Heart Failure Abnormalities Research Articles

Afterload increase challenge unmasks systolic abnormalities in heart failure with preserved ejection fraction

Provocative maneuvers have the potential to overcome the low sensitivity of resting echocardiography and biomarkers in the detection of heart failure with preserved ejection fraction (HFpEF). We investigate the mechanical response of the left ventricle to an afterload challenge in patients with preclinical and early-stage HFpEF (es-HFpEF). Three groups of patients (non-HFpEF - n=42, pre-HFpEF - n=43, and es-HFpEF - n=39) underwent echocardiography at rest and during an afterload challenge induced by handgrip maneuver combined with pneumatic constriction of limbs. Patients in the non-HF group displayed a median ΔLPSS=-4% (IQR: -10%, +2%), LPSS rest<16% in 3/42(7%) and LPSS stress<16% in 6/43(14%). Subjects in the pre-HFpEF group displayed median ΔLPSS=-3% (IQR: -10%, +5%) LPSS rest<16% in 13/43(30%) and LPSS stress<16% in 19/43 (44%). 11/43 (25%) subjects in this group increased at least one absolute point in LPSS during stress. Patients in es-HFpEF group displayed a median ΔLPSS=-10% (IQR: -18%, -1%), LPSS rest<16% in 15/39(38%) and LPSS stress<16% in 25/39(64%). Changes in LPSS (ΔLPSS) were significantly greater in es-HFpEF than pre-HFpEF (p=0.022). In multivariate analysis, this group effect was maintained after adjustment of the LPSS for systolic blood pressure, use of β-blockers, LV mass, RWT, age, and sex. Our data suggest that patients with HFpEF have a marked decrease in peak strain during acute pressure overload. Longitudinal studies are needed to test and compare the clinical impact of each pattern in early and long-term follow-ups.

Thyroid Abnormalities in Heart Failure.

The effects of hyperthyroidism and hypothyroidism on the heart and cardiovascular system are well documented. It has also been shown that various forms of heart disease including but not limited to congenital, hypertensive, ischemic, cardiac surgery, and heart transplantation cause an alteration in thyroid function tests including a decrease in serum liothyronine (T3). This article discusses the basic science and clinical data that support the hypothesis that these changes pose pathophysiologic and potential novel therapeutic challenges.

Skeletal muscle abnormalities in heart failure with preserved ejection fraction.

Almost half of all heart failure (HF) disease burden is due to HF with preserved ejection fraction (HFpEF). The primary symptom in patients with HFpEF, even when well compensated, is severe exercise intolerance and is associated with their reduced quality of life. Recently, studies showed that HFpEF patients have multiple skeletal muscle (SM) abnormalities, and these are associated with decreased exercise intolerance. The SM abnormalities are likely intrinsic to the HFpEF syndrome, not a secondary consequence of an epiphenomenon. These abnormalities are decreased muscle mass, reduced type I (oxidative) muscle fibers, and reduced type I-to-type II fiber ratio as well as a reduced capillary-to-fiber ratio, abnormal fat infiltration into the thigh SM, increased levels of atrophy genes and proteins, reduction in mitochondrial content, and rapid depletion of high-energy phosphate during exercise with markedly delayed repletion of high-energy phosphate during recovery in mitochondria. In addition, patients with HFpEF have impaired nitric oxide bioavailability, particularly in the microvasculature. These SM abnormalities may be responsible for impaired diffusive oxygen transport and/or impaired SM oxygen extraction. To date, exercise training (ET) and caloric restriction are some of the interventions shown to improve outcomes in HFpEF patients. Improvements in exercise tolerance following aerobic ET are largely mediated through peripheral SM adaptations with minimal change in central hemodynamics and highlight the importance of targeting SM to improve exercise intolerance in HFpEF. Focusing on the abnormalities mentioned above may improve the clinical condition of patients with HFpEF.

Treatments for skeletal muscle abnormalities in heart failure: sodium-glucose transporter 2 and ketone bodies.

