Showing papers by "David A. Kass published in 2013"

Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection fraction

Abstract: Aims Exercise intolerance is a hallmark of heart failure with preserved ejection fraction (HFpEF), yet its mechanisms remain unclear. The current study sought to determine whether increases in cardiac output (CO) during exercise are appropriately matched to metabolic demands in HFpEF. Methods and results Patients with HFpEF (n = 109) and controls (n = 73) exercised to volitional fatigue with simultaneous invasive (n = 96) or non-invasive (n = 86) haemodynamic assessment and expired gas analysis to determine oxygen consumption (VO2) during upright or supine exercise. At rest, HFpEF patients had higher LV filling pressures but similar heart rate, stroke volume, EF, and CO. During supine and upright exercise, HFpEF patients displayed lower peak VO2 coupled with blunted increases in heart rate, stroke volume, EF, and CO compared with controls. LV filling pressures increased dramatically in HFpEF patients, with secondary elevation in pulmonary artery pressures. Reduced peak VO2 in HFpEF patients was predominantly attributable to CO limitation, as the slope of the increase in CO relative to VO2 was 20% lower in HFpEF patients (5.9 ± 2.5 vs. 7.4 ± 2.6 L blood/L O2, P = 0.0005). While absolute increases in arterial–venous O2 difference with exercise were similar in HFpEF patients and controls, augmentation in arterial–venous O2 difference relative to VO2 was greater in HFpEF patients (8.9 ± 3.4 vs. 5.5 ± 2.0 min/dL, P < 0.0001). These differences were observed in the total cohort and when upright and supine exercise modalities were examined individually. Conclusion While diastolic dysfunction promotes congestion and pulmonary hypertension with stress in HFpEF, reduction in exercise capacity is predominantly related to inadequate CO relative to metabolic needs.

Right Ventricular Dysfunction in Systemic Sclerosis–Associated Pulmonary Arterial Hypertension

Abstract: Background—Systemic sclerosis–associated pulmonary artery hypertension (SScPAH) has a worse prognosis compared with idiopathic pulmonary arterial hypertension (IPAH), with a median survival of 3 years after diagnosis often caused by right ventricular (RV) failure. We tested whether SScPAH or systemic sclerosis–related pulmonary hypertension with interstitial lung disease imposes a greater pulmonary vascular load than IPAH and leads to worse RV contractile function. Methods and Results—We analyzed pulmonary artery pressures and mean flow in 282 patients with pulmonary hypertension (166 SScPAH, 49 systemic sclerosis–related pulmonary hypertension with interstitial lung disease, and 67 IPAH). An inverse relation between pulmonary resistance and compliance was similar for all 3 groups, with a near constant resistance×compliance product. RV pressure–volume loops were measured in a subset, IPAH (n=5) and SScPAH (n=7), as well as SSc without PH (n=7) to derive contractile indexes (end-systolic elastance [Ees] an...

Nitric oxide synthases in heart failure.

Abstract: Significance: The regulation of myocardial function by constitutive nitric oxide synthases (NOS) is important for the maintenance of myocardial Ca2+ homeostasis, relaxation and distensibility, and protection from arrhythmia and abnormal stress stimuli. However, sustained insults such as diabetes, hypertension, hemodynamic overload, and atrial fibrillation lead to dysfunctional NOS activity with superoxide produced instead of NO and worse pathophysiology. Recent Advances: Major strides in understanding the role of normal and abnormal constitutive NOS in the heart have revealed molecular targets by which NO modulates myocyte function and morphology, the role and nature of post-translational modifications of NOS, and factors controlling nitroso-redox balance. Localized and differential signaling from NOS1 (neuronal) versus NOS3 (endothelial) isoforms are being identified, as are methods to restore NOS function in heart disease. Critical Issues: Abnormal NOS signaling plays a key role in many cardiac disorders, while targeted modulation may potentially reverse this pathogenic source of oxidative stress. Future Directions: Improvements in the clinical translation of potent modulators of NOS function/dysfunction may ultimately provide a powerful new treatment for many hearts diseases that are fueled by nitroso-redox imbalance. Antioxid. Redox Signal. 18, 1078–1099.

