Marked Diastolic Dysfunction Research Articles

Identification of novel risk profiles for ventricular arrythmias in hypertrophic cardiomyopathy through clustering analysis including left ventricular strain data

Abstract Aims The excess mortality in hypertrophic cardiomyopathy (HCM) patients is mainly attributed to the occurrence of ventricular arrythmias (VA) and sudden cardiac death (SCD). The prediction of VA remains challenging and could be improved. The aim of the study was to characterize VA risk profile in HCM patients through clustering analysis combining clinical and conventional imaging parameters with information derived from left ventricular longitudinal strain analysis (LV-LS). Methods A total of 434 HCM patients (65% men, mean age 56 years) were retrospectively included from two referral centers from two different countries and followed longitudinally (mean duration 6 years). Mechanical and temporal parameters were automatically extracted from the LV-LS segmental curves of each patient in addition to conventional clinical and imaging data. A total of 287 features were analyzed using a clustering approach (k-means). The first endpoint for ventricular arrythmias (VA) included suspected SCD, aborted cardiac arrest, appropriate ICD therapy (AIT), sustained ventricular tachycardia (SVT) and non-sustained ventricular tachycardia (NSVT) during follow-up. Results 4 clusters were identified with a higher rhythmic risk for cluster 1 and 4 (VA rates of 26%(28/108), 13%(13/97), 12%(14/120), and 31%(34/109) for cluster 1,2,3 and 4 respectively) (Figure 1). These 4 clusters have been mainly separated based on LV strain parameters with severe and homogeneous decrease of myocardial deformation for cluster 4 (global longitudinal strain (GLS) -11%), a small decrease for cluster 2 and 3 (GLS -17.2 and -16.3%, respectively) and a marked mechanical and temporal dispersion for cluster 1 associated with a moderate decrease of the GLS (-15.3%; p <0.0001 for GLS comparison between clusters) (Figure 2). Patients from cluster 4 had the most severe phenotype (mean LV mass index 123 vs. 112 g/m²; p=0.0003) with marked diastolic dysfunction (left atrial volume index (LAVI) 46.6 vs. 41.5 ml/m² for others clusters; p=0.04) and impaired exercise capacity (% predicted peak work 58.6 vs. 69.5%; p= 0.025). Patient from cluster 2 had the less severe phenotype (mean LV mass index 99.6 vs. 121 g/m²; p=0.0001 and LAVI 37.2 vs. 44.3 ml/m²; p=0.04). Patients from cluster 3 and 1 had a moderate phenotype and were older in cluster 3 (mean age 62.1 vs. 54.1 years; p < 0.0001) and had more obstructive form in cluster 1 (peak gradient LV outflow tract ≥ 30 mmHg for 36 vs. 23% of patients; p=0.046) with a larger left atrium size (LAVI 45.8 vs. 41.7 ml/m²; p=0.0023). Conclusion Using a clustering approach processing LV-LS parameters in HCM patients identified 4 clusters with specific LV-strain patterns and different rhythmic risk level. In the future, the automatic extraction and analysis of LV strain parameters could help to improve the risk stratification for SCD in HCM patients.Figure 1:Survival curvesFigure 2:Different strain patterns

Diabetes and Excess Aldosterone Promote Heart Failure With Preserved Ejection Fraction.

Background The pathobiology of heart failure with preserved ejection fraction (HFpEF) is still poorly understood, and effective therapies remain limited. Diabetes and mineralocorticoid excess are common and important pathophysiological factors that may synergistically promote HFpEF. The authors aimed to develop a novel animal model of HFpEF that recapitulates key aspects of the complex human phenotype with multiorgan impairments. Methods and Results The authors created a novel HFpEF model combining leptin receptor-deficient db/db mice with a 4-week period of aldosterone infusion. The HFpEF phenotype was assessed using morphometry, echocardiography, Ca2+ handling, and electrophysiology. The sodium-glucose cotransporter-2 inhibitor empagliflozin was then tested for reversing the arrhythmogenic cardiomyocyte phenotype. Continuous aldosterone infusion for 4 weeks in db/db mice induced marked diastolic dysfunction with preserved ejection fraction, cardiac hypertrophy, high levels of B-type natriuretic peptide, and significant extracardiac comorbidities (including severe obesity, diabetes with marked hyperglycemia, pulmonary edema, and vascular dysfunction). Aldosterone or db/db alone induced only a mild diastolic dysfunction without congestion. At the cellular level, cardiomyocyte hypertrophy, prolonged Ca2+ transient decay, and arrhythmogenic action potential remodeling (prolongation, increased short-term variability, delayed afterdepolarizations), and enhanced late Na+ current were observed in aldosterone-treated db/db mice. All of these arrhythmogenic changes were reversed by empagliflozin pretreatment of HFpEF cardiomyocytes. Conclusions The authors conclude that the db/db+aldosterone model may represent a distinct clinical subgroup of HFpEF that has marked hyperglycemia, obesity, and increased arrhythmia risk. This novel HFpEF model can be useful in future therapeutic testing and should provide unique opportunities to better understand disease pathobiology.