Various skeletal muscle abnormalities are known to occur in heart failure (HF) and are closely associated with exercise intolerance. Particularly, abnormal energy metabolism caused by mitochondrial dysfunction in skeletal muscle is a cause of decreased endurance exercise capacity. However, to date, no specific drug treatment has been established for the skeletal muscle abnormalities and exercise intolerance occurring in patients with HF. Sodium-glucose transporter 2 (SGLT2) inhibitors promote glucose excretion by suppressing glucose reabsorption in the renal tubules, which has a hypoglycemic effect independent of insulin secretion. Recently, large clinical trials have demonstrated that treatment with SGLT2 inhibitors suppresses cardiovascular events in patients who have HF with systolic dysfunction. Mechanisms of the therapeutic effects of SGLT2 inhibitors for HF have been suggested to be diuretic, suppression of neurohumoral factor activation, renal protection, and improvement of myocardial metabolism, but this has not been clarified to date. SGLT2 inhibitors are known to increase blood ketone bodies. This suggests that they may improve the abnormal skeletal muscle metabolism in HF, that is, improve fatty acid metabolism, suppress glycolysis, and use ketone bodies in mitochondrial energy production. Ultimately, they may improve aerobic metabolism in skeletal muscle, suppress anaerobic metabolism, and improve aerobic exercise capacity at the level of the anaerobic threshold. The potential actions of such SGLT2 inhibitors explain their effectiveness in HF and may be candidates for new drug treatments aimed at improving exercise intolerance. In this review, we outlined the effects of SGLT2 inhibitors on skeletal muscle metabolism, with a particular focus on ketone metabolism.

Management of Hyperkalemia in Heart Failure.

Hyperkalemia is a common electrolyte abnormality in heart failure (HF) that can cause potentially life-threatening cardiac arrhythmias and sudden cardiac death. HF patients with diabetes, chronic kidney disease and older age are at higher risk of hyperkalemia. Moreover, hyperkalemia is also often associated with the use of renin-angiotensin-aldosterone system inhibitors (RAASi) including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists and sacubitril-valsartan. In clinical practice, the occurrence of hyperkalemia is a major concern among the clinicians and often limits RAASi use and/or lead to dose reduction or discontinuation, thereby reducing their potential benefits for HF. Furthermore, recurrent hyperkalemia is frequent in the long-term and is associated with an increase in hyperkalemia-related hospitalizations. Therefore, management of hyperkalemia has a special importance in HF patients. However, treatment options in chronic management are currently limited. Dietary restriction of potassium is usually ineffective with variable adherence. Sodium polystyrene sulfonate is commonly used, but its effectiveness is uncertain and reported to be associated with intestinal toxicity. New therapeutic options such as potassium binders have been suggested as potentially beneficial agents in the management of hyperkalemia. This document discusses prevalence, predictors and management of hyperkalemia in HF, emphasizing the importance of careful patient selection for medical treatment, uptitration of the doses of RAASi, regular surveillance of potassium and treatment options of hyperkalemia.

Pathophysiological and diagnostic importance of fatty acid-binding protein 1 in heart failure with preserved ejection fraction

Elevated intracardiac pressure at rest and/or exercise is a fundamental abnormality in heart failure with preserved ejection fraction (HFpEF). Fatty acid-binding protein 1 (FABP1) is proposed to be a sensitive biomarker for liver injury. We sought to determine whether FABP1 at rest would be elevated in HFpEF and would correlate with echocardiographic markers of intracardiac pressures at rest and during exercise. In this prospective study, subjects with HFpEF (n = 22) and control subjects without HF (n = 23) underwent resting FABP1 measurements and supine bicycle exercise echocardiography. Although levels of conventional hepatic enzymes were similar between groups, FABP1 levels were elevated in HFpEF compared to controls (45 [25–68] vs. 18 [14–24] ng/mL, p = 0.0008). FABP1 levels were correlated with radiographic and blood-based markers of congestion, hemodynamic derangements during peak exercise (E/e’, r = 0.50; right atrial pressure, r = 0.35; pulmonary artery systolic pressure, r = 0.46), reduced exercise cardiac output (r = − 0.49), and poor exercise workload achieved (r = − 0.40, all p < 0.05). FABP1 distinguished HFpEF from controls with an area under the curve of 0.79 (p = 0.003) and had an incremental diagnostic value over the H2FPEF score (p = 0.007). In conclusion, FABP1 could be a novel hepatic biomarker that associates with hemodynamic derangements, reduced cardiac output, and poor exercise capacity in HFpEF.