Nitroxyl (HNO) a Novel Approach for the Acute Treatment of Heart Failure

Abstract: Background— The nitroxyl (HNO) donor, Angeli’s salt, exerts positive inotropic, lusitropic, and vasodilator effects in vivo that are cAMP independent. Its clinical usefulness is limited by chemical instability and cogeneration of nitrite which itself has vascular effects. Here, we report on effects of a novel, stable, pure HNO donor (CXL-1020) in isolated myoctyes and intact hearts in experimental models and in patients with heart failure (HF). Methods and Results— CXL-1020 converts solely to HNO and inactive CXL-1051 with a t1/2 of 2 minutes. In adult mouse ventricular myocytes, it dose dependently increased sarcomere shortening by 75% to 210% (50–500 μmol/L), with a ≈30% rise in the peak Ca2+ transient only at higher doses. Neither inhibition of protein kinase A nor soluble guanylate cyclase altered this contractile response. Unlike isoproterenol, CXL-1020 was equally effective in myocytes from normal or failing hearts. In anesthetized dogs with coronary microembolization-induced HF, CXL-1020 reduced left ventricular end-diastolic pressure and myocardial oxygen consumption while increasing ejection fraction from 27% to 40% and maximal ventricular power index by 42% (both P <0.05). In conscious dogs with tachypacing-induced HF, CXL-1020 increased contractility assessed by end-systolic elastance and provided venoarterial dilation. Heart rate was minimally altered. In patients with systolic HF, CXL-1020 reduced both left and right heart filling pressures and systemic vascular resistance, while increasing cardiac and stroke volume index. Heart rate was unchanged, and arterial pressure declined modestly. Conclusions— These data show the functional efficacy of a novel pure HNO donor to enhance myocardial function and present first-in-man evidence for its potential usefulness in HF. Clinical Trial Registration— URL: . Unique identifiers: [NCT01096043][1], [NCT01092325][2]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01096043&atom=%2Fcirchf%2F6%2F6%2F1250.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01092325&atom=%2Fcirchf%2F6%2F6%2F1250.atom

Protein Kinase G Positively Regulates Proteasome-Mediated Degradation of Misfolded Proteins

Abstract: Background—Proteasome functional insufficiency is implicated in a large subset of cardiovascular diseases and may play an important role in their pathogenesis. The regulation of proteasome function is poorly understood, hindering the development of effective strategies to improve proteasome function. Methods and Results—Protein kinase G (PKG) was manipulated genetically and pharmacologically in cultured cardiomyocytes. Activation of PKG increased proteasome peptidase activities, facilitated proteasome-mediated degradation of surrogate (enhanced green fluorescence protein modified by carboxyl fusion of degron CL1) and bona fide (CryABR120G) misfolded proteins, and attenuated CryABR120G overexpression–induced accumulation of ubiquitinated proteins and cellular injury. PKG inhibition elicited the opposite responses. Differences in the abundance of the key 26S proteasome subunits Rpt6 and β5 between the PKG-manipulated and control groups were not statistically significant, but the isoelectric points were shif...

Electromechanical dyssynchrony and resynchronization of the failing heart.

Abstract: Patients with heart failure and decreased function frequently develop discoordinate contraction because of electric activation delay. Often termed dyssynchrony, this further decreases systolic function and chamber efficiency and worsens morbidity and mortality. In the mid- 1990s, a pacemaker-based treatment termed cardiac resynchronization therapy (CRT) was developed to restore mechanical synchrony by electrically activating both right and left sides of the heart. It is a major therapeutic advance for the new millennium. Acute chamber effects of CRT include increased cardiac output and mechanical efficiency and reduced mitral regurgitation, whereas reduction in chamber volumes ensues more chronically. Patient candidates for CRT have a prolonged QRS duration and discoordinate wall motion, although other factors may also be important because ≈30% of such selected subjects do not respond to the treatment. In contrast to existing pharmacological inotropes, CRT both acutely and chronically increases cardiac systolic function and work, yet it also reduces long-term mortality. Recent studies reveal unique molecular and cellular changes from CRT that may also contribute to this success. Heart failure with dyssynchrony displays decreased myocyte and myofilament function, calcium handling, β-adrenergic responsiveness, mitochondrial ATP synthase activity, cell survival signaling, and other changes. CRT reverses many of these abnormalities often by triggering entirely new pathways. In this review, we discuss chamber, circulatory, and basic myocardial effects of dyssynchrony and CRT in the failing heart, and we highlight new research aiming to better target and implement CRT, as well as leverage its molecular effects.

HNO enhances SERCA2a activity and cardiomyocyte function by promoting redox-dependent phospholamban oligomerization.

