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1.
The conundrum of patients with obesity, exercise intolerance, elevated ventricular filling pressures and a measured ejection fraction in the normal range.
Packer, M
European journal of heart failure. 2019;(2):156-162
Abstract
Patients with obesity, a reduced exercise capacity, increased cardiac filling pressures and a measured left ventricular ejection fraction in the normal range do not have a homogeneous disorder, but instead, exhibit one of three phenotypes. First, many obese people exhibit sodium retention, plasma volume expansion and cardiac enlargement, and some are likely to have heart failure that is related to hypervolaemia, even though cardiac index and circulating levels of natriuretic peptides are not meaningfully increased. Second, in some middle-aged men and women (particularly those with minimal co-morbidities), levels of natriuretic peptides increase markedly and can lower systemic vascular resistance, thus leading to high-output heart failure (HOHF) and glomerular hyperfiltration. Third, older obese people, particularly women with multiple co-morbidities, exhibit the syndrome of heart failure with a preserved ejection fraction (HFpEF). Despite degrees of plasma volume expansion similar to HOHF, these patients exhibit only modestly increased ventricular dimensions and circulating levels of natriuretic peptides (despite a high prevalence of atrial fibrillation), and glomerular function is characteristically impaired. A conceptual framework is proposed to distinguish among the three phenotypes seen in obese patients with exercise intolerance, increased ventricular filling pressures and a measured left ventricular ejection fraction in the normal range, since they may respond differently to therapeutic interventions. Efforts are needed to enhance the recognition of heart failure in obese people and to ensure that clinical trials that are designed to study patients with HFpEF actually enrol those who have the disease.
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2.
The use of diuretics in heart failure with congestion - a position statement from the Heart Failure Association of the European Society of Cardiology.
Mullens, W, Damman, K, Harjola, VP, Mebazaa, A, Brunner-La Rocca, HP, Martens, P, Testani, JM, Tang, WHW, Orso, F, Rossignol, P, et al
European journal of heart failure. 2019;(2):137-155
Abstract
The vast majority of acute heart failure episodes are characterized by increasing symptoms and signs of congestion with volume overload. The goal of therapy in those patients is the relief of congestion through achieving a state of euvolaemia, mainly through the use of diuretic therapy. The appropriate use of diuretics however remains challenging, especially when worsening renal function, diuretic resistance and electrolyte disturbances occur. This position paper focuses on the use of diuretics in heart failure with congestion. The manuscript addresses frequently encountered challenges, such as (i) evaluation of congestion and clinical euvolaemia, (ii) assessment of diuretic response/resistance in the treatment of acute heart failure, (iii) an approach towards stepped pharmacologic diuretic strategies, based upon diuretic response, and (iv) management of common electrolyte disturbances. Recommendations are made in line with available guidelines, evidence and expert opinion.
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3.
Obesity-related heart failure with preserved ejection fraction: new treatment strategies.
Chrysant, SG, Chrysant, GS
Hospital practice (1995). 2019;(2):67-72
Abstract
OBJECTIVES Obesity has risen in the US and worldwide, and has become a major risk factor for type 2 diabetes mellitus (T2DM), hypertension, cardiovascular disease, and mostly HF with preserved ejection fraction (HFpEF). Also, the prevalence of HF is quite high in the US accounting for 6.6 million adults at present and is projected to reach 8.5 million by the year 2030 and is equally divided between HFpEF and heart failure reduced ejection fraction (HFrEF). Patients with HFpEF are resistant to treatment with drugs usually used for the treatment of HFrEF, but the reasons for this resistance are not clearly known. METHODS In order to get a better perspective on the current status of the underlying pathophysiology and treatment of patients with HFpEF, a Medline search of the English language literature was conducted between 2015 and 2018 using the terms obesity, HFpEF, diabetes, treatment, SGLT2 inhibitors, and neprilysin inhibitors and 24 pertinent papers were selected. RESULTS The review of these papers revealed that patients with HFpEF have expanded plasma volume, restricted left ventricular distension with increased end-diastolic volume and depressed natriuretic peptide levels. In this respect, drugs that cause increased diuresis and natriuresis should a reasonable choice to treat these patients. The recently FDA approved sodium-glucose cotransporter-2 (SGLT2) inhibitors for the treatment of T2DM, are a good choice, for the treatment of HFpEF, since they cause osmotic diuresis from glucose excretion and increase salt and water excretion and decrease plasma volume. In addition, they produce loss of calories leading to weight and blood pressure reduction and have shown to prevent the new onset HFpEF and decrease hospitalizations and death from this disease. CONCLUSION The results of this analysis has shown that HFpEF has different pathophysiology from HFrEF and is difficult to treat. Drugs that block renal tubular glucose reabsorption and cause osmotic diuresis and natriuresis could be a good choice to treat patients with HFpEF alone or in combination with diuretics and other drugs.
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4.