SERCA2a stimulation by istaroxime improves intracellular Ca2+ handling and diastolic dysfunction in a model of diabetic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by CVie Therapeutics Limited (Taipei, Taiwan) and Windtree Therapeutics (Warrington, USA) Diabetic cardiomyopathy is a multifactorial disease characterized by an early onset of diastolic dysfunction (DD) that precedes the development of systolic impairment. Mechanisms that can restore cardiac relaxation improving intracellular Ca2+ dynamics represent a promising therapeutic approach for cardiovascular diseases associated to DD. Istaroxime has the double property to accelerate Ca2+ uptake into sarcoplasmic reticulum (SR) through the SR Ca2+ pump (SERCA2a) stimulation and to inhibit Na+/K+ ATPase (NKA). The project aims to characterize istaroxime effects at a concentration (100 nM) marginally affecting NKA, in order to highlight its effects dependent on the stimulation of SERCA2a in a model of mild diabetes. Streptozotocin (STZ) treated diabetic rats were studied at 9 weeks after STZ injection in comparison to controls (CTR). Istaroxime effects were evaluated in vivo and in left ventricular (LV) preparations. STZ animals showed 1) marked DD not associated to cardiac fibrosis, 2) LV mass reduction associated to reduced LV cell dimension and T-tubules loss, 3) reduced LV SERCA2 protein level and activity and 4) slower SR Ca2+ uptake rate, 5) LV action potential (AP) prolongation and increased short-term variability (STV) of AP duration, 6) increased diastolic Ca2+, 7) unaltered SR Ca2+ content and stability in intact cells. Acute istaroxime infusion (0.11 mg/kg/min for 15 min) reduced DD in STZ rats. Accordingly, in STZ myocytes istaroxime (100 nM) stimulated SERCA2a activity and blunted STZ-induced abnormalities in LV Ca2+ dynamics. In CTR myocytes, istaroxime increased diastolic Ca2+ level due to NKA blockade albeit minimal, while its effects on SERCA2a were almost absent. SERCA2a stimulation by istaroxime improved STZ-induced DD and intracellular Ca2+ handling anomalies. Thus, SERCA2a stimulation can be considered a promising therapeutic approach for DD treatment. Abstract Figure.

SERCA2a stimulation by istaroxime improves intracellular Ca2+ handling and diastolic dysfunction in a model of diabetic cardiomyopathy.

Aims Diabetic cardiomyopathy is a multifactorial disease characterized by an early onset of diastolic dysfunction (DD) that precedes the development of systolic impairment. Mechanisms that can restore cardiac relaxation improving intracellular Ca2+ dynamics represent a promising therapeutic approach for cardiovascular diseases associated to DD. Istaroxime has the dual properties to accelerate Ca2+ uptake into sarcoplasmic reticulum (SR) through the SR Ca2+ pump (SERCA2a) stimulation and to inhibit Na+/K+ ATPase (NKA). This project aims to characterize istaroxime effects at a concentration (100 nmol/L) marginally affecting NKA, in order to highlight its effects dependent on the stimulation of SERCA2a in an animal model of mild diabetes.Methods and results Streptozotocin (STZ) treated diabetic rats were studied at 9 weeks after STZ injection in comparison to controls (CTR). Istaroxime effects were evaluated in vivo and in left ventricular (LV) preparations. STZ animals showed (i) marked DD not associated to cardiac fibrosis, (ii) LV mass reduction associated to reduced LV cell dimension and T-tubules loss, (iii) reduced LV SERCA2 protein level and activity and (iv) slower SR Ca2+ uptake rate, (v) LV action potential (AP) prolongation and increased short-term variability (STV) of AP duration, (vi) increased diastolic Ca2+, and (vii) unaltered SR Ca2+ content and stability in intact cells. Acute istaroxime infusion (0.11 mg/kg/min for 15 min) reduced DD in STZ rats. Accordingly, in STZ myocytes istaroxime (100 nmol/L) stimulated SERCA2a activity and blunted STZ-induced abnormalities in LV Ca2+ dynamics. In CTR myocytes, istaroxime increased diastolic Ca2+ level due to NKA blockade albeit minimal, while its effects on SERCA2a were almost absent.Conclusions SERCA2a stimulation by istaroxime improved STZ-induced DD and intracellular Ca2+ handling anomalies. Thus, SERCA2a stimulation can be considered a promising therapeutic approach for DD treatment.

Microvascular Loss and Diastolic Dysfunction in Severe Symptomatic Cardiac Allograft Vasculopathy.