Abstract: Aims: Nitroxyl (HNO) interacts with thiols to act as a redox-sensitive modulator of protein function. It enhances sarcoplasmic reticular Ca2+ uptake and myofilament Ca2+ sensitivity, improving cardiac contractility. This activity has led to clinical testing of HNO donors for heart failure. Here we tested whether HNO alters the inhibitory interaction between phospholamban (PLN) and the sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) in a redox-dependent manner, improving Ca2+ handling in isolated myocytes/hearts. Results: Ventriculocytes, sarcoplasmic reticulum (SR) vesicles, and whole hearts were isolated from control (wildtype [WT]) or PLN knockout (pln−/−) mice. Compared to WT, pln−/− myocytes displayed enhanced resting sarcomere shortening, peak Ca2+ transient, and blunted β-adrenergic responsiveness. HNO stimulated shortening, relaxation, and Ca2+ transient in WT cardiomyocytes, and evoked positive inotropy/lusitropy in intact hearts. These changes were markedly blunted in pln−/− cells/hearts. HNO enhanced SR Ca2+ uptake in WT but not pln−/− SR-vesicles. Spectroscopic studies in insect cell microsomes expressing SERCA2a±PLN showed that HNO increased Ca2+-dependent SERCA2a conformational flexibility but only when PLN was present. In cardiomyocytes, HNO achieved this effect by stabilizing PLN in an oligomeric disulfide bond-dependent configuration, decreasing the amount of free inhibitory monomeric PLN available. Innovation: HNO-dependent redox changes in myocyte PLN oligomerization relieve PLN inhibition of SERCA2a. Conclusions: PLN plays a central role in HNO-induced enhancement of SERCA2a activity, leading to increased inotropy/lusitropy in intact myocytes and hearts. PLN remains physically associated with SERCA2a; however, less monomeric PLN is available resulting in decreased inhibition of the enzyme. These findings offer new avenues to improve Ca2+ handling in failing hearts. Antioxid. Redox Signal. 19, 1185–1197.

Identification of Chemicals Inducing Cardiomyocyte Proliferation in Developmental Stage-Specific Manner with Pluripotent Stem Cells

Abstract: Background— The proliferation of cardiomyocytes is highly restricted after postnatal maturation, limiting heart regeneration. Elucidation of the regulatory machineries for the proliferation and growth arrest of cardiomyocytes is imperative. Chemical biology is efficient to dissect molecular mechanisms of various cellular events and often provides therapeutic potentials. We have been investigating cardiovascular differentiation with pluripotent stem cells. The combination of stem cell and chemical biology can provide novel approaches to investigate the molecular mechanisms and manipulation of cardiomyocyte proliferation. Methods and Results— To identify chemicals that regulate cardiomyocyte proliferation, we performed a screening of a defined chemical library based on proliferation of mouse pluripotent stem cell–derived cardiomyocytes and identified 4 chemical compound groups: inhibitors of glycogen synthase kinase-3, p38 mitogen-activated protein kinase, and Ca2+/calmodulin-dependent protein kinase II, and activators of extracellular signal–regulated kinase. Several appropriate combinations of chemicals synergistically enhanced proliferation of cardiomyocytes derived from both mouse and human pluripotent stem cells, notably up to a 14-fold increase in mouse cardiomyocytes. We also examined the effects of identified chemicals on cardiomyocytes in various developmental stages and species. Whereas extracellular signal–regulated kinase activators and Ca2+/calmodulin-dependent protein kinase II inhibitors showed proliferative effects only on cardiomyocytes in early developmental stages, glycogen synthase kinase-3 and p38 mitogen-activated protein kinase inhibitors substantially and synergistically induced re-entry and progression of cell cycle in neonatal but also as well as adult cardiomyocytes. Conclusions— Our approach successfully uncovered novel molecular targets and mechanisms controlling cardiomyocyte proliferation in distinct developmental stages and offered pluripotent stem cell–derived cardiomyocytes as a potent tool to explore chemical-based cardiac regenerative strategies.

Cardiac Resynchronization Therapy Improves Altered Na Channel Gating in Canine Model of Dyssynchronous Heart Failure

