Showing papers by "David A. Kass published in 2006"

Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction.

Abstract: Background— Nearly half of patients with heart failure have a preserved ejection fraction (HFpEF). Symptoms of exercise intolerance and dyspnea are most often attributed to diastolic dysfunction; however, impaired systolic and/or arterial vasodilator reserve under stress could also play an important role. Methods and Results— Patients with HFpEF (n=17) and control subjects without heart failure (n=19) generally matched for age, gender, hypertension, diabetes mellitus, obesity, and the presence of left ventricular hypertrophy underwent maximal-effort upright cycle ergometry with radionuclide ventriculography to determine rest and exercise cardiovascular function. Resting cardiovascular function was similar between the 2 groups. Both had limited exercise capacity, but this was more profoundly reduced in HFpEF patients (exercise duration 180±71 versus 455±184 seconds; peak oxygen consumption 9.0±3.4 versus 14.4±3.4 mL · kg−1 · min−1; both P<0.001). At matched low-level workload, HFpEF subjects displayed ≈40%...

L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial.

Abstract: ContextThe amino acid L-arginine is a substrate for nitric oxide synthase and is increasingly used as a health supplement. Prior studies suggest that L-arginine has the potential to reduce vascular stiffness.ObjectiveTo determine whether the addition of L-arginine to standard postinfarction therapy reduces vascular stiffness and improves ejection fraction over 6-month follow-up in patients following acute ST-segment elevation myocardial infarction.Design and SettingSingle-center, randomized, double-blind, placebo-controlled trial with enrollment from February 2002 to June 2004.PatientsA total of 153 patients following a first ST-segment elevation myocardial infarction were enrolled; 77 patients were 60 years or older.InterventionPatients were randomly assigned to receive L-arginine (goal dose of 3 g 3 times a day) or matching placebo for 6 months.Main Outcome MeasuresChange in gated blood pool–derived ejection fraction over 6 months in patients 60 years or older randomized to receive L-arginine compared with those assigned to receive placebo. Secondary outcomes included change in ejection fraction in all patients enrolled, change in noninvasive measures of vascular stiffness, and clinical events.ResultsBaseline characteristics, vascular stiffness measurements, and left ventricular function were similar between participants randomized to receive placebo or L-arginine. The mean (SD) age was 60 (13.6) years; of the participants, 104 (68%) were men. There was no significant change from baseline to 6 months in the vascular stiffness measurements or left ventricular ejection fraction in either of the 2 groups, including those 60 years or older and the entire study group. However, 6 participants (8.6%) in the L-arginine group died during the 6-month study period vs none in the placebo group (P = .01). Because of the safety concerns, the data and safety monitoring committee closed enrollment.ConclusionsL-Arginine, when added to standard postinfarction therapies, does not improve vascular stiffness measurements or ejection fraction and may be associated with higher postinfarction mortality. L-Arginine should not be recommended following acute myocardial infarction.Clinical Trial RegistrationClinicalTrials.gov Identifier: NCT00051376

Compartmentalized phosphodiesterase-2 activity blunts beta-adrenergic cardiac inotropy via an NO/cGMP-dependent pathway.

Abstract: beta-Adrenergic signaling via cAMP generation and PKA activation mediates the positive inotropic effect of catecholamines on heart cells. Given the large diversity of protein kinase A targets within cardiac cells, a precisely regulated and confined activity of such signaling pathway is essential for specificity of response. Phosphodiesterases (PDEs) are the only route for degrading cAMP and are thus poised to regulate intracellular cAMP gradients. Their spatial confinement to discrete compartments and functional coupling to individual receptors provides an efficient way to control local [cAMP]i in a stimulus-specific manner. By performing real-time imaging of cyclic nucleotides in living ventriculocytes we identify a prominent role of PDE2 in selectively shaping the cAMP response to catecholamines via a pathway involving beta3-adrenergic receptors, NO generation and cGMP production. In cardiac myocytes, PDE2, being tightly coupled to the pool of adenylyl cyclases activated by beta-adrenergic receptor stimulation, coordinates cGMP and cAMP signaling in a novel feedback control loop of the beta-adrenergic pathway. In this, activation of beta3-adrenergic receptors counteracts cAMP generation obtained via stimulation of beta1/beta2-adrenoceptors. Our study illustrates the key role of compartmentalized PDE2 in the control of catecholamine-generated cAMP and furthers our understanding of localized cAMP signaling.

