Rapid Progression Of Heart Failure Research Articles

Risks of Ventricular Arrhythmia and Heart Failure in Carriers of RBM20 Variants.

Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P<0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF.

A patient with atrial fibrillation and grade III left atrial spontaneous echo contrast after borreliosis. Case report

In the presented case report, a patient with persistent atrial fibrillation developed due to borreliosis and grade III left atrial spontaneous echo contrast (SEC) according to transesophageal echocardiography, in order to rule out intracardiac thrombosis and concomitant Lyme carditis, contrastenhanced cardiac magnetic resonance imaging was performed. Given the rapid progression of heart failure on the background of tachycardia, the lack of evidence for left atrial appendage thrombosis and myocarditis, electrical cardioversion was performed with the restoration of sinus rhythm and without thromboembolic complications during further follow-up. The issues of the clinical and prognostic significance of SEC, the potential of various diagnostic methods, and the management of such patients are discussed.

Gold nanoparticle probes for colorimetric detection of plasma galectin-3: a simple and rapid approach.

Galectin-3 (Gal-3) is a carbohydrate-binding protein associated with the development and progress of heart failure. Here, we report the first colorimetric and low-cost approach for detecting and quantifying Gal-3 using gold nanoparticles (AuNPs) bioconjugated with Gal-3 antibody. The interaction of Gal-3 with the resulting nanoprobes led to a linear response of the absorbance ratio A750nm/A526nm to Gal-3 concentration, accompanied by a change in color intensity. The assay showed a linear optical response even in complex samples, such as saliva and fetal bovine serum (FBS), up to a concentration of 200 μg L-1. The limit of detection (LOD) followed the trend LODPBS (10.0 μg L-1) < LODsaliva (22.6 μg L-1) < LODFBS (25.3 μg L-1). The potential applicability of this method to the analysis of human plasma samples was also demonstrated. Compared to conventional detection techniques, this colorimetric assay provides faster results (∼1 h) and is more cost-effective due to the use of simple and unexpensive equipment. This assay represents an exciting solution for the rapid screening of high risk for rapid progression of heart failure in patient samples (Gal-3 > 25.9 μg L-1).

198 ROLE OF CARDIAC MAGNETIC RESONANCE IMAGING IN ARRHYTMICH RISK STRATIFICATION

Abstract Introduction Danon disease (DD) is a rare multi-systemic disorder firstly described by Danon et al. in 1981 and characterized by a triad consisting with hypertrophic cardiomyopathy, skeletal myopathy, and intellectual disability. It is an inherited dominant X-linked condition, due to mutations in the lysosome-associated membrane protein 2 (LAMP2) gene. Typically, males present a more severe phenotype with earlier onset and rapid heart failure progression with extracardiac manifestations; female patients manifest a milder phenotype with later onset and isolated cardiac involvement. Female carriers may develop dilated cardiomyopathy (DCM). In recent years, it has been described a severe arrhythmogenic phenotype, particularly in women, with a high risk of sudden cardiac death (SCD). Case presentation Case 1 is a 16 y.o. woman referred to our outpatient cardiomyopathies clinic, diagnosed with left ventricle (LV) hypertrophy on the basis of ECG and echocardiography, performed in 2016, in view of cutaneous nevus surgical exeresis. At echocardiographic evaluation we found an asymmetric LV hypertrophy with preserved LV ejection fraction (LVEF 65%). A cMRI was performed, showing mild LV thickening and left ventricular hypertrabeculation morphology, mainly in the LV lateral wall, but not all criteria for LV noncompaction (NC) were satisfied. There was no late gadolinium enhancement (LGE) accumulation. She underwent a genetic screening with inconclusive results, so we started a clinical outpatient follow-up showing no significant arrhythmias at ECG Holter and no limitation of physical activities. In 2021, when she was 21 yo, her father died suddenly and no autoptic examination was performed. A genetic exam was repeated, highlighting a LAMP2 gene mutation. In 2016 her 3 years older sister, Case 2, underwent a familiar screening. She had a long history of mild dyspnea occurring during exertion. Echocardiography showed asymmetric hypertrophy with marked thickening of infero-lateral wall (25 mm,) with normal systolic function (EF 70%). She underwent a cMRI, highlighting diffuse asymmetric hypertrophy (max 24 mm) with LGE in lateral wall and lower septum. First genetic test was nonconclusive but after her father's death another test was performed, demonstrating LAMP2 gene mutation. In 2021 a follow-up cMRI showed markedly reduced myocardial thickness of the apex, with a pattern of noncompaction myocardial. We found a LVEF at lower limits, depressed longitudinal function (MAPSE 8 mm) and manly severe progression of fibrotic degeneration. ECG Holter revealed premature ventricular complex, in absence of nonsustained ventricular tachycardia. Following the evolution of fibrosis, cardioverter defibrillator (ICD) implantation was performed. Case 1 was clinically stable during strict follow-up. Conclusion Cardiac magnetic resonance imaging (cMRI) may be useful in arrhythmic risk stratification, accurate systolic dysfunction evaluation, and proper timing and indication for ICD implantation.