Abstract: Background— Slowed Na+ current ( I Na) decay and enhanced late I Na ( I Na-L) prolong the action potential duration (APD) and contribute to early afterdepolarizations. Cardiac resynchronization therapy (CRT) shortens APD compared with dyssynchronous heart failure (DHF); however, the role of altered Na+ channel gating in CRT remains unexplored. Methods and Results— Adult dogs underwent left-bundle branch ablation and right atrial pacing (200 beats/min) for 6 weeks (DHF) or 3 weeks followed by 3 weeks of biventricular pacing at the same rate (CRT). I Na and I Na-L were measured in left ventricular myocytes from nonfailing, DHF, and CRT dogs. DHF shifted voltage-dependence of I Na availability by −3 mV compared with nonfailing, enhanced intermediate inactivation, and slowed recovery from inactivation. CRT reversed the DHF-induced voltage shift of availability, partially reversed enhanced intermediate inactivation but did not affect DHF-induced slowed recovery. DHF markedly increased I Na-L compared with nonfailing. CRT dramatically reduced DHF-induced enhanced I Na-L, abbreviated the APD, and suppressed early afterdepolarizations. CRT was associated with a global reduction in phosphorylated Ca2+/Calmodulin protein kinase II, which has distinct effects on inactivation of cardiac Na+ channels. In a canine AP model, alterations of I Na-L are sufficient to reproduce the effects on APD observed in DHF and CRT myocytes. Conclusions— CRT improves DHF-induced alterations of Na+ channel function, especially suppression of I Na-L, thus, abbreviating the APD and reducing the frequency of early afterdepolarizations. Changes in the levels of phosphorylated Ca2+/Calmodulin protein kinase II suggest a molecular pathway for regulation of I Na by biventricular pacing of the failing heart.

Mutation of the Protein Kinase I Alpha Leucine Zipper Domain Produces Hypertension and Progressive Left Ventricular Hypertrophy: A Novel Mouse Model of Age-Dependent Hypertensive Heart Disease

Abstract: Hypertensive heart disease causes significant mortality in older patients, yet there is an incomplete understanding of molecular mechanisms that regulate age-dependent hypertensive left ventricular hypertrophy (LVH). Therefore, we tested the hypothesis that the cGMP-dependent protein kinase G I alpha (PKGIα) attenuates hypertensive LVH by evaluating the cardiac phenotype in mice with selective mutations of the PKGIα leucine zipper domain. These leucine zipper mutant (LZM) mice develop basal hypertension. Compared with wild-type controls, 8-month-old adult LZM mice developed increased left ventricular end-diastolic pressure but without frank LVH. In advanced age (15 months), the LZM mice developed overt pathological LVH. These findings reveal a role of PKGIα in normally attenuating hypertensive LVH. Therefore, mutation of the PKGIα LZ domain produces a clinically relevant model for hypertensive heart disease of aging.

Hypertrophy Signaling Pathways in Experimental Chronic Aortic Regurgitation

Abstract: The development of left ventricular hypertrophy and dysfunction in aortic regurgitation (AR) has only been sparsely studied experimentally. In a new model of chronic AR in rats, we examined activation of molecular pathways involved in myocardial hypertrophy. Chronic AR was produced by damaging one or two valve cusps, resulting in eccentric remodeling and left ventricular dysfunction, with no increase in overall fibrosis. Western blotting showed increased activation of Akt and p38 at 12 weeks and of c-Jun amino-terminal kinase at 2 weeks, decreased activation of extracellular regulated kinase 5 at both 2 and 12 weeks, while activation of calcium/calmodulin-dependent protein kinase II and extracellular regulated kinase 1/2 was unchanged. Expression of calcineurin and ANF was also unchanged. Eccentric hypertrophy and early cardiac dysfunction in experimental AR are associated with a pattern of activation of intracellular pathways different from that seen with pathological hypertrophy in pressure overload, and more similar to that associated with benign physiological hypertrophy.

Abstract 300: Protein Kinase G Positively Regulates Proteasome-mediated Degradation of Misfolded Proteins

Abstract: Objectives: Proteasome functional insufficiency is implicated in a large subset of cardiovascular diseases and may play an important role in their pathogenesis, evidenced by increased protein aggregates and ubiquitinated proteins. The regulation of proteasome function is poorly understood, hindering the development of effective strategies to improve proteasome function. We sought to establish the role of protein kinase G (PKG) in these debilitating conditions, for which there is currently no cure. Methods and Results: PKG was manipulated genetically and pharmacologically in cultured cardiomyocytes. Activation of PKG increased proteasome peptidase activities, facilitated proteasome-mediated degradation of surrogate (GFPu) and bona fide misfolded proteins (CryABR120G), and attenuated CryABR120G overexpression-induced accumulation of ubiquitinated proteins and cellular injury. PKG inhibition elicited the opposite responses. Differences in the abundance of the key 26S proteasome subunits Rpt6 and β5 between PKG manipulated and the control groups were not statistically significant, but the isoelectric points of were shifted by PKG activation. In transgenic mice expressing a surrogate substrate (GFPdgn), PKG activation by sildenafil increased myocardial proteasome activities and significantly decreased myocardial GFPdgn protein levels. Sildenafil treatment significantly increased myocardial PKG activity and significantly reduced myocardial accumulation of CryABR120G, ubiquitin conjugates, and aberrant protein aggregates in mice with CryABR120G-based desmin-related cardiomyopathy. No discernible effect on bona fide native substrates of the ubiquitin-proteasome system was observed from PKG manipulation in vitro or in vivo. Conclusions: PKG positively regulates proteasome activities and proteasome-mediated degradation of misfolded proteins likely through posttranslational modifications to proteasome subunits. Improved protein quality control is liekly a new mechanism underlying the benefit of PKG stimulation in treating cardiac diseases. Stimulation of PKG by measures such as sildenafil administration is potentially a novel therapeutic strategy to treat cardiac proteinopathies.

