Increase In Peak Systolic Pressure Research Articles

Abstract 12821: Progressive Improvement in Left Ventricular Performance Associated With Progressive Regional Dyssynchrony

Background : We have shown that non-excitatory epicardial stimulation (NES) increases measures of cardiac function mediated by local release of norepinephrine. In this further investigation we determined whether NES is accompanied by improved indices of left ventricular (LV) performance, reflected in PV loops and timing of aortic valve opening and closing. Methods : Anesthetized pigs (n=6) were instrumented with a LV high-fidelity pressure/volume conductance transducer, thoracic aortic pressure transducer, left atrial (LA)/ LV epicardial electrodes, and sonomicrometer segment length (SL) gauges placed proximal (lateral base) and distal (posterior mid LV) to the LV stimulation site. During constant LA pacing, LV pulses (0.8ms, 2-3x threshold volts) were applied during the absolute refractory period for 3 minutes (3x), before and after β-receptor blockade (BB, metoprolol). Data were analyzed at baseline, and at an estimated 30%, 60% and 100% of developed ventricular dyssynchrony (DVD) contraction pattern. Results: Consistent with earlier findings, NES resulted in an early shortening and relaxation pattern of the proximal SL manifest as an 80% decrease in the LVP vs. SL loop area in the absence of change in the remote segment. This was accompanied by an increase in peak systolic pressure and LV dP/dt max. Although NES did not change the area of the LVP vs. LV volume loop (stroke work) or alter the interval from LV electrical activation (R wave) to the onset of LV pressure increase, aortic valve opening occurred up to 14.1 ± 2.8 ms earlier (p <0.01) compared to baseline. The duration of an open aortic valve slightly increased (6.0 ± 3.9 ms) whereas ejection duration from valve opening to peak Pao decreased 18.2 ± 3.0 ms (p < 0.01). Conclusion : These findings demonstrate that NES elicits a local contractile dysynchrony resulting in an enhanced cardiac inotropic state characterized by more rapid global LV contraction with earlier aortic valve opening with no change in stroke work.

Abstract 14303: Structural Remodeling in the Left Ventricular Myocardium Underlies Systolic Dysfunction in Myocardial Infarction

Introduction: Myocardial infarction (MI) leads to myofiber death and the formation of a fibrotic scar in the left ventricular free wall (LVFW) myocardium. Acute MI induces remodeling events in the LV consisting of alterations in the architecture and biomechanical properties of the LVFW, collectively leading to LV systolic dysfunction. We implemented a multi-modality pipeline bridging architectural remodeling, LVFW passive behavior adaptation, and ventricular dysfunction in MI. We hypothesize that biomechanical remodeling of the LV serves as an important predictor of clinical outcomes in MI. Methods: MI was induced in rats via the ligation of the LAD artery, and hearts were harvested at five time points: pre-MI, and 1-wk to 4-wk post-MI (n=6 for each time point). Echocardiography and terminal LV catheterization were performed. LVFW specimens were harvested and subjected to biaxial testing, followed by picrosirius red staining. Histological slides were analyzed to quantify fiber architecture. Results: Comparisons for 3-wk MI versus control groups are reported (animal-specific results for representative rats are shown in Fig. 1). Echocardiography imaging showed a decrease in EF (84±5 vs 73±10%; p=0.053) and a decrease in ESV (0.122±0.045 vs 0.31±0.195ml; p=0.013). LV catheterization revealed a decrease in SV (50±0.86 vs 10±0.38μL; p<0.001) and an increase in peak systolic pressure (36.62±0.87 vs 44.91±0.99 mmHg; p<0.001), indicating systolic dysfunction. Biaxial testing revealed longitudinal stiffening of the LVFW at 3-wk post-MI. Scarring and a shift in myofiber orientation towards the longitudinal direction corroborated changes in the LVFW mechanical behavior in the MI group. Conclusions: LV systolic dysfunction in MI is significantly influenced by disruption in myofiber architecture and fiber orientation remodeling in the LVFW. Assessment of LVFW remodeling events provides important incremental information over traditional organ-level indices.

Assessing Pressure-Volume Relationship in Developing Heart of Zebrafish In-Vivo.