Clinical Course and Lipid Metabolism Indicators in Patients with Chronic Heart Failure of Ischemic Genesis and Coexisting Hypothyroidism

Cardiac diseases, especially chronic heart failure which, according to the World Health Organization, affects 1.5-2% of the global population, are the number one cause of mortality and morbidity worldwide, including Ukraine. Chronic heart failure is often accompanied by endocrine disorders, especially hypothyroidism, the diagnosis of which has increased over the past 10 years, and which facilitates the rapid progression of heart failure due to reduced metabolic processes and altered lipid metabolism.&#x0D; The objective of the research was to study clinical manifestations, lipid metabolism indicators and their relationship in patients with chronic heart failure of ischemic genesis and coexisting primary hypothyroidism.&#x0D; Materials and Methods. 73 patients with the average age of 55.92±2.66 years were examined. They were divided into 2 groups: Group I included 38 patients with chronic heart failure and coexisting hypothyroidism; Group II comprised 35 heart failure patients without hypothyroidism. The clinical course of chronic heart failure itself and chronic heart failure with coexisting hypothyroidism was studied, the patients’ quality of life was evaluated, the myocardial function was studied by means of the 6-minute walk test, the indicators of lipid profile were analyzed by determining the serum levels of total cholesterol, low-density lipoprotein cholesterol. To assess thyroid function, thyroid-stimulating hormone and thyroxine levels were determined by the electrochemiluminescence immunoassay.&#x0D; Results and Discussion. The clinical course and quality of life of patients with chronic heart failure and coexisting hypothyroidism were worse as compared to patients without hypothyroidism. The serum levels of total cholesterol, low-density lipoprotein cholesterol differed between both groups of patients (p&lt;0.05).&#x0D; Conclusions. Blood lipid profile was more significantly impaired in the patients with chronic heart failure of ischemic genesis and coexisting primary hypothyroidism that could result in the rapid progression of chronic heart failure, a more severe clinical course, and more frequent complications. The quality of life was higher in patients with heart failure without hypothyroidism and their condition was significantly better.