Treatment with brain-derived neurotrophic factor for skeletal muscle abnormalities in heart failure

Exercise tolerance is limited in patients with heart failure (HF), and the limited exercise tolerance is an independent determinant of poor prognosis. It is known that skeletal muscle abnormalities are important factors for limited exercise tolerance. The cause of skeletal muscle abnormalities in HF is unclear.

Altered Hemodynamics and End-Organ Damage in Heart Failure: Impact on the Lung and Kidney.

Heart failure is characterized by pathologic hemodynamic derangements, including elevated cardiac filling pressures ("backward" failure), which may or may not coexist with reduced cardiac output ("forward" failure). Even when normal during unstressed conditions such as rest, hemodynamics classically become abnormal during stressors such as exercise in patients with heart failure. This has important upstream and downstream effects on multiple organ systems, particularly with respect to the lungs and kidneys. Hemodynamic abnormalities in heart failure are affected by processes that extend well beyond the cardiac myocyte, including important roles for pericardial constraint, ventricular interaction, and altered venous capacity. Hemodynamic perturbations have widespread effects across multiple heart failure phenotypes, ranging from reduced to preserved ejection fraction, acute to chronic disease, and cardiogenic shock to preserved perfusion states. In the lung, hemodynamic derangements lead to the development of abnormalities in ventilatory control and efficiency, pulmonary congestion, capillary stress failure, and eventually pulmonary vascular disease. In the kidney, hemodynamic perturbations lead to sodium and water retention and worsening renal function. Improved understanding of the mechanisms by which altered hemodynamics in heart failure affect the lungs and kidneys is needed in order to design novel strategies to improve clinical outcomes.

The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies.

The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies.

The NADPH oxidase inhibitor apocynin improves cardiac sympathetic nerve terminal innervation and function in heart failure.

What is the central question of this study? Does NADPH oxidase activation mediate cardiac sympathetic nerve denervation and dysfunction in heart failure. What is the main findings and its importance? Cardiac sympathetic nerve terminal density and function were reduced in heart failure after myocardial infarction in rabbits. The NADPH oxidase inhibitor apocynin prevented the reduction in cardiac sympathetic nerve terminal density and function in heart failure. This suggest that NADPH oxidase activation mediates cardiac sympathetic nerve terminal abnormalities in heart failure. NADPH oxidase may be a potential therapeutic target for cardiac sympathetic denervation and dysfunction in heart failure. Congestive heart failure (CHF) is characterized by cardiac sympathetic nerve terminal abnormalities, as evidenced by decreased noradrenaline transporter (NAT) density and cardiac catecholaminergic and tyrosine hydroxylase (TH) profiles. These alterations are associated with increased reactive oxygen species (ROS). NADPH oxidase is a major source of ROS in CHF. In this study, we tested the hypothesis that NADPH oxidase activation mediates cardiac sympathetic nerve terminal abnormalities in CHF. CHF was produced by myocardial infarction (MI) in rabbits. Rabbits with MI or a sham operation were randomized to orally receive an NADPH oxidase inhibitor, apocynin (6mgkg-1 day-1 ), or placebo for 30days. MI rabbits exhibited left ventricular dilatation, systolic dysfunction, and increases in NADPH oxidase activity and 4-hydroxynonenal expression in the remote non-infarcted myocardium, all of which were prevented by treatment with apocynin. Cardiac catecholaminergic histofluorescence profiles and immunostained TH and PGP9.5 expression were decreased, and the decreases were ameliorated by apocynin treatment. NAT, TH and PGP9.5 protein and mRNA expression were reduced and the reduction was mitigated by apocynin treatment. The effects of apocynin were confirmed by utilizing the NADPH oxidase inhibitor diphenyleneiodonium in a separate experiment. In conclusion, the NADPH oxidase inhibitor apocynin attenuated increased myocardial oxidative stress and decreased cardiac sympathetic nerve terminals in CHF after MI in rabbits. These findings suggest that the activation of NADPH oxidase mediates cardiac sympathetic nerve terminal abnormalities in CHF, and the inhibition of NADPH oxidase may be beneficial for the treatment of heart failure.

