drive a “tailored therapy,” allowing clinicians to identify high-risk patients and possibly to reduce the incidence of complications secondary to fluid management strategies.
Heart failure is a complex clinical syndrome and represents the final path of numerous heart diseases. Coronary artery disease is recognized as the primary risk factor for heart failure development, being the main etiological factor in more than 50% of heart failure patients in North America and Europe. Regardless of overt coronary artery disease, myocardial ischemia is a common finding in failing hearts, likely due to structural or functional coronary circulation alterations. Ischemia is a self-propagating process which irreversibly impairs the cardiac function and negatively impacts prognosis. Thus, a better and thorough understanding of myocardial ischemia pathophysiology in heart failure would likely lead to significantly improved outcomes in these patients. This review aims to describe the mechanisms of myocardial ischemia and coronary artery disease in heart failure, focusing on coronary circulation dysfunctions due to increased parietal stress or non-obstructive coronary disease, and discussing the association and management of coronary artery disease in patients with heart failure.
Post-cardiac surgery acute kidney injury (AKI) is common and is associated with a significant increase in morbidity and mortality. We aimed to systematically review randomised trials that assessed the renoprotective utility of pharmacological agents in patients undergoing cardiac surgery. We searched PubMed, Embase and the Cochrane Central Register of Controlled Trials for randomised controlled trials comparing renoprotective pharmacological interventions with control in adult patients undergoing cardiac surgery with cardiopulmonary bypass. We extracted data for mortality, need for renal replacement therapy (RRT), incidence of AKI, and creatinine clearance at 24–48 h. About 49 randomised controlled trials involving 4605 patients were included. Pharmacological interventions included dopamine, fenoldopam, calcium channel antagonists, natriuretic peptides, diuretics, and N-acetylcysteine. Most trials were of poor quality, with small sample sizes, under-reporting of randomisation procedure, allocation concealment and method of blinding. No pharmacological intervention significantly reduced mortality. Fenoldopam and Atrial Natriuretic Peptide (ANP) reduced the need for renal replacement therapy by 5% (NNT 20, 95% CI 11.3, 83.0) and 3.5% (NNT 29, 95% CI 17.1, 84.4), respectively. Brain Natriuretic Peptide resulted in a 10% reduction in the incidence of AKI (NNT 11, 95% CI 6.2, 32.0). Dopamine caused a significant reduction in creatinine clearance (−4.26 ml/min, 95% CI −7.14, −1.39). The quality of studies that have assessed pharmacological renoprotective agents in cardiac surgery is generally poor. Fenoldopam, ANP and BNP show evidence of renoprotection. Randomised studies evaluating the effect of novel renoprotective agents that are powered to detect clinically relevant differences in outcomes are required.
Resuscitation guidelines remain uniform across all cardiac arrest patients, focusing on the delivery of chest compressions to a standardized rate and depth and algorithmic vasopressor dosing. However, individualizing resuscitation to the appropriate hemodynamic and ventilatory goals rather than a standard one-size-fits-all treatment seems a promising new therapeutic strategy. In this article, we present a new physiology-guided treatment strategy to titrate the resuscitation efforts to patient's physiologic response after cardiac arrest. This approach can be applied during resuscitation attempts in highly monitored patients, such as those in the operating room or the intensive care unit, and could serve as a method for improving tissue perfusion and oxygenation while decreasing post-resuscitation adverse effects.
The majority of patients with chronic heart failure (HF) receive long-term treatment with loop diuretics. The comparative effectiveness of different loop diuretics is unknown. We searched PubMed, clinicaltrials.gov, the Cochrane Central Register of Controlled Trials and the European Union Clinical Trials Register for randomised clinical trials exploring the efficacy of the loop diuretics azosemide, bumetanide, furosemide or torasemide in patients with HF. Comparators included placebo, standard medical care or any other active treatment. The primary endpoint was all-cause mortality. Secondary endpoints included cardiovascular mortality, HF-related hospitalisation and any combined endpoint thereof. Hypokalaemia and acute renal failure were defined as additional safety endpoints. Evidence was synthesised using network meta-analysis (NMA). Thirty-four trials reporting on 2647 patients were included. The overall quality of evidence was rated as moderate. NMA demonstrated no significant differences between loop diuretics with respect to all-cause mortality, cardiovascular mortality or hypokalaemia. In contrast, torasemide ranked best in terms of HF hospitalisation, and there was a trend towards benefits with torasemide with regard to occurrence of acute renal failure. Sensitivity analyses excluding trials with a follow-up <6months, trials with a cross-over design and those including <25 patients confirmed the main results. We found no significant superiority of either loop diuretic with respect to mortality and safety endpoints. However, clinicians may prefer torasemide, as it was associated with fewer HF-related hospitalisations.
Cardiorenal syndrome (CRS) results from the complex and bidirectional interaction between the failing heart and the kidneys. Limited information exists about the pathophysiology and treatment options for worsening kidney function in the setting of heart failure with preserved ejection fraction (HFpEF). This review summarizes the salient pathophysiological pathways in CRS in patients with HFpEF, with emphasis on type 1 and type 2 phenotypes, and outlines diagnostic and therapeutic strategies that are applicable in this population. Elevated central venous and intra-abdominal pressure, left ventricular hypertrophy, LV strain, RAAS activation, oxidative injury, pulmonary hypertension, and RV dysfunction play key roles in the pathogenesis of CRS in the backdrop of HFpEF. The availability of biomarkers of renal and cardiac injury offer a new dimension in accurately diagnosing and quantifying end organ damage in CRS and will improve the accuracy of goal-directed therapies in this population. Novel targeted therapies such as the development of angiotensin/neprilysin inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors offer new territory in realizing potential benefits in reduction of cardio-renal adverse outcomes in this population. Future studies focusing exclusively on renal outcomes in patients with HFpEF are crucial in delivering optimal therapies in this subset of patients.