Neuroendocrine predictors of vasoplegia after cardiopulmonary bypass

PurposeVasoplegia often complicates on-pump cardiac surgery. Systemic inflammatory response induced by extracorporeal circulation represents the major determinant, but adrenal insufficiency and postoperative vasopressin deficiency may have a role. Pathophysiological meaning of perioperative changes in endocrine markers of hydro-electrolyte balance has not still fully elucidated. Objectives of the present research study were to estimate the incidence of vasoplegia in a homogeneous cohort of not severe cardiopathic patients, to define the role of presurgical adrenal insufficiency, to evaluate copeptin and NT-proBNP trends in the perioperative.MethodsWe conducted a prospective cohort study in the cardiac intensive care unit of a tertiary referral center. We evaluated 350 consecutive patients scheduled for cardiac surgery; 55 subjects completed the study. Both standard and low-dose corticotropin stimulation tests were performed in the preoperative; copeptin and NT-proBNP were evaluated in the preoperative (T0), on day 1 (T1) and day 7 (T2) after surgery.ResultsNine subjects (16.3%) developed vasoplegic syndrome with longer bypass and clamping time (p < 0.001). Reduced response to low-dose ACTH test was not associated to vasoplegia. Preoperative copeptin > 16.9 pmol/L accurately predicted the syndrome (AUC 0.86, 95% CI 0.73–0.94; OR 1.17, 95% CI 1.04–1.32). An evident correlation was observed at 7 days postoperative between NT-proBNP and copeptin (r 0.88, 95% CI 0.8–0.93; p < 0.001).ConclusionPreoperative impaired response to low-dose ACTH stimulation test is not a risk factor for post-cardiotomic vasoplegia; conversely, higher preoperative copeptin predicts the complication. On-pump cardiac surgery could be an interesting model of rapid heart failure progression.

Outcomes in Patients With Hypertrophic Cardiomyopathy and Left Ventricular Systolic Dysfunction

BackgroundEnd-stage (ES) hypertrophic cardiomyopathy (HCM) has been considered a particularly grim and unfavorable disease complication, associated with substantial morbidity and mortality, frequently requiring heart transplant. Previous reports have included small numbers of patients with relatively short follow-up, predominantly in prior treatment eras. ObjectivesThe purpose of this study was to re-evaluate clinical profile and prognosis for end-stage heart failure in a large HCM cohort with contemporary management strategies. MethodsPatients at Tufts HCM Institute, from 2004 to 2017, were identified with ES and systolic dysfunction (ejection fraction [EF] <50%), followed for 5.8 ± 4.7 years (up to 18 years). ResultsOf the 2,447 patients, 118 (4.8%) had ES-HCM (EF 39 ± 9%; range 12% to 49%) at age 48 ± 15 years. Notably, over follow-up, 57 patients (48%) achieved clinical stability in New York Heart Association functional classes I/II with medical treatment (or cardiac resynchronization therapy), including 6 patients ≥10 years from ES diagnosis (up to 14 years). In total, 61 other patients (52%) developed refractory heart failure to disabling New York Heart Association functional classes III/IV (5.2%/year); 67% have survived, including 31 with heart transplant. Of the 118 ES patients, 21 had appropriate implantable cardioverter-defibrillator (ICD) therapy terminating potentially lethal tachyarrhythmias, with no difference in frequency of events in patients with EF 35% to 49% versus EF <35% (17% vs. 19%; p = 0.80). With all available treatment modalities, ES-related mortality was 1.9%/year, with 10-year survival of 85% (95% confidence interval: 77% to 94%). Mortality was 4-fold lower than previously reported for ES (8.0%/year), but exceeded 10-fold HCM with preserved EF (0.2%/year; p < 0.001). ConclusionsAlthough ES remains an important complication of HCM, contemporary treatment strategies, including ICDs and heart transplant, are associated with significantly lower mortality than previously considered. Primary prevention ICDs should be considered when EF is <50% in HCM. Rapid heart failure progression is not an inevitable consequence of ES, and some patients experience extended periods of clinical stability.

Rapid Progression of Heart Failure in a Patient with Idiopathic Inflammatory Myopathy.

Idiopathic inflammatory myopathy (IIM) is a rare autoimmune myopathy that includes polymyositis, dermatomyositis, inclusion body myositis and autoimmune necrotizing myositis. Cardiac involvement was considered a rare occurrence in IIM however, recent reports suggests that cardiac involvement is a common feature and portends poor prognosis as it is usually encountered in advanced disease. IIM leads to myocarditis with subsequent development of myocardial fibrosis, cardiac conduction system disease and cardiomyopathy resulting in both systolic and diastolic heart failure. Conduction abnormalities such as first, second and third degree atrioventricular blocks, right and left bundle branch blocks associated with IIM have been reported. We present a case of a 44-year-old woman with biopsy proven-IIM whose left ventricular ejection fraction (LVEF) and electrocardiogram (ECG) were recorded as normal two years prior. On presentation to our hospital ECG revealed atrial tachycardia and 2D echocardiogram revealed heart failure with reduced ejection fraction (20-30%). Patient quickly progressed to complete heart block. A cardiac resynchronization therapy-defibrillator (CRT-D) insertion was planned but patient succumbed to sepsis.