Cardiac allograft vasculopathy (CAV) remains an important source of mortality after heart transplant. The aim of our study was to identify structural and microvasculature changes in severe CAV. The study group included heart transplant recipients with severe CAV who underwent retransplantation (severe CAV, n=20). Control groups included time from transplant matched cardiac transplant recipients without CAV (transplant control, n=20), severe ischemic cardiomyopathy patients requiring left ventricular assist device implantation (ischemic control, n=18), and normal hearts donated for research (donor control, n=10). We collected baseline demographic information, echocardiography data, and performed histopathologic examination of myocardial microvasculature. Echocardiographic features of severe CAV included lack of eccentric remodeling and presence of significant diastolic dysfunction. In contrast, diastolic function was preserved in transplant control subjects. Histopathologic examination showed increased interstitial fibrosis among severe CAV, transplant controls, and ischemic control patients. Compared with transplant controls, severe CAV subjects had reduced capillary density and increased capillary wall thickness ( P<0.05). Our results suggest that the marked diastolic dysfunction and resultant symptoms in patients with severe CAV may be secondary to the loss of microvasculature and remodeling of remaining microvessels rather than a consequence of interstitial fibrosis. The clinical significance and potential therapeutic implications of these unique microvasculature characteristics warrant further investigation.

Cardiomyocyte Functional Etiology in Heart Failure With Preserved Ejection Fraction Is Distinctive-A New Preclinical Model.

BackgroundAmong the growing numbers of patients with heart failure, up to one half have heart failure with preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF is a substantial and escalating unmet clinical need—and the lack of HFpEF‐specific animal models represents a major preclinical barrier in advancing understanding of HFpEF. As established treatments for heart failure with reduced ejection fraction (HFrEF) have proven ineffective for HFpEF, the contention that the intrinsic cardiomyocyte phenotype is distinct in these 2 conditions requires consideration. Our goal was to validate and characterize a new rodent model of HFpEF, undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology.Methods and ResultsThe selectively inbred Hypertrophic Heart Rat (HHR) strain exhibits adult cardiac enlargement (without hypertension) and premature death (40% mortality at 50 weeks) compared to its control strain, the normal heart rat. Hypertrophy was characterized in vivo by maintained systolic parameters (ejection fraction at 85%–90% control) with marked diastolic dysfunction (increased E/E′). Surprisingly, HHR cardiomyocytes were hypercontractile, exhibiting high Ca2+ operational levels and markedly increased L‐type Ca2+ channel current. In HHR, prominent regions of reparative fibrosis in the left ventricle free wall adjacent to the interventricular septum were observed.ConclusionsThus, the cardiomyocyte remodeling process in the etiology of this HFpEF model contrasts dramatically with the suppressed Ca2+ cycling state that typifies heart failure with reduced ejection fraction. These findings may explain clinical observations, that treatments considered appropriate for heart failure with reduced ejection fraction are of little benefit for HFpEF—and suggest a basis for new therapeutic strategies.

Abstract 245: Heart Failure With Preserved Ejection Fraction- a New Animal Model and a Novel Mechanistic Perspective

Diagnosis of heart failure with preserved ejection fraction (HFpEF) is becoming the prevalent form of disease type. Established treatments for heart failure with reduced ejection fraction (HFrEF) have proven minimally effective for HFpEF. This may reflect differences in underlying cardiomyocyte pathophysiology. In HFrEF cardiomyocyte phenotype is characterized by impaired contractile response and diminished systolic Ca 2+ levels. Studies of intact HFpEF-derived cardiomyocytes are lacking. Progress in understanding the etiology of HFpEF has been impeded by limited availability of appropriate pre-clinical models. Our goal was to validate and characterize a new rodent model of HFpEF, the ‘Hypertrophic Heart Rat’ (HHR), undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology. The selectively inbred HHR strain exhibits adult cardiac enlargement (without hypertension) and premature mortality (40% at age 50 weeks) compared to the control ‘Normal Heart Rat’ (NHR). Echo analyses established that cardiac hypertrophy was characterized in vivo by maintained systolic parameters (i.e. ejection fraction at 85-90% control) with marked diastolic dysfunction (i.e. increased E/E’). Diastolic dysfunction was detectable in young adult HHR, as an early disease marker. Histological examination identified regions of focal reparative fibrosis in HHR hearts, most prominent in the transverse midwall area of the left ventricle adjacent to the interventricular septum. Evaluation of cardiomyocyte function using left ventricular myocytes isolated from hearts of 30 week (prefailing ) HHR revealed a hypercontractile phenotype with high Ca 2+ operational levels and arrhythmogenic vulnerability. HHR cardiomyocytes exhibited dramatically increased L-type Ca 2+ channel current density (almost 2-fold), and molecular analyses identified hyperphosphorylation of key sarcoplasmic reticulum Ca 2+ regulatory proteins, without change in total phospho-titin. These findings strongly support the contention that HFpEF and HFrEF can have different underlying cardiomyocyte phenotypes. New directions for HFpEF therapies are indicated, and the HHR provides a new model for preclinical HFpEF investigations.