Predictors of Sudden Cardiac Death and Appropriate Shock in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial

Abstract: Background— The factors that determine the risk for sudden death or implantable cardioverter defibrillator therapy in patients receiving cardiac resynchronization therapy (CRT) therapies are largely unknown. Methods and Results— We hypothesized that clinical measures of heart failure severity and the presence of comorbid conditions would predict the risk of malignant arrhythmias in the 1520 patients enrolled in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial. Outcomes in the CRT group after implantable cardioverter defibrillator therapy were also evaluated. The CRT-defibrillator device reduced the risk of sudden death by 56% compared with drug therapy (17 of 595 [2.9%] versus 18 of 308 [5.8%], P 20% (HR, 0.55 [95% CI, 0.35 to 0.87]; P=0.01), QRS duration >160 ms (HR, 0.63 ...

Single-beat estimation of end-diastolic pressure-volume relationship: A novel method with potential for noninvasive application

Abstract: Whereas end-systolic and end-diastolic pressure-volume relations (ESPVR, EDPVR) characterize left ventricular (LV) pump properties, clinical utility of these relations has been hampered by the need...

Tetrahydrobiopterin and Cardiovascular Disease

Abstract: Tetrahydrobiopterin (BH4) is an essential cofactor for the aromatic amino acid hydroxylases, which are essential in the formation of neurotransmitters, and for nitric oxide synthase. It is presently used clinically to treat some forms of phenylketonuria (PKU) that can be ameliorated by BH4 supplementation. Recent evidence supports potential cardiovascular benefits from BH4 replacement for the treatment of hypertension, ischemia-reperfusion injury, and cardiac hypertrophy with chamber remodeling. Such disorders exhibit BH4 depletion because of its oxidation and/or reduced synthesis, which can result in functional uncoupling of nitric oxide synthase (NOS). Uncoupled NOS generates more oxygen free radicals and less nitric oxide, shifting the nitroso-redox balance and having adverse consequences on the cardiovascular system. While previously difficult to use as a treatment because of chemical instability and cost, newer methods to synthesize stable BH4 suggest its novel potential as a therapeutic agent. This review discusses the biochemistry, physiology, and evolving therapeutic potential of BH4 for cardiovascular disease.

Mechanisms and Use of Calcium-Sensitizing Agents in the Failing Heart

Abstract: Depressed cardiac contractility is central to many forms of cardiac disease and reflects the heart’s inability to generate adequate force despite being provided physiological activator calcium and chamber load. Yet, successful methods to enhance cardiac contractility have remained elusive. Agents such as dobutamine or milrinone that work through the β-receptor-cAMP-protein kinase A pathway are used to manage acute hemodynamic decompensation, but short-term and, particularly, long-term use can increase risks of arrhythmia and worsen outcome. These and other data have led to the conclusion that successful heart failure management should probably avoid the targeting of contractility improvement. Leading hypotheses for the failure of existing inotropic therapies is that they increase activator calcium, worsen arrhythmia, activate maladaptive Ca2+-dependent signaling cascades, and increase myocardial oxygen consumption, making hearts less efficient. An alternative approach to avoid such complications would be to directly influence the manner by which intracellular calcium is transduced into muscle force. The class of molecules that achieve this are often termed “calcium sensitizers” and have attracted growing clinical interest for more than 20 years.1 The mechanisms by which such effects are achieved vary widely and include direct activators of motor proteins such as myosin, enhancers of force generated by a cross-bridge, and agents that augment Ca2+–troponin C (TnC) binding and its consequences. To date, many such drugs have had additional effects, such as inhibiting cAMP phosphodiesterase (PDE3a), that likely contributed to their vasodilation/venodilation and Ca2+-dependent increases in heart rate and contractility. Other agents, such as levosimendan, also inhibit ATP-sensitive potassium channels, which can induce further effects. This review discusses basic molecular mechanisms for drugs that alter the myofilament response to calcium, how such agents affect muscle and whole-organ physiology, and what their clinical testing has revealed. In doing so, we attempted to bridge the …

Hemodynamic Modulation of Endocardial Thromboresistance

Abstract: Background— Patients with heart failure are at increased risk for thromboembolic events, including stroke. Historically attributed to blood stasis, little is known about the adverse effects of elevated chamber filling pressure on endocardial function, which could predispose to intracardiac thrombus formation. Methods and Results— We investigated changes in the expression of thrombomodulin, a key component of the anticoagulant protein C pathway, in rats subjected to acute atrial pressure overload caused by aortic banding. Acute elevation of left atrial filling pressure, without an associated decline in ventricular systolic function, caused a 70% inhibition of atrial endocardial thrombomodulin expression and resulted in increased local thrombin generation. Targeted restoration of atrial thrombomodulin expression with adenovirus-mediated gene transfer successfully reduced thrombin generation to baseline levels. In vitro co-culture studies revealed that thrombomodulin downregulation is caused by the paracrine...