Non-invasive intraventricular pressure differences estimated with cardiac MRI in subjects without heart failure and with heart failure with reduced and preserved ejection fraction

ObjectiveNon-invasive assessment of left ventricular (LV) diastolic and systolic function is important to better understand physiological abnormalities in heart failure (HF). The spatiotemporal pattern of LV blood flow velocities during...

Abstract 256: Optimal Medical Therapy Does Not Prevent Readmission in GWG-HF Patients with Ventricular Conduction Abnormalities

Background: Conduction system abnormalities in heart failure (HF) patients have been associated with worse prognosis and higher mortality. Cardiac resynchronization has been successful in reducing readmission in patients with LBBB, but not other in ventricular conduction abnormalities. Effects of co-morbidities on readmission rates in HF patients with conduction abnormalities on and optimal, guideline directed medical therapy (OGDMT) were not well investigated. Methods: The study cohort included 2583 consecutive heart failure patients with sinus, non-paced rhythm (41.4% females, 65.2 ± 14.9 years old, EF 42.2% ± 14.1%) on modern medical therapy enrolled in Get With The Guidelines (GWTG) Registry at a single academic medical center. LBBB was noted in 7.6%, IVCD in 4.1%, and RBBB in 8.21%. Common comorbidities included HTN in 68.8%, CAD in 42.2%, DM in 38%, hyperlipidemia in 51.5%, and chronic lung disease in 24.5%. Results: The HF readmissions were significantly more common in patients with conduction abnormalities (21.2 vs. 15.4%, p=0.0016). Readmission rates were similar in patients with LBBB (20.9%), RBBB (21.2%) or nonspecific IVCD (21.5%). Patients with RBBB were older (70.5±14.8 vs. 63.9±14.7, p&lt;0.01) Caucasian (81.1 vs. 71.5%, p&lt;0.01) male (68.4 vs. 58.3%, p&lt;0.01) with histories of CAD (51.4 vs. 40.2%, p&lt;0.01), CVA/TIA (14.2 vs. 9.9%, p=0.04), hyperlipidemia (60.4 vs. 51.0%, p&lt;0.01) and COPD or asthma (30.19%, p=0.04) despite fewer of them with history of smoking in last 12 months (21.2 vs. 31.5%, p=0.013). There was no difference between patients with RBBB and the rest of the cohort in utilization of ACE inhibitors, ARBs, or Hydralazine/Nitrates (77.1 vs. 82%, p=0.111), beta-adrenergic blockers (90.5 vs. 89.5%, p=0.625), or aldosterone receptor antagonists (19.6 vs. 19.5%, p=0.981). Conclusion: Ventricular conduction abnormalities are associated with increased risk of readmission in HF patients despite OGDMT. RBBB may serve as a surrogate marker for increased non-cardiac co-morbidity, where aggressive treatment of associated illness burden may translate in reduced readmission rates.

GW29-e1585 NADPH oxidase mediates cardiac sympathetic nerve terminal abnormalities in heart failure

Heart failure is characterized by cardiac sympathetic nerve terminal abnormalities, including the decreases of norepinephrine transporter (NET) density and cardiac catecholaminergic and tyrosine hydroxylase (TH) profiles. The alterations in cardiac sympathetic nerve terminals in heart failure are

Haemodynamics, dyspnoea, and pulmonary reserve in heart failure with preserved ejection fraction.