During embryogenesis, the developing heart transforms from a linear peristaltic tube into a multi-chambered pulsatile pump with blood flow-regulating valves. In this work, we report how hemodynamic parameters evolve during the heart's development, leading to its rhythmic pumping and blood flow regulation as a functioning organ. We measured the time course of intra-ventricular pressure from zebrafish embryos at 3, 4, and 5 days post fertilization (dpf) using the servo null method. We also measured the ventricular volume and monitored the opening/closing activity of the AV and VB valves using 4D selective plane illumination microscopy (SPIM). Our results revealed significant increases in peak systolic pressure, stroke volume and work, cardiac output, and power generation, and a total peripheral resistance decrease from zebrafish at 4, 5 dpf versus 3 dpf. These data illustrate that the early-stage zebrafish heart's increasing efficiency is synchronous with the expected changes in valve development, chamber morphology and increasing vascular network complexity. Such physiological measurements in tractable laboratory model organisms are critical for understanding how gene variants may affect phenotype. As the zebrafish emerges as a leading biomedical model organism, the ability to effectively measure its physiology is critical to its translational relevance.

Intermittent cardiac overload results in adaptive hypertrophy and provides protection against left ventricular acute pressure overload insult.

The present study aimed to test whether a chronic intermittent workload could induce an adaptive cardiac phenotype Chronic intermittent workload induced features of adaptive hypertrophy This was paralleled by protection against acute pressure overload insult The heart may adapt favourably to balanced demands, regardless of the nature of the stimuli. The present study aimed to test whether submitting the healthy heart to intermittent and tolerable amounts of workload, independently of its nature, could result in an adaptive cardiac phenotype. Male Wistar rats were subjected to treadmill running (Ex) (n = 20), intermittent cardiac overload with dobutamine (ITO) (2 mg kg(-1) , s.c.; n = 20) or placebo administration (Cont) (n = 20) for 5 days week(-1) for 8 weeks. Animals were then killed for histological and biochemical analysis or subjected to left ventricular haemodynamic evaluation under baseline conditions, in response to isovolumetric contractions and to sustained LV acute pressure overload (35% increase in peak systolic pressure maintained for 2 h). Baseline cardiac function was enhanced only in Ex, whereas the response to isovolumetric heartbeats was improved in both ITO and Ex. By contrast to the Cont group, in which rats developed diastolic dysfunction with sustained acute pressure overload, ITO and Ex showed increased tolerance to this stress test. Both ITO and Ex developed cardiomyocyte hypertrophy without fibrosis, no overexpression of osteopontin-1 or β-myosin heavy chain, and increased expression of sarcoplasmic reticulum Ca(2+) protein. Regarding hypertrophic pathways, ITO and Ex showed activation of the protein kinase B/mammalian target of rapamycin pathway but not calcineurin. Mitochondrial complex IV and V activities were also increased in ITO and Ex. Chronic submission to controlled intermittent cardiac overload, independently of its nature, results in an adaptive cardiac phenotype. Features of the cardiac overload, such as the duration and magnitude of the stimuli, may play a role in the development of an adaptive or maladaptive phenotype.

Effects of an Angiotensin II Antagonist on Ischemic and Nonischemic Isolated Rat Hearts

Background. Increasing evidence suggests that a locally integrated or intramyocardial renin-angiotensin system plays a significant role in ischemia-reperfusion injury. We evaluated the effects of losartan, an angiotensin II type 1 receptor blocking agent, on ischemic and nonischemic isolated rat hearts. Methods. Using the modified Langendorff model, hearts were perfused with either low or high doses of losartan (18.2 mmol/L or 182.2 mmol/L, respectively) or with saline added to Krebs-Henseleit solution during phase I of the study. During phase II, hearts were exposed to a 60-minute period of global ischemia. Ischemic arrest was induced with warm cardioplegic solution (KCl, 16 mEq/L) containing either high-dose losartan (182.2 mmol/L) or Krebs-Henseleit solution only. Results. During phase I of the study, no statistically significant differences were observed between the low-dose losartan group and the control group. However, hearts treated with high-dose losartan demonstrated an increase in peak systolic pressure, maximum first derivative of pressure, pressure-time integral, coronary flow, and oxygen consumption ( p < 0.0001). During phase II, hearts treated with losartan showed a significantly better recovery on reperfusion, as reflected by better contractility ( p < 0.001), higher oxygen consumption ( p < 0.001), higher coronary flow ( p < 0.0001), and lower creatine phosphokinase levels (41.1 ± 1.7 versus 73.3 ± 5.6 U/L; p < 0.001). Conclusions. High doses of losartan have a positive inotropic effect on normally perfused hearts. Given in cardioplegic solution, the drug has a significant protective effect on ischemic isolated rat hearts.