Redox and Nitrosative Regulation of Cardiac Remodeling

Abstract: Heart disease is a major cause of death and morbidity worldwide, particularly so in industrialized nations. A major contributor to its varied pathophysiology is abnormal oxidative/reductive and nitrosative stress. While oxidant-scavenging therapies for cardiovascular disease have been disappointing to date, new insights into the precise sources of oxidative/nitrosative stress, its compartmentalized targets, and the modulators designed to control it are paving the way for a very different approach. This issue of the journal presents a Forum highlighting recent work from an international network of investigators that focuses on the role of oxidative/nitrosative stress in the remodeling heart. Antioxid. Redox Signal. 18, 1021–1023.

Abstract 15865: Diastolic Pulmonary Artery Pressure to Pulmonary Capillary Wedge Pressure Gradient (DPG) in Over 5700 Patients With an Elevated Transpulmonary Gradient Does Not Predict Survival After Cardiac Transplantation

Abstract: Background: The transpulmonary gradient (TPG) has been commonly used to differentiate those patients with true pulmonary vascular disease from those with more passive pulmonary hypertension (PH). H...

Response to increased load in systemic sclerosis-associated PAH and idiopathic PAH

Abstract: Background: Patients with Systemic Sclerosis-associated pulmonary hypertension (SScPAH) have worse survival than patients with idiopathic PAH (IPAH). We hypothesized that the RV adapts differently in SScPAH vs IPAH. Methods: We examined 58 prospectively obtained cardiac MRIs (cMRI) in 34 SScPAH and 24 IPAH patients all diagnosed by right heart catheterization (RHC). cMRI and RHC measurements were recorded for all patients. Regression analysis was used to assess the association between diagnosis and RV measurements after adjusting for age and RV load. Results: Clinical and demographic variables are shown in Table 1. Univariate regression showed RV mass index (RVMi) varied linearly with measures of RV load. ANCOVA analysis suggested an interaction between diagnosis and RVMi adjusting for PVR and age (p=0.09). A spline model showed a significantly lower rate of increase in RVMi (0.51vs2.03g/m2*WU) in SScPAH vs IPAH at PVR>7 WU. Conclusion: RVMi varies linearly with measures of RV load. After adjusting for differences in RV load and age, SScPAH patients had a significantly decreased rate of hypertrophy with increasing PVR that was most prominent at PVR>7WU. This difference in adaptive hypertrophy may, in part, explain poorer survival in SScPAH despite lower measures of load. View this table: Table 1: Demographic and Catheterization Data ![Figure][1] [1]: pending:yes

Gapdh cascade inhibitor compounds and methods of use and treatment of stress induced disorders including mental illness

Abstract: The present invention provides compounds and composition comprising analogs of deprenyl and their use in the inhibition of nuclear GAPDH-Siah1 binding and the activation of p300 and MEF2. Also provided herein are methods of prevention and treatment of stress induced disorders of the body, including, for example, major mental illness, such as schizophrenia, mood disorders, and addiction, as well as in stress-associated diseases involving other organs, such as cardiac hypertrophy, in vivo, comprising administering to a mammal a therapeutically effective amount of analogs of deprenyl.

Identification of protein kinase G I alpha interacting proteins as potential targets to prevent cardiac remodeling

Abstract: Background We recently reported that mutation of the cGMP-dependent Protein Kinase G I alpha (PKGIa) N-terminal leucine zipper (LZ) domain (in the PKGIa LZ mutant, or LZM, mouse) accelerates cardiac remodeling and heart failure after left ventricular (LV) pressure overload, and prevents the anti-remodeling effect of sildenafil [1]. We therefore hypothesized that PKGIa attenuates remodeling by regulating cardiac signaling pathways that are dependent on substrate interactions mediated by its LZ domain. As a first step to identifying cardiac proteins downstream of PKGIa, we screened myocardial lysates for PKGIa LZ domain-interacting proteins. Our previous work revealed a requirement for the PKGIa LZ domain for the activation of anti-remodeling myocardial JNK activity after LV pressure overload. MLK3 is a MAPKKK that contains an LZ domain and activates JNK.