Increases in left ventricular filling pressure are a fundamental haemodynamic abnormality in heart failure with preserved ejection fraction (HFpEF). However, very little is known regarding how elevated filling pressures cause pulmonary abnormalities or symptoms of dyspnoea. We sought to determine the relationships between simultaneously measured central haemodynamics, symptoms, and lung ventilatory and gas exchange abnormalities during exercise in HFpEF. Subjects with invasively-proven HFpEF (n = 50) and non-cardiac causes of dyspnoea (controls, n = 24) underwent cardiac catheterization at rest and during exercise with simultaneous expired gas analysis. During submaximal (20 W) exercise, subjects with HFpEF displayed higher pulmonary capillary wedge pressures (PCWP) and pulmonary artery pressures, higher Borg perceived dyspnoea scores, and increased ventilatory drive and respiratory rate. At peak exercise, ventilation reserve was reduced in HFpEF compared with controls, with greater dead space ventilation (higher VD/VT). Increasing exercise PCWP was directly correlated with higher perceived dyspnoea scores, lower peak exercise capacity, greater ventilatory drive, worse New York Heart Association (NYHA) functional class, and impaired pulmonary ventilation reserve. This study provides the first evidence linking altered exercise haemodynamics to pulmonary abnormalities and symptoms of dyspnoea in patients with HFpEF. Further study is required to identify the mechanisms by which haemodynamic derangements affect lung function and symptoms and to test novel therapies targeting exercise haemodynamics in HFpEF.

Meet the First Authors.

Meet the First Authors.

Retinal microvascular dysfunction in heart failure.

Retinal vessel analysis (RVA) represents a novel, non-invasive, and reliable method to study the microcirculation in the eye. The goal of this study was to assess the extent of retinal microvascular dysfunction in patients with chronic heart failure (CHF) compared to controls and established measures of vascular function. In this prospective, single-centre, observational study, 74 patients with compensated CHF (mean age 63.5 ± 11.2 years, 32% female, mean left-ventricular ejection fraction 37 ± 12.8%), 74 patients with cardiovascular risk factors (CVRF; 64.1 ± 12.7 years, 34% female), and 74 healthy controls (HC; 57.8 ± 14.2 years, 35% female) were included. The primary endpoint, flicker-induced dilatation of retinal arterioles (FIDart), was significantly reduced in patients with CHF compared to CVRF and HC (mean FIDart 0.9 ± 0.2 vs. 2.3 ± 0.3 and vs. 3.6 ± 0.3%, respectively, both P < 0.001 before and after propensity score-weighted analysis). Similar differences were seen for venular FID. FIDart was less impaired in patients with dilated compared to ischaemic cardiomyopathy. No significant differences were observed for arteriovenous ratio and flow-mediated dilatation. Impaired FIDven was associated with echocardiographically estimated systolic pulmonary artery pressure and left atrial volume index. Retinal microvascular dilatation in response to flicker light is impaired in CHF. RVA may represent a new and useful method to non-invasively monitor microvascular abnormalities in heart failure in an easy and standardized way without the use of radiation.

Contribution of Central Abnormalities to Exertional Dyspnea and Ventilatory Response in Heart Failure with Preserved Ejection Fraction