Cardiorenal syndrome in heart failure with preserved ejection fraction-an under-recognized clinical entity.
Agrawal, A, Naranjo, M, Kanjanahattakij, N, Rangaswami, J, Gupta, S
Heart failure reviews. 2019;(4):421-437
Abstract
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.
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5.
Sacubitril/valsartan: A practical guide.
Fonseca, C, Brito, D, Ferreira, J, Franco, F, Morais, J, Silva Cardoso, J, ,
Revista portuguesa de cardiologia. 2019;(5):309-313
Abstract
Renin-angiotensin-aldosterone system (RAAS) inhibitors are a cornerstone in the treatment of heart failure with reduced ejection fraction (HFrEF). Sacubitril/valsartan modulates the neurohormonal axis by inhibiting both angiotensin receptors and neprilysin, and improves neurohormonal balance more than blocking the RAAS alone. The PARADIGM-HF trial validated this new treatment option for patients with HFrEF. Sacubitril/valsartan was also more effective than enalapril in slowing disease progression by decreasing the risk of worsening heart failure requiring hospitalization or emergency admission and the need for intensified therapy, heart failure devices or cardiac transplantation. More than 70% of patients included in PARADIGM-HF were in NYHA class II, and overall, the results indicate that sacubitril/valsartan should be started in the earliest symptomatic stages of the disease. As PARADIGM-HF has excellent robustness for a cardiovascular trial, sacubitril/valsartan has been included as a new treatment option with a strong level of recommendation in the main international guidelines. This expert task force proposes a practical guide to the use of this new drug that has been endorsed by the Working Group on Heart Failure of the Portuguese Society of Cardiology.
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6.
Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond.
Tschöpe, C, Kherad, B, Klein, O, Lipp, A, Blaschke, F, Gutterman, D, Burkhoff, D, Hamdani, N, Spillmann, F, Van Linthout, S
European journal of heart failure. 2019;(1):14-22
Abstract
Heart failure (HF) is responsible for substantial morbidity and mortality and is increasing in prevalence. Although there has been remarkable progress in the treatment of HF with reduced ejection fraction (HFrEF), morbidity and mortality are still substantial. Cardiac contractility modulation (CCM) signals, consisting of biphasic high-voltage bipolar signals delivered to the right ventricular septum during the absolute refractory period, have been shown to improve symptoms, exercise tolerance and quality of life and reduce the rate of HF hospitalizations in patients with ejection fractions (EF) between 25% and 45%. CCM therapy is currently approved in the European Union, China, India, Australia and Brazil for use in symptomatic HFrEF patients with normal or slightly prolonged QRS duration. CCM is particularly beneficial in patients with baseline EF between 35% and 45%, which includes half the range of HF patients with mid-range EFs (HFmrEF). At the cellular level, CCM has been shown in HFrEF patients to improve calcium handling, to reverse the foetal myocyte gene programme associated with HF, and to facilitate reverse remodelling. This review highlights the preclinical and clinical literature related to CCM in HFrEF and HFmrEF and outlines the potential of CCM for HF with preserved EF, concluding that CCM may fill an important unmet need in the therapeutic approach to HF across the range of EFs.
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7.
Is Heart Failure with Preserved Ejection Fraction a Kidney Disorder?
Shah, KS, Fang, JC
Current hypertension reports. 2019;(11):86
Abstract
PURPOSE OF REVIEW Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome of exertional intolerance, cardiac dysfunction, and fluid overload and is associated with significant morbidity and mortality. RECENT FINDINGS As our understanding of this syndrome has evolved, we are beginning to recognize the similarities and associations with chronic kidney disease (CKD). Salt and fluid retention are common in CKD and may be the sentinel event leading ultimately to the syndrome of HFpEF. Mechanisms linking both disease states include hypervolemia, inflammation, and endothelial dysfunction, which are also common to comorbidities that drive both HFpEF and CKD. In this review, we will discuss recent clinical research focusing on HFpEF, CKD, and comorbidities including hypertension and diabetes mellitus. We will review strategies for volume management and novel therapeutic approaches with new classes of drugs, including sodium-glucose cotransporters and angiotensin receptor/neprilysin inhibitors, which may work through targeting of both the heart and the kidney. Lastly, we emphasize why focusing on the alleviation of factors provoking renal injury and slowing the progression of renal dysfunction may provide the most therapeutic benefit in patients who have been diagnosed with HFpEF.
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8.
Differences between intravenous iron products: focus on treatment of iron deficiency in chronic heart failure patients.