Females Are Protected From Iron-Overload Cardiomyopathy Independent of Iron Metabolism: Key Role of Oxidative Stress.

BackgroundSex‐related differences in cardiac function and iron metabolism exist in humans and experimental animals. Male patients and preclinical animal models are more susceptible to cardiomyopathies and heart failure. However, whether similar differences are seen in iron‐overload cardiomyopathy is poorly understood.Methods and ResultsMale and female wild‐type and hemojuvelin‐null mice were injected and fed with a high‐iron diet, respectively, to develop secondary iron overload and genetic hemochromatosis. Female mice were completely protected from iron‐overload cardiomyopathy, whereas iron overload resulted in marked diastolic dysfunction in male iron‐overloaded mice based on echocardiographic and invasive pressure‐volume analyses. Female mice demonstrated a marked suppression of iron‐mediated oxidative stress and a lack of myocardial fibrosis despite an equivalent degree of myocardial iron deposition. Ovariectomized female mice with iron overload exhibited essential pathophysiological features of iron‐overload cardiomyopathy showing distinct diastolic and systolic dysfunction, severe myocardial fibrosis, increased myocardial oxidative stress, and increased expression of cardiac disease markers. Ovariectomy prevented iron‐induced upregulation of ferritin, decreased myocardial SERCA2a levels, and increased NCX1 levels. 17β‐Estradiol therapy rescued the iron‐overload cardiomyopathy in male wild‐type mice. The responses in wild‐type and hemojuvelin‐null female mice were remarkably similar, highlighting a conserved mechanism of sex‐dependent protection from iron‐overload‐mediated cardiac injury.ConclusionsMale and female mice respond differently to iron‐overload‐mediated effects on heart structure and function, and females are markedly protected from iron‐overload cardiomyopathy. Ovariectomy in female mice exacerbated iron‐induced myocardial injury and precipitated severe cardiac dysfunction during iron‐overload conditions, whereas 17β‐estradiol therapy was protective in male iron‐overloaded mice.

Left ventricular myocardial perfusion in young patients evaluated for hypertrophic cardiomyopathy at rest and during adenosine hyperemia using cardiac magnetic resonance imaging

Methods Twelve controls (22.8 ± 4.5 years), fourteen subjects at risk (18.9 ± 3.8) and ten HCM patients (22.3 ± 6.4) were examined using echocardiography and cardiovascular magnetic resonance (CMR) at rest and during hyperemia (adenosine 140 μg/kg/min). Patients with left ventricular outflow tract obstruction were excluded from the study. Myocardial perfusion was calculated as the ratio of coronary sinus flow and left ventricular mass (LVM) from CMR. Myocardial fibrosis was assessed using late gadolinium enhancement. Diastolic function was quantified using both echocardiography and CMR. The Mann-Whitney test was used to compare the groups and results were considered significant if p < 0.05. Results are presented as mean ± SEM if not otherwise stated. The study was approved by the Ethical Board and informed consent was obtained. Results There was no significant difference in MP (ml/min/g) at rest in controls, subjects at risk and HCM patients (0.8 ± 0.1, 1.0 ± 0.1, 0.9 ± 0.1, respectively, p = ns). During hyperemia, MP was similar in controls and subjects at risk (3.9 ± 0.3 and 5.0 ± 0.5, p = 0.11, but lower in HCM patients (2.5 ± 0.4, p < 0.05 compared to both). Even when fibrosis was excluded from LVM the MP was lower in HCM patients compared to the other groups. Two subjects showed mild diastolic dysfunction (E/e’ = 16), otherwise none of the investigated subjects showed marked diastolic dysfunction (E/e’<15).

Mitral valve prolapse as display heart connective tissue dysplasia. Clinical and hemodynamic aspects