A Practical Approach to the Identification and Management of Sleep-Disordered Breathing in Heart Failure Patients.

Sleep-disordered breathing (SDB) is a major health problem affecting much of the general population. Although SDB is responsible for rapid progression of heart failure (HF) and the worsening morbidity and mortality, advanced HF state is associated with accelerated development of SDB. In the face of recent developments in SDB treatment and availability of effective therapeutic options known to improve quality of life, exercise tolerance, and heart function, most HF patients with SDB are left unrecognized and untreated. This article provides an overview of SDB in HF with focus on practical approaches intended to facilitate screening and treatment.

Limb-girdle muscular dystrophy with severe heart failure overlapping with lipodystrophy in a patient with LMNA mutation p.Ser334del

Laminopathies, a group of heterogeneous disorders associated with lamin A/C gene (LMNA) mutations, encompass a wide spectrum of clinical phenotypes, which may present as separate disease or as overlapping syndromes. We describe a 35-year-old female in whom a novel sporadic heterozygous mutation c.1001_1003delGCC (p.Ser334del) of the LMNA gene was found. The patient presented with overlapping syndrome of heart failure secondary to dilated cardiomyopathy, limb-girdle dystrophy and partial lipodystrophy. Endomyocardial biopsy revealed strong up-regulation of HLA classes I and II antigens on microvessels and induction of the class I antigens on cardiomyocytes. On muscle biopsy, a wide range of fiber sizes and small clusters of inflammatory infiltrations were found. In the rapid progression of heart failure with arrhythmias or conduction defect, accompanied with muscle atrophy and lipodystrophy, the genetic disease should be taken into consideration. In addition, undefined inflammatory response and fibrosis in the heart or skeletal muscle might further justify screening of the lamin A/C gene.

Differences in biochemical and genetic biomarkers in patients with heart failure of various etiologies

Background/objectivesTo evaluate whether biomarkers reflecting pathophysiological pathways and selected single nucleotide polymorphisms differ between patients (pts) with heart failure (HF). Methods110 pts with were involved, including HF pts with preserved ejection fraction (HFpEF, n=51) with hypertensive origin, HF pts with reduced ejection fraction (HFrEF) with ischemic aetiology (ICM) (n=32) and HFrEF with dilated cardiomyopathy (DCM) (n=27). We assessed selected HF biomarkers, echocardiographic examinations and functional polymorphisms selected from six candidate genes: CYP27B1, NOS3, IL-6, TGF beta, TNF alpha, and PPAR gamma. ResultsHigher concentrations of TNF alpha were observed in pts with hypertensive HFpEF compared to pts with DCM (p=0.008). Pts with HFpEF had higher concentrations of TGF beta 1 compared to DCM and ICM (p=0.0001 and p=0.0003, respectively). For the NOS3 −786 C/T rs2070744 polymorphism in DCM there were significantly more CT heterozygotes than in ICM and HFpEF. In multivariate analysis TGF beta 1 (p=0.001) and syndecan 4 (p=0.001) were the only factors distinguishing HFrEF pts with DCM vs HFpEF and also TGF beta 1 (p=0.001) and syndecan 4 (p=0.023) were the only factors distinguishing HFrEF pts with ICM vs HFpEF pts. ConclusionsInflammation mediated through TNF alpha and TGF beta 1 may represent an important component of an inflammatory response that partially drives the pathophysiology of HFpEF. NOS3 −786 C/T rs2070744 polymorphism in DCM may serve as a marker for more rapid progression of heart failure. The only biomarkers independently distinguishing HFpEF and HFrEF are syndecan 4 and TGF beta 1.

A hole in my heart: mitral abscess and fistula.