Introduction: Exercise intolerance is attributed to cardiac and peripheral abnormalities in heart failure with preserved ejection fraction (HFpEF). However, no study has evaluated the relationships between hemodynamics, dyspnea and ventilatory response in HFpEF. Methods and Results: Subjects with invasively-diagnosed HFpEF (n = 50) and participants with dyspnea but no identifiable cardiac pathology (controls, n = 24) underwent invasive catheterization at rest and during exercise with simultaneous expired gas analysis and spiroergometry. Compared to controls, subjects with HFpEF displayed higher exercise pulmonary capillary wedge pressures (PCWP) and pulmonary artery pressures, greater Borg perceived dyspnea and fatigue scores, and increased respiratory rate relative to exercise intensity (Figure). Exercise PCWP was directly correlated with Borg dyspnea and effort scores (r = 0.31 and r = 0.39, both P < .01). The ratio of dead space ventilation to tidal volume (VD/VT) was greater in HFpEF during exercise (0.25 ± 0.09 vs. 0.33 ± 0.11, P = .002), and this was correlated with exercise PA pressures (r = 0.42, P = .0003). Compared to controls, HFpEF subjects displayed lower increase in VT during peak exercise (ΔVT 831 ± 464 vs. 454 ± 233 ml, P = .001). Peak VT was inversely correlated with exercise PCWP (r = −0.38, P = .0007). Peak VO2 was markedly impaired in HFpEF subjects (8.1 ± 2.4 vs. 14.2 ± 4.0 ml/kg/min, P < .0001) and varied inversely with exercise PCWP (r = −0.65, P < .0001). Conclusions: Central hemodynamic derangements that develop during exercise in people with HFpEF are correlated with subjective symptoms of dyspnea, impaired tidal volume reserve, and increased dead space ventilation relative to tidal volume, supporting the relevance of central hemodynamics as a key mediator of disability in HFpEF and important therapeutic target.

Electromagnetic induction and radiation-induced abnormality of wave propagation in excitable media

Continuous wave emitting from sinus node of the heart plays an important role in wave propagating among cardiac tissue, while the heart beating can be terminated when the target wave is broken into turbulent states by electromagnetic radiation. In this investigation, local periodical forcing is applied on the media to induce continuous target wave in the improved cardiac model, which the effect of electromagnetic induction is considered by using magnetic flux, then external electromagnetic radiation is imposed on the media. It is found that target wave propagation can be blocked to stand in a local area and the excitability of media is suppressed to approach quiescent but homogeneous state when electromagnetic radiation is imposed on the media. The sampled time series for membrane potentials decrease to quiescent state due to the electromagnetic radiation. It could accounts for the mechanism of abnormality in heart failure exposed to continuous electromagnetic field.

Coagulation Abnormalities in Heart Failure: Pathophysiology and Therapeutic Implications.

Heart failure (HF) represents a heterogeneous condition characterized by vulnerabilities in the blood, vasculature, and impaired flow dynamics that predispose to both arterial and venous thrombosis. Despite evidence-based advances in the medical and device management of chronic HF, it remains a leading cause of morbidity and mortality in the USA due to repeat hospitalizations and comorbid conditions such as atrial fibrillation (AF) and stroke. The presence of platelet activation and hypercoagulability in HF has been well documented. Anticoagulation is effective in HF when comorbidities such as AF and prior venous thromboembolism exist. However, data is less clear for HF in sinus rhythm. Moreover, there is a paucity of data regarding antiplatelet therapy in HF. No consensus guidelines exist regarding the precise role of antiplatelet or antithrombotic therapy in HF. This review addresses the pathophysiology of coagulation abnormalities in HF, examines the available evidence regarding the use of anticoagulants and antiplatelet agents in HF, and discusses its therapeutic implications.

Pharmacologic Approaches to Electrolyte Abnormalities in Heart Failure.

Electrolyte abnormalities are common in heart failure and can arise from a variety of etiologies. Neurohormonal activation from ventricular dysfunction, renal dysfunction, and heart failure medications can perturb electrolyte homeostasis which impact both heartfailure-related morbidity and mortality. These include disturbances in serum sodium, chloride, acid-base, and potassium homeostasis. Pharmacological treatments differ for each electrolyte abnormality and vary from older, established treatments like the vaptans or acetazolamide, to experimental or theoretical treatments like hypertonic saline or urea, or to newer, novel agents like the potassium binders: patiromer and zirconium cyclosilicate. Pharmacologic approaches range from limiting electrolyte intake or directly repleting the electrolyte, to blocking or promoting their resorption, and to neurohormonal antagonism. Because of the prevalence and clinical impact of electrolyte abnormalities, understanding both the older and newer therapeutic options is and will continue to be necessity for the management of heart failure.