Martin-Malo, A, Borchard, G, Flühmann, B, Mori, C, Silverberg, D, Jankowska, EA
ESC heart failure. 2019;(2):241-253
Abstract
Iron deficiency is the leading cause of anaemia and is highly prevalent in patients with chronic heart failure (CHF). Iron deficiency, with or without anaemia, can be corrected with intravenous (i.v.) iron therapy. In heart failure patients, iron status screening, diagnosis, and treatment of iron deficiency with ferric carboxymaltose are recommended by the 2016 European Society of Cardiology guidelines, based on results of two randomized controlled trials in CHF patients with iron deficiency. All i.v. iron complexes consist of a polynuclear Fe(III)-oxyhydroxide/oxide core that is stabilized with a compound-specific carbohydrate, which strongly influences their physico-chemical properties (e.g. molecular weight distribution, complex stability, and labile iron content). Thus, the carbohydrate determines the metabolic fate of the complex, affecting its pharmacokinetic/pharmacodynamic profile and interactions with the innate immune system. Accordingly, i.v. iron products belong to the new class of non-biological complex drugs for which regulatory authorities recognized the need for more detailed characterization by orthogonal methods, particularly when assessing generic/follow-on products. Evaluation of published clinical and non-clinical studies with different i.v. iron products in this review suggests that study results obtained with one i.v. iron product should not be assumed to be equivalent to other i.v. iron products that lack comparable study data in CHF. Without head-to-head clinical studies proving the therapeutic equivalence of other i.v. iron products with ferric carboxymaltose, in the highly vulnerable population of heart failure patients, extrapolation of results and substitution with a different i.v. iron product is not recommended.
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9.
Therapeutic Approach to Patients with Heart Failure with Reduced Ejection Fraction and End-stage Renal Disease.
Inampudi, C, Alvarez, P, Asleh, R, Briasoulis, A
Current cardiology reviews. 2018;(1):60-66
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Abstract
BACKGROUND Several risk factors including Ischemic heart disease, uncontrolled hypertension, high output Heart Failure (HF) from shunting through vascular hemodialysis access, and anemia, contribute to development of HF in patients with End-Stage Renal Disease (ESRD). Guidelinedirected medical and device therapy for Heart Failure with Reduced Ejection Fraction (HFrEF) has not been extensively studied and may have limited safety and efficacy in patients with ESRD. RESULTS Maintenance of interdialytic and intradialytic euvolemia is a key component of HF management in these patients but often difficult to achieve. Beta-blockers, especially carvedilol which is poorly dialyzed is associated with cardiovascular benefit in this population. Despite paucity of data, Angiotensin-converting Enzyme Inhibitors (ACEI) or Angiotensin II Receptor Blockers (ARBs) when appropriately adjusted by dose and with close monitoring of serum potassium can also be administered to these patients who tolerate beta-blockers. Mineralocorticoid receptors in patients with HFrEF and ESRD have been shown to reduce mortality in a large randomized controlled trial without any significantly increased risk of hyperkalemia. Implantable Cardiac-defibrillators (ICDs) should be considered for primary prevention of sudden cardiac death in patients with HFrEF and ESRD who meet the implant indications. Furthermore in anemic iron-deficient patients, intravenous iron infusion may improve functional status. Finally, mechanical circulatory support with leftventricular assist devices may be related to increased mortality risk and the presence of ESRD poses a relative contraindication to further evaluation of these devices.
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10.
Derangements in adrenergic-adipokine signalling establish a neurohormonal basis for obesity-related heart failure with a preserved ejection fraction.
Packer, M
European journal of heart failure. 2018;(5):873-878
Abstract
Among patients with heart failure and a preserved ejection (HFpEF), obesity is associated with a distinct phenotype that is characterized by adiposity-driven plasma volume expansion and cardiac overfilling, which is coupled with an impairment of ventricular distensibility. These pathophysiological abnormalities may be related to the increased actions of specific adipocyte-derived signalling molecules (aldosterone, neprilysin and leptin) that work in concert with increased renal sympathetic nerve traffic and activated beta2 -adrenergic receptors to promote sodium retention, microvascular rarefaction, cardiac fibrosis and systemic inflammation. This interplay leads to striking activation of the mineralocorticoid receptor, possibly explaining why obese patients with heart failure are most likely to benefit from spironolactone and eplerenone in large-scale clinical trials. Additionally, adipocytes express and release neprilysin, which (by degrading endogenous natriuretic peptides) can further promote plasma volume expansion and cardiac fibrosis. Heightened neprilysin activity may explain the low circulating levels of natriuretic peptides in obesity, the accelerated breakdown of natriuretic peptides in HFpEF, and the cardiac decompression following neprilysin inhibition in HFpEF patients who are obese. Furthermore, as adipose tissue accumulates and becomes dysfunctional, its secretion of leptin promotes renal sodium retention, microvascular changes and fibrotic processes in the heart, and systemic inflammation; these effects may be mediated or potentiated by the activation of beta2 -adrenergic receptors. These adrenergic-adipokine interactions provide a mechanistic framework for novel therapeutic strategies to alleviate the pathophysiological abnormalities of obesity-related HFpEF. Ongoing trials are well-positioned to test this hypothesis.