A 73-year-old male was admitted with a 2-week history of shortness of breath, fatigue, fever, and frequent falls at home. The patient reported a history of diabetes mellitus and multiple myeloma requiring intermittent chemotherapy. Blood cultures were positive for methicillin-sensitive Staphylococcus aureus and intravenous antibiotics were initiated. A transesophageal echocardiogram (Fig. 1a) showed prolapse of the posterior leaflet of the mitral valve with mobile densities on the ventricular surface and a fluctuant mitral annulus suggestive of vegetation (arrowhead) and abscess (arrow). Severe mitral regurgitation was noted through the cavity with flow reversal in both the right and left upper pulmonary veins. Color-flow Doppler showed aliasing through the abscess (Fig. 1b), suggesting an extracardiac conduit. The video in the online Supplementary Data captures the large ruptured abscess creating an external conduit permitting regurgitant flow from the left ventricle to the left atrium. During hospitalization the patient developed respiratory failure requiring intubation secondary to rapid progression of heart failure. Surgical repair was subsequently pursued as this was felt to be the patient’s only chance at survival. At the time of surgery, the patient was found to have a large abscess cavity which had eroded through the myocardium involving the entire middle and most of the lateral segments of the posterior mitral valve. Further debridement indicated separation through the atrioventricular groove creating a fistula communicating with the pericardium. This fistula was repaired along with pericardial patch and replacement of the mitral valve. The patient responded well post-operatively and several months later showed improvement in symptoms and returned exercise tolerance. Echocardiography remains a staple in diagnosing infective endocarditis (IE) through modified Duke Criteria and should be performed in all patients with a moderate or high suspicion of endocarditis [1]. S. aureus IE has been associated with higher secondary complications rates and higher mortality [1, 2]. For advanced and destructive disease such as in our case, surgical intervention decreases mortality rates especially in patients with S. aureus IE [1–4]. Although post-operative surgical mortality rates have improved, and are now \10 % overall, they can be much higher in patients presenting with heart failure [2]. Recent valvular heart disease guidelines issued by the American College of Cardiology support surgical evaluation in patients with large abscesses, perivalvular extension, fistulas and severe valvular insufficiencies as in our case [4]. Our patient was fortunate enough to have a good result because of early surgical intervention with extensive debridement and mitral valve replacement. Electronic supplementary material The online version of this article (doi:10.1007/s12574-015-0266-0) contains supplementary material, which is available to authorized users.

Heart affected by amyloidosis – a case study (RCD code: III-3A.2)

We present a case of a 65-year old woman, who was admitted to hospital due to recurrent pulmonary oedema. Patient's history included chronic obstructive pulmonary disease. Echocardiography revealed a concentric hypertrophy of the left ventricle walls without the narrowing of the outflow tract, accompanied by the mild/moderate mitral stenosis, preserved systolic and mildly impaired diastolic function of the left ventricle. Those comorbidities were not severe but their coexistence contributed to rapid heart failure progression. During another admission for pulmonary oedema the patient had cardiac arrest in the mechanism of the pulseless electrical activity, which triggered the diagnostics of amyloidosis. Right heart catheterization was performed showing an unusually high wedge pressure. Histological analysis confirmed the diagnosis of amyloid light-chain (AL) amyloidosis, so the patient was scheduled for the first course of chemotherapy. Unfortunately, shortly after discharge, the patient developed pulmonary oedema and died before an admission to the hospital. This case shows the adverse course of the disease, fast progression of unspecific symptoms that may attribute to multiple comorbidities. JRCD 2015; 2 (5): 156–160

Unsuccessful treatment of accelerated hypertension and persistent hyperkinetic state in a haemodialysed patient with high-output arteriovenous fistula