Relevance: According to modern concepts to the syndrome include VDS prolapse heart valves, atrial septal aneurysm and sinuses, ectopic fastened chord mitral valve, and many others. Mitral valve prolapse (MVP) is the most frequent variant of valvular heart disease and is found in many young people. According to some authors, its frequency in the population is between 1.8 and 38%. However, its true prevalence, frequency combination valve disease among themselves and with other VDS, the most frequently detected phenomena electrocardiographic and hemodynamic parameters, the issues of forecasting and developing therapies to date are still poorly understood. Another important aspect — the social nature of the problem, since the PLA is often diagnosed in young adults, that is, in the main, and conscription of child-bearing age. Objective: To investigate the prevalence of PMK, clinical features, to identify the most frequent electrocardiographic phenomena and rhythm disorders and examine the status of intracardiac hemodynamics in patients with PMC, depending on the degree of mitral valve prolapse and the presence of regurgitation. Practical significance: This study will help in the diagnosis of the disease, prognosis and assessment of the course and in patients with MVP. The study involved 62 patients 2 RCH cardiology department with mitral valve prolapse. Of these, 56 were men (90.3%), 6 women (9.6%). The average age of the patients was 22.8 years. Besides general clinical methods we used non-invasive methods of investigation of the cardiovascular system, which included electrocardiography (ECG) and echocardiography (M-mode). Hemodynamically significant mitral valve prolapse with regurgitation was detected in 41 men. In evaluating the data of electrocardiography in 56.1% of the surveyed group they had identified a variety of cardiac arrhythmias. PMK is often accompanied by the following electrocardiographic phenomena: blockade of the right and left bundle-branch block (41.1%), syndrome W-P-W (14.7%), sinus tachycardia (11.7%), sinus bradycardia (26.4%), supraventricular and ventricular ectopic beats (14.7%), left ventricular hypertrophy (29.4%), paroxysmal supraventricular tachycardia (2.4%), and complete AV-block (2.4%). Conclusions: PMK is quite frequent pathologies among young people and is not echo phenomenon. The average age of the patients was 22.8 years. Patients diagnosed with MVP regardless of the degree of regurgitation are recommended with ECG monitoring and exercise testing (bicycle ergometry) to identify LDCs. The combination of PMC with myxomatous degeneration of the valves worsens prognosis, intracardiac hemodynamics and is a predictor of arrhythmias. This revealed the greatest changes in intracardiac hemodynamics in patients with PMC registered with LDCs. The most pronounced hemodynamic changes are marked by complications PMK II–III degree of regurgitation with various LDCs. The presence of cardiac arrhythmias in patients with mitral valve prolapse is associated with an increase in end-diastolic volume of the left ventricle and the volume of the left atrium, the mitral regurgitate volume as compared with the healthy subjects. By echocardiography in patients with MVP is marked diastolic dysfunction. The increase in severity over time, IBC and the degree of mitral valve regurgitation can lead to a progressive disruption of intracardiac hemodynamics.

Long-term levosimendan treatment improves systolic function and myocardial relaxation in mice with cardiomyocyte-specific disruption of theSerca2gene

In human heart failure (HF), reduced cardiac function has, at least partly, been ascribed to altered calcium homeostasis in cardiomyocytes. The effects of the calcium sensitizer levosimendan on diastolic dysfunction caused by reduced removal of calcium from cytosol in early diastole are not well known. In this study, we investigated the effect of long-term levosimendan treatment in a murine model of HF where the sarco(endo)plasmatic reticulum ATPase (Serca) gene is specifically disrupted in the cardiomyocytes, leading to reduced removal of cytosolic calcium. After induction of Serca2 gene disruption, these mice develop marked diastolic dysfunction as well as impaired contractility. SERCA2 knockout (SERCA2KO) mice were treated with levosimendan or vehicle from the time of KO induction. At the 7-wk end point, cardiac function was assessed by echocardiography and pressure measurements. Vehicle-treated SERCA2KO mice showed significantly diminished left-ventricular (LV) contractility, as shown by decreased ejection fraction, stroke volume, and cardiac output. LV pressure measurements revealed a marked increase in the time constant (τ) of isovolumetric pressure decay, showing impaired relaxation. Levosimendan treatment significantly improved all three systolic parameters. Moreover, a significant reduction in τ toward normalization indicated improved relaxation. Gene-expression analysis, however, revealed an increase in genes related to production of the ECM in animals treated with levosimendan. In conclusion, long-term levosimendan treatment improves both contractility and relaxation in a heart-failure model with marked diastolic dysfunction due to reduced calcium transients. However, altered gene expression related to fibrosis was observed.

Evaluation of Left Ventricular Relaxation and Filling Pressures in Obstructive Hypertrophic Cardiomyopathy: Comparison between Invasive Hemodynamics and Two‐Dimensional Speckle Tracking