Relationship between cardiac function and substrate oxidation in hearts of diabetic rats.

The effects of streptozotocin-induced diabetes on myocardial substrate oxidation and contractile function were investigated using 13C nuclear magnetic resonance (NMR) spectroscopy. To determine the consequences of diabetes on glucose oxidation, hearts were perfused with [1-13C]glucose (11 mM) alone as well as in the presence of insulin (to stimulate glucose transport) and dichloroacetate (to stimulate pyruvate dehydrogenase). The contribution of glucose to the tricarboxylic acid (TCA) cycle was significantly decreased in hearts from diabetic animals compared with controls, with glucose alone and with insulin; however, the addition of dichloroacetate significantly increased the contribution of glucose to the TCA cycle. Contractile function in hearts from diabetic animals was significantly depressed with glucose as the sole substrate, regardless of the presence of insulin or dichloroacetate (P < 0.0005). To determine whether diabetes had any direct effects on beta-oxidation and the TCA cycle, hearts were perfused with glucose (11 mM) plus [6-13C]hexanoate (0.5 mM) as substrates. In control hearts, with glucose plus hexanoate as substrates, hexanoate contributed 98.9 +/- 2% of the substrate entering the TCA cycle; this was significantly decreased to 90.7 +/- 0.6% in the diabetic group (P < 0.02). The addition of hexanoate to the perfusate resulted in a significant increase in peak systolic pressure in the diabetic group (P < 0.001) such that contractile function was indistinguishable from controls.

Oxygen cost of stress development in hypertrophied and failing hearts from the spontaneously hypertensive rat.

Left ventricular isovolumic stress development and metabolic parameters were studied in 18-24-month-old spontaneously hypertensive rats (SHRs) and age-matched Wistar-Kyoto (WKY) rat controls using the isolated, isovolumic (balloon in left ventricle) buffer-perfused rat heart preparation. After WKY rats and all SHRs were compared, SHRs were divided into two groups: those animals with (SHR-F) and without (SHR-NF) evidence of heart failure. Hearts were perfused at 100 mm Hg using a constant pressure system at a temperature of 37 degrees C. In the baseline state, peak systolic pressure was greatest in the SHR-NF group and lowest in the SHR-F group. Peak midwall stress was greatest in the WKY group and, again, lowest in the SHR-F group. Oxygen consumption was lowest in the SHR-F group. When the oxygen cost of stress development was estimated by normalizing myocardial oxygen consumption by peak developed midwall stress, values were lowest in the WKY, greater in the SHR-NF, and greatest in the SHR-F group. Lactate production did not occur in the baseline state in any of the groups. Functional and metabolic responses to graded hypoxia, induced by changing the gas mixture of the perfusate from 95% to 50%, 25%, and 0% oxygen at perfusion pressures of 100 and 130 mm Hg, were studied. Increasing perfusion pressure generally resulted in small increases in peak systolic pressure and myocardial oxygen consumption but did not substantially reverse the contractile or metabolic deficit present in the SHR-F group.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased myocardial inositol trisphosphate levels during α1-adrenergic stimulation and reperfusion of ischaemic rat heart

Although stimulated [ 3H] inositol phosphate turnover has been demonstrated in isolated, perfused [ 3H] inositol prelabelled rat hearts, there is still no information regarding Ins(1,4,5)P 3 levels in intact cardiac muscle. Using a D-myo-Ins(1,4,5)P 3 assay system, Ins(1,4,5)P 3 levels were determined in isolated perfused rats hearts during ischaemia, reperfusion and α 1-adrenergic stimulation via noradrenaline (3 × 10 −5 m). Control hearts contained ± 674 pmols Ins(1,4,5)P 3/g dry heart weight. Myocardial Ins(1,4,5)P 3 levels were significantly decreased (± 389 pmols/g dry heart weight) after exposure to 20 mins of normothermic ischaemic cardiac arrest (NICA). Reperfusion produced a marked increase in Ins(1,4,5,)P 3 levels (± 1 115 pmols/g dry heart weight) after only 30 s. Noradrenaline caused a 3–4 fold increase in tissue Ins(1,4,5)P 3 levels within 30 s. After 20 mins stimulation with noradrenaline, the Ins(1,4,5)P 3 levels were still significantly elevated. The rise in tissue Ins(1,4,5)P 3 levels during reperfusion as well as during noradrenaline administration was counteracted by