The case we describe concerns a rapid progression of heart failure (HF) in a patient with hypertension crises (HC), haemodialysed (HD) with the use of a high-output arteriovenous fistula (AVF). The 48-year-old male with a body mass index of 19.27 kg/m2, renal insufficiency due to glomerulonephritis, treated with HD for two years (3 × 4.0 h/week), and with uncontrolled hypertension was admitted to the Military Institute of Medicine. On examination, reduced exercise tolerance, paroxysmal nocturnal dyspnoea and blood pressure (BP) 190/90 mm Hg were found. Laboratory tests revealed NT-pro B-type natriuretic peptide 302,009.0 pg/mL (n < 300.0). Echocardiography (ECHO) showed left ventricular (LV) hypertrophy (LV mass index [LVMI] 345.81 g/m2), enlarged LV diastolic diameter [LVDD] 7.15 cm), with slightly decreased ejection fraction (EF 49%), Doppler signs of elevated cardiac output (CO 15.05 L/min; cardiac index (CI) 8.91 L/min/m2), and pseudonormalised pattern of mitral inflow with elevated LV diastolic pressure (E/E’ 31). In ultrasonographic examination of left shoulder AVF, an aneurysmal expansion of the lumen from 5.5 mm to 35 mm (Fig. 1), and significantly increased flow up to 2,532 mL/min (Fig. 2) were detected. Cardiopulmonary recirculation rate (CPR) was 0.17. Computed tomography excluded renal artery stenosis. In polysomnography, heavy central apnoea with an apnoea/hypopnoea index of 35.4/h was found. In 48-h ambulatory BP monitoring (ABPM), BP was 162/95 mm Hg. Treatment of sleep apnoea was implemented by a continuous positive airway pressure device, but this did not improve BP control. Upon discharge from hospital, the patient was overtreated with eight hypotensive drugs. After a month, HC occurred (BP 220/120 mm Hg) associated with acute coronary syndrome without ST-segment elevation. Coronarography found non-obstructive atherosclerotic plaques. Because of the suspicion of hyperkinetic state related to a lack of BP control, AVF was narrowed by implanting a polytetrafluorethylene graft of 4 mm diameter (Fig. 3). Despite AVF flow being reduced to 1,400 mL/min, after two months another HC (BP 220/125 mm Hg) with pulmonary oedema was presented. The next HC took place three months later. Although ECHO showed features of LV hypertrophy regression (LVMI 335.62 g/m2), and significant decreases of CO (8.16 L/min) and CI (4.86 L/min/m2), a decrease of EF (40%) and an LV dilatation enlargement (LVDD 7.7 cm) were also observed. AVF flow increased up to 1,750 mL/min and significant CPR 0.21 was indicated. In 24-h ABPM, BP was 173/105 mm Hg. The hypotensive treatment used has been confirmed by experts and seems to be optimal and safe for the cardiovascular system. Probably, AVF banding was performed too late, and progression of HF and lack of BP control improvement were observed. In hyperkinetic AVF, blood flow exceeds 2,000 mL/min and CPR is over 0.2–0.3. Currently, in cases of difficulties in surgical AVF creation and the necessity of haemodialysotherapy termination as a result of a lack of vascular access, banding or closure of the AVF is a very rare event. However, in some cases, early ligation of AVF may be the only effective procedure, especially when there is rapid progression of HF.

Role of ER Stress in Ventricular Contractile Dysfunction in Type 2 Diabetes

BackgroundDiabetes mellitus (DM) is associated with an increased risk of ischemic heart disease and of adverse outcomes following myocardial infarction (MI). Here we assessed the role of endoplasmic reticulum (ER) stress in ventricular dysfunction and outcomes after MI in type 2 DM (T2DM).Methodology and Principal FindingsIn hearts of OLETF, a rat model of T2DM, at 25∼30 weeks of age, GRP78 and GRP94, markers of ER stress, were increased and sarcoplasmic reticulum calcium ATPase (SERCA)2a protein was reduced by 35% compared with those in LETO, a non-diabetic control. SERCA2a mRNA levels were similar, but SERCA2a protein was more ubiquitinated in OLETF than in LETO. Left ventricular (LV) end-diastolic elastance (Eed) was higher in OLETF than in LETO (53.9±5.2 vs. 20.2±5.6 mmHg/µl), whereas LV end-systolic elastance and positive inotropic responses to β-adrenergic stimulation were similar in OLETF and LETO. 4-Phenylbutyric acid (4-PBA), an ER stress modulator, suppressed both GRP up-regulation and SERCA2a ubiquitination and normalized SERCA2a protein level and Eed in OLETF. Sodium tauroursodeoxycholic acid, a structurally different ER stress modulator, also restored SERCA2a protein level in OLETF. Though LV dysfunction was modest, mortality within 48 h after coronary occlusion was markedly higher in OLETF than in LETO (61.3% vs. 7.7%). Telemetric recording showed that rapid progression of heart failure was responsible for the high mortality rate in OLETF. ER stress modulators failed to reduce the mortality rate after MI in OLETF.ConclusionsER stress reduces SERCA2a protein via its augmented ubiquitination and degradation, leading to LV diastolic dysfunction in T2DM. Even at a stage without systolic LV dysfunction, susceptibility to lethal heart failure after infarction is markedly increased, which cannot be explained by ER stress or change in myocardial response to sympathetic nerve activation.