Hypertrophic cardiomyopathy (HCM) is usually associated with marked diastolic dysfunction, characterized by impaired myocardial relaxation and increased myocardial stiffness. The noninvasive evaluation of diastolic function in these patients remains a challenge since usual methods have shown a modest correlation with invasive measurements of left ventricular (LV) relaxation and filling pressures. We retrospectively analyzed 44 patients with obstructive HCM who underwent cardiac catheterization and echocardiography performed within 48 hours. Standard echocardiographic diastolic parameters and systolic and diastolic myocardial mechanics (including longitudinal and circumferential strain [S] and strain rate [Sr]), LV rotation, and early reverse rotation rate (fraction of early apical reverse rotation [FEARR]) were correlated with diastolic hemodynamic indices. Estimated LA pressure by echo and the LV end-diastolic pressure (LVEDP) or the LV pre-A pressure did not correlate. Longitudinal strain was low and circumferential strain was abnormally higher than normal. FEARR and negative dp/dt inversely correlated (R =-0.57, P = 0.0001), and early diastolic Sr to systolic Sr ratio (SrE/SrS) correlated with the LVEDP (r = 0.61, P < 0.0001). Furthermore, a SrE to SrS ratio ≥ 0.79 had a sensitivity of 87% and a specificity of 75% for predicting elevated LVEDP (≥ 15 mmHg). Average circumferential strain rate during atrial contraction and LV pre-A pressure (r =-0.62, P < 0.001) inversely correlated. FEARR is decreased in HCM and appears to be a good measure of diastolic dysfunction. Myocardial mechanics can be used to assess LV relaxation and filling pressures in patients with obstructive HCM.

Tumor Necrosis Factor-α and Its Receptors 1 and 2

In healthy hearts, tumor necrosis factor-α (TNF-α) concentration is low, and TNF-α is mainly located in endothelium and resident mast cells.1 TNF-α receptors (TNFRs) 1 (TNFR1) and 2 (TNFR2) are expressed on most cardiac cells, including cardiomyocytes.2 During myocardial ischemia, preformed TNF-α is released within minutes from resident mast cells and macrophages.3 With persistent ischemia, TNF-α also originates from cardiomyocytes.4 In rats after myocardial infarction (MI), TNFR1 density is increased for 10 days, whereas TNFR2 density remains unchanged.5 In contrast, TNFR1 and TNFR2 are both downregulated in the failing heart, whereas soluble TNFRs are increased6 owing to proteolytic cleavage of cardiomyocyte TNFR and release from circulating exosome-like vesicles.7 Increased soluble TNFRs decrease TNF-α bioactivity while at the same time prolonging its half-life.8 Article p 1386 TNF-α contributes to both reversible (contractile dysfunction4,9) and irreversible (MI) injury.1 Preischemic treatment with TNF-α antibodies10 or soluble TNFR1,11 permanent TNF-α knockout,12 or knockout of TNFR1 but not TNFR213 all reduce infarct size. The latter finding highlights the functional difference of TNFR1 and TNFR2 activation for ischemia/reperfusion injury: Only TNFR1 signaling is detrimental (Figure). Figure. Signaling cascade activated (→) or inhibited (⊣) by TNFR1 (red) or TNFR2 (blue) activation. sTNFR1 indicates soluble TNFR1; sTNFR2, soluble TNFR2; S1-P, sphingosine-1-phosphate; NF-κB, nuclear factor-κB; SOCS3, suppressor of cytokine signaling 3; ROS, reactive oxygen species; Akt-P, phosphorylated Akt, a homologue of the transforming v-Akt; NADPH-Ox, NADPH oxidase; STAT3-P, phosphorylated signal transducer and activator of transcription; Jnk-P, phosphorylated c-jun N-terminal kinase; p38-P, phosphorylated mitogen-activated protein kinase; Erk-P, phosphorylated extracellular signal-regulated kinase; PKC, protein kinase C; CamK, calcium/calmodulin-dependent kinase; MMP-2/9, matrix metalloproteinases 2 and 9; and IL-6, interleukin 6. Red indicates proteins involved in apoptosis; purple, proteins involved in growth; green, …

Matrix Metalloproteinases and Their Tissue Inhibitors in Cardiac Amyloidosis

Background— Cardiac amyloidosis is characterized by amyloid infiltration resulting in extracellular matrix disruption. Amyloid cardiomyopathy due to immunoglobulin light chain protein (AL-CMP) deposition has an accelerated clinical course and a worse prognosis compared with non–light chain cardiac amyloidoses (ie, forms associated with wild-type or mutated transthyretin [TTR]). We therefore tested the hypothesis that determinants of proteolytic activity of the extracellular matrix, the matrix metalloproteinases (MMPs), and their tissue inhibitors (TIMPs) would have distinct patterns and contribute to the pathogenesis of AL-CMP versus TTR-related amyloidosis. Methods and Results— We studied 40 patients with systemic amyloidosis: 10 AL-CMP patients, 20 patients with TTR-associated forms of cardiac amyloidosis, ie, senile systemic amyloidois (involving wild-type TTR) or mutant TTR, and 10 patients with AL amyloidosis without cardiac involvement. Serum MMP-2 and -9, TIMP-1, -2, and -4, brain natriuretic peptide values, and echocardiography were determined. AL-CMP and TTR-related amyloidosis groups had similar degrees of increased left ventricular wall thickness. However, brain natriuretic peptide, MMP-9, and TIMP-1 levels were distinctly elevated accompanied by marked diastolic dysfunction in the AL-CMP group versus no or minimal increases in the TTR-related amyloidosis group. Brain natriuretic peptide, MMPs, and TIMPs were not correlated with the degree of left ventricular wall thickness but were correlated to each other and to measures of diastolic dysfunction. Immunostaining of human endomyocardial biopsies showed diffuse expression of MMP-9 and TIMP-1 in AL-CMP and limited expression in TTR-related amyloidosis hearts. Conclusions— Despite comparable left ventricular wall thickness with TTR-related cardiac amyloidosis, AL-CMP patients have higher brain natriuretic peptide, MMPs, and TIMPs, which correlated with diastolic dysfunction. These findings suggest a relationship between light chains and extracellular matrix proteolytic activation that may play an important role in the functional and clinical manifestations of AL-CMP, distinct from the other non–light chain cardiac amyloidoses.