Differential regional gene expression from cardiac dyssynchrony induced by chronic right ventricular free wall pacing in the mouse.

Abstract: Routine clinical right ventricular pacing generates left ventricular dyssynchrony manifested by early septal shortening followed by late lateral contraction, which, in turn, reciprocally stretches ...

Metalloproteinase Inhibitor Counters High-Energy Phosphate Depletion and AMP Deaminase Activity Enhancing Ventricular Diastolic Compliance in Subacute Heart Failure

Abstract: Cardiac matrix metalloproteinases (MMPs) stimulated by the sympathomimetic action of angiotensin II (AII) exacerbate chamber diastolic stiffening in models of subacute heart failure. Here we tested the hypothesis that MMP inhibition prevents such stiffening by favorably modulating high-energy phosphate (HEP) stores more than by effects on matrix remodeling. Dogs were administered AII i.v. for 1 week with tachypacing superimposed in the last two days (AII+P; n = 8). A second group (n = 9) underwent the same AII+P protocol but was preceded by oral treatment with an MMP inhibitor PD166793 [(S)-2-(4-bromo-biphenyl-4-sulfonylamino-3-methyl butyric acid] 1 week before and during the AII+P period. Pressure-volume analysis was performed in conscious animals, and myocardial tissue was subjected to in vitro and in situ zymography, collagen content, and HEP analysis (high-performance liquid chromatography). As reported previously, AII+P activated MMP9 and MMP2 and specifically exacerbated diastolic stiffening (+130% in chamber stiffness). PD166793 cotreatment prevented these changes, although myocardial collagen content, subtype, and cross-linking were unaltered. AII+P also reduced ATP, free energy of ATP hydrolysis (DeltaG(ATP)), and phosphocreatine while increasing free [ADP], AMP catabolites (nucleoside-total purines), and lactate. PD166793 reversed most of these changes, in part due to its inhibition of AMP deaminase. MMP activation may influence cardiac diastolic function by mechanisms beyond modulation of extracellular matrix. Interaction between MMP activation and HEP metabolism may play an important role in mediating diastolic dysfunction. Furthermore, these data highlight a potential major role for increased AMP deaminase activity in diastolic dysfunction.

Cardiac resynchronization therapy and cardiac reserve: How you climb a staircase may alter its steepness

Abstract: One of the primary mechanisms by which a heart can increase its pump performance is beating more frequently. Elevating heart rate enhances net cardiac output by the simple algebra of having more stroke volumes ejected per minute but also by an intrinsic effect of stimulation frequency on contractility. The latter, known as the force-frequency relation (FFR), relates to rate-dependent increases in calcium entry into a myocyte (more action potentials and thus Ca2+ channel openings per minute) coupled with greater Ca2+ uptake into the sarcoplasmic reticulum.1–3 The net effect is an increase in calcium released to the myofilaments with each stimulation, resulting in a “positive staircase” as heart rate rises from normal basal levels to fast physiological rates (&180 bpm in normal humans). This process has a limit, as calcium becomes effectively trapped within the sarcoplasmic reticulum when heart rate is faster than the kinetics of Ca2+ cycling can accommodate, leading to a “negative staircase” at more rapid rates.1,3 Article p 953 The FFR plays an important role in normal contractile reserve under stress, yielding a near 100% rise in cardiac chamber contractility in healthy adults when heart rate is varied from 60 to 150 bpm.4 As with many features of contractile regulation, however, the FFR becomes abnormal in the failing heart, characterized by both blunting of the peak response and a shift to a lower heart rate at which the maximal response is observed.1,5–7 In a patient with heart failure, this could result in a flat or even negative response, as heart rate varies over the physiological range. A number of factors are thought responsible for this, including downregulation of adrenergic responsiveness,8 depression, and/or reduced activation of critical proteins involved with excitation-contraction coupling, such the sarcoplasmic reticular ATPase, phospholamban,9–11 sodium/calcium exchanger, …

Use of a Nitric Oxide Synthase Modulator for the Treatment of Cardiac Indications

Abstract: The invention features compositions and methods for modulating NOS that are useful for the prevention and treatment of cardiac diseases and disorders, including cardiac hypertrophy and cardiac dilation. In particular, the invention provides compositions comprising tetrahydrobiopterin (BH4), alone or in combination with one or more additional compounds.