Galectin-3: A Novel Blood Test for the Evaluation and Management of Patients With Heart Failure

Replacement of functional myocytes with crosslinked collagen as a result of tissue fibrosis is a final common pathway that is central to the progression of heart failure (HF), irrespective of etiology. In response to a variety of mechanical and neurohormonal stimuli, macrophages secrete galectin-3, which works as a paracrine and endocrine factor to stimulate additional macrophages, pericytes, myofibroblasts, and fibroblasts. The response to this signal is cellular proliferation and secretion of procollagen I. This protein is then irreversibly crosslinked to form collagen and result in cardiac fibrosis. With a commercially available assay, galectin-3 can now be measured in blood and has been found to aid in the prognosis of both systolic and nonsystolic HF. Measurement of galectin-3 before hospital discharge, on outpatient evaluation for suspected HF, and approximately twice per year for those with stable symptoms is supported by the evidence available at this time. Levels > 25.9 ng/mL, independent of symptoms, clinical findings, and other laboratory measures, predict a patient who is likely to have rapid progression of HF, resulting in hospitalization and death. In addition, a doubling in galectin-3 level over the course of 6 months, irrespective of baseline value, identifies a high-risk patient in whom additional care management efforts and advanced therapies could be warranted.

Abstract P144: ER Stress-Mediated Reduction of SERCA2a Protein Is Not Involved in Increase in Lethal Heart Failure After Myocardial Infarction in Obese Type 2 Diabetes

Rationale: Our previous studies showed that increased endoplasmic reticulum (ER) stress in the myocardium impairs cytoprotective signaling in obese type 2 diabetes mellitus (T2DM). Objective: We examined roles of ER stress in alterations of ventricular function and mortality after myocardial infarction by T2DM. Methods and Results: SERCA2a protein level was significantly lower by 45% and Ser16- and Thr17-phosphorylated phospholamban levels tended to be lower in a rat model of T2DM (OLETF) than those in non-diabetic control rats (LETO). Treatment with an ER stress modulator, 4-phenylbutyric acid (4-PBA) or tauroursodeoxycholic acid (TUDCA), restored SERCA2a protein in OLETF to the level of that in LETO. Although left ventricular (LV) ejection fractions were comparable in OLETF and LETO, LV end-systolic elastance (1685±86 vs. 1953±68 mmHg/ml) and LVdP/dtmax (5886±337 vs. 7389±457 mmHg/s) were lower and tau was larger (12.1±0.9 vs. 8.9±0.8 msec) in OLETF. These impairments of LV function in OLETF were restored by treatment with 4-PBA (LV end-systolic elastance: 1813±58 mmHg/ml, LVdP/dtmax: 7053±546 mmHg/s and tau: 8.5±0.5 msec). Elevation of LV systolic pressure and dP/dtmax levels by dobutamine infusion was reduced, and inhibitory effects of verapamil on the dobutamine-induced positive inotropism were blunted in OLETF. In patch-clamp experiments using isolated cardiomyocytes, increase in L-type Ca 2+ channel current after isoproterenol treatment was markedly attenuated in OLETF as compared with the change in LETO. Mortality rate within 48 hrs after myocardial infarction was significantly higher in OLETF than in LETO (64.0% vs. 7.7%). Telemetric recording indicated that rapid progression of heart failure but not arrhythmia was responsible for the high mortality rate in OLETF. In contrast to the improvement of baseline ventricular dysfunction, neither 4-PBA nor TUDCA significantly reduced mortality rate after infarction in OLETF. Conclusions: ER stress plays a major role in reduction of SERCA2a by T2DM. Blunted response of cardiac L-type Ca 2+ channels to adrenoceptor activation, rather than reduced SERCA2a, may contribute to increase in lethal heart failure after myocardial infarction in T2DM.