Abstract 2402: Matrix Metalloproteinases and their Tissue Inhibitors in Cardiac Amyloidosis: Relationship to Structural and Functional Changes and to Light Chain Amyloid Deposition in the Heart

Cardiac amyloidosis is characterized by amyloid infiltration resulting in extracellular matrix disruption. Systemic deposition of immunoglobulin light chain (LC) fibrils (AL or “primary”) amyloidosis can lead to cardiac amyloidosis with heart failure. AL cardiomyopathy (AL-CMP) has an accelerated clinical course and a worse prognosis compared to non-LC cardiac amyloidoses. We therefore tested the hypothesis that determinants of proteolytic activity of the extracellular matrix, the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), would have distinct patterns and contribute to the pathogenesis of AL-CMP. We studied 40 patients with systemic amyloidosis: 10 AL-CMP patients, 20 patients with non-LC cardiac amyloidosis: i.e. amyloidosis associated with either wild-type transthyretin (TTR), senile systemic amyloidois (SSA) or a mutant TTR (ATTR), and 10 patients with AL amyloidosis without cardiac involvement. Plasma MMP-2, MMP-9, TIMP-1, TIMP-2 and TIMP-4, brain natriuretic peptide (BNP) values and echocardiographic parameters were determined. AL-CMP and non-LC groups had similar degrees of increased left ventricular wall thickness (LVWT) and mass index (LVMI). However, BNP, MMP-9 and TIMP-1 levels were distinctly elevated and accompanied by marked diastolic dysfunction in the AL-CMP group vs. no or minimal increases in the non-LC group. BNP, MMPs and TIMPs were not associated with the degree of LVWT but were to each other and to measures of diastolic dysfunction. Immunostaining of human endomyocardial biopsies showed diffuse expression of MMP-9 and TIMP-1 in AL-CMP and limited expression in non-LC hearts. Despite comparable LVWT and LVMI with non-LC cardiac amyloidosis, AL-CMP patients have higher BNP, MMP-9 and TIMP-1, which correlated with diastolic dysfunction. These findings suggest a relationship between LC and extracellular matrix proteolytic activation that may play an important role in the functional and clinical manifestations of AL-CMP.

Rapid reversal of critical haemodynamic compromise with nitric oxide in a parturient with amniotic fluid embolism

We describe a case of amniotic fluid embolism presenting as cardiovascular collapse during labour. After initial resuscitation and emergency caesarean section, the patient was transferred to the intensive care unit with profound hypoxaemia, a high inotropic drug requirement and severe coagulopathy. A transoesophageal echocardiogram demonstrated acute right ventricular overload, severe pulmonary artery hypertension and marked diastolic dysfunction of the left ventricle secondary to a dilated right ventricle. The introduction of nitric oxide at 40 ppm produced a dramatic improvement in her cardiorespiratory status. Mother and baby both survived with no apparent long term sequelae.

Uremic cardiomyopathy: role of circulating digitalis like substances

Patients with chronic renal failure develop a cardiomyopathy characterized by marked diastolic dysfunction and left ventricular hypertrophy. Interestingly, they also have substantial increases in the circulating concentrations of digitalis like substances. Digitalis like substances produce reactive oxygen species as part of the signal cascade induced by binding to the sodium pump and patients, and this signal cascade appears to induce hypertrophy of cardiac myocytes grown in culture. Also, patients with chronic renal failure develop an oxidant stress state without a known mechanism. From these data, we propose that it is these digitalis like substances which cause cardiomyopathy of renal failure as well as the systemic oxidant stress state.

Role of Diastole in Left Ventricular Function, II: Diagnosis and Treatment

Left ventricular diastolic dysfunction plays an important role in congestive heart failure. Although once thought to be lower, the mortality of diastolic heart failure may be as high as that of systolic heart failure. Diastolic heart failure is a clinical syndrome characterized by signs and symptoms of heart failure with preserved ejection fraction (0.50) and abnormal diastolic function. One of the earliest indications of diastolic heart failure is exercise intolerance followed by fatigue and, possibly, chest pain. Other clinical signs may include distended neck veins, atrial arrhythmias, and the presence of third and fourth heart sounds. Diastolic dysfunction is difficult to differentiate from systolic dysfunction on the basis of history, physical examination, and electrocardiographic and chest radiographic findings. Therefore, objective diagnostic testing with cardiac catheterization, Doppler echocardiography, and possibly measurement of serum levels of B-type natriuretic peptide is often required. Three stages of diastolic dysfunction are recognized. Stage I is characterized by reduced left ventricular filling in early diastole with normal left ventricular and left atrial pressures and normal compliance. Stage II or pseudonormalization is characterized by a normal Doppler echocardiographic transmitral flow pattern because of an opposing increase in left atrial pressures. This normalization pattern is a concern because marked diastolic dysfunction can easily be missed. Stage III, the final, most severe stage, is characterized by severe restrictive diastolic filling with a marked decrease in left ventricular compliance. Pharmacological therapy is tailored to the cause and type of diastolic dysfunction.

Non-invasive hemodynamic evaluation of patients with LV dysfunction and intractable dyspnea with first pass radionuclide angiography: comparison with echocardiography

Introduction: Advanced heart failure is characterized by recurrent episodes of dyspnea with or without obvious signs of congestion and fluid retention. These patients have many potential cardiac and pulmonary causes for recurrent dyspnea and repeating an echo each time is often uninformative and frequently limited technically in CHF patients, particularly if significant pulmonary disease also exists. We therefore sought to use first pass radionuclide angiography (FPRNA) to non-invasively evaluate the hemodynamic status of these very symptomatic and failing patients. Methods: Consecutive patients with LV dysfunction and severe dyspnea underwent upright FPRNA after injection of 15-45 millicurie of sestamibi. Imaging was performed using a Sim-400 multicrystal camera. All hemodynamic data were based on acquired raw and derived data. Included patients also underwent echocardiography which was independently reviewed. Results: 52 patients (80% male) met criteria. Mean age 68.7 years. Mean LVEF by echo 29.7% and 32.2% by FPRNA (NS p=0.53). Mean RVEF by FPRNA was 43.85%. 65% had RVEF <40%. Peak LV filling was 1.41 +/− 0.58 (normal value is >2.5), suggesting marked diastolic dysfunction. Mean cardiac output was 6.2 and mean index was 3.2. The LV was markedly enlarged in this population reflecting advanced heart disease. Mean LV end diastolic volume was 230 cc and end systolic volume was 162cc, both values over twice the accepted normal range. 69.2% had MR by echo (21.2% were rated as 1+, 13.5% as 2+, 17.3% each as 3+ and 4+). Most importantly, the normalized mean pulmonary transit time (corrected for heart rate) was found to directly correlate with the degree of MR on echo (Spearman's rho 0.346, p=0.02). This has not been previously shown in severe CHF. Conclusion: In this study we sought to establish that reliable non-invasive hemodynamic data can easily be obtained from very symptomatic patients with LV dysfunction. The advantages of FPRNA are that patients are imaged upright and the results are quantitative. Accurate evaluation of MR is possible by normalizing the PMTT, thereby allowing this normally subjective echo data to be quantified and followed serially. In addition quantitative data on LV and RV systolic function, LV diastolic function and pulmonary circulation can be obtained and followed serially. By comparing such serial results, abnormalities in specific parameters may yield clues to whether dyspnea is of cardiac or pulmonary origin in severe CHF.

Remodelling and left ventricular diastolic function in relation to blood pressure variability in patients with arterial hypertension and coronary heart disease

Sixty five patients (mean age 55.7 ± 8,7 years), including 51 patients with arterial hypertension (AH) (mean age 54,9 ± 8,6 years) and 14 patients with a combination of AG and coronary heart disease (CHD) with postinfarction cardiosclerosis (mean age 54,9 ± 8,6 years) were examined. According to the values of average daily blood pressure variability (HPV), the patients were divided into subgroups with normal (11 patients with AH and 3 patients with AH and CHD) and increased (39 patients with AH and 12 patients with AH and CUD) BPV. Patients with isolated AH were found to have developed concentric hypertrophy of the left ventricle (LV), and moderate LV diastolic dysfunction mainly with impaired relaxation and the patients with a combination of AH and CHD with postinfarction cardiosclerosis had more significant LV structural and geometric derangements with a tendency for the development of eccentric hypertrophy of the LV, as well as more marked diastolic dysfunction with a larger proportion of the pseudo-normal and restrictive types of LV diastolic function. Patients with increased average daily BPV were found to have more significant LV structural, geometrical, and diastolic impairments.