A case of cardiac amyloidosis with rapid progression of heart failure

A case of cardiac amyloidosis with rapid progression of heart failure

Prediction of Short-Term Outcomes in Patients With Idiopathic Dilated Cardiomyopathy Referred for Transplantation Using Standard Echocardiography and Strain Imaging

Objective We sought to evaluate the short-term prognostic value of echocardiography including two-dimensional (2D) strain imaging in patients with end-stage idiopathic dilated cardiomyopathy (IDCM). Methods To evaluate the short-term (6-month) prognostic value of different parameters used for the assessment of IDCM patients referred for heart transplantation, we performed at the baseline transthoracic echocardiography including 2D strain imaging, N-terminal pro-BNP measurements, and exercise testing for all patients included in the study. After 6 months, all parameters, including endsystolic strain (ESS), peak systolic strain rate (SSR max), early and late diastolic strain rates, their ratio (diastolic strain rate E [DSR E], dialostolic strain rate A [DSR A], diastolic strain rate E and A wave ratio [DSR E/A]), and systolic intraventricular dyssynchrony indexes (IVDSI) were tested for their prognostic value to predict a patient's outcome. Results At the baseline stable patients had significantly lower transmitral E and A wave ratio (E/A), DSR E/A, higher DSR A values, longer transmitral E wave deceleration time (DcT), higher longitudinal ESS and SSR max values, lower systolic circumferential and longitudinal IVDSI. Conclusion The highest sensitivity for rapid heart failure progression was shown by DcT <100 ms, E/A > 1.5, DSR A < 0.3/s, circumferential IVDSI > 0.16, and longitudinal IVDSI > 0.22 (91%, 78%, 94%, 83%, and 75%, respectively).

Viral Detection and Tumor Necrosis Factor Alpha Profile in Tracheal Aspirates From Children With Suspicion of Myocarditis

Pediatric myocarditis is a serious disease resulting in significant morbidity and mortality. Tracheal aspirate (TA) has been demonstrated to be a sensitive diagnostic tool to detect viral agents responsible for respiratory disorders and myocardial dysfunction. Tumor necrosis factor alpha (TNFalpha) is thought to play an important role in the pathogenesis of these disorders. The aim of the present study was to investigate the presence of different viruses and the expression of TNFalpha in children with clinical suspicion of myocarditis. Forty-five TAs from children (20 males/25 females, mean age 4.4+/-5.0 y) with myocardial dysfunction and respiratory symptoms were analyzed for detection of viral genomes by using molecular techniques. In 10 cases endomyocardial biopsy was also performed due to a severe and rapid progression of heart failure. TNFalpha mRNAs of TA and TNFalpha protein plasma levels were quantified. Viral etiology was detected in 25/45 (56%) cases: the most frequent etiology was enterovirus (19 cases, 59%). Polymerase chain reaction viral concordance was found in TA and endomyocardial biopsy. TNFalpha mRNA and TNFalpha serum levels were significantly more expressed in viral cases than nonviral cases (1.26+/-0.76 vs. 0.56+/-0.76, P=0.001). More impaired cardiac function (particularly ejection fraction) was detected in viral positive than in viral negative cases (39.91+/-20.09 vs. 55.61+/-20.36, P=0.04). TA seems to be an excellent tool for viral investigation in pediatric patients with suspicion of myocarditis. The analysis of TNFalpha in TA may represent an important marker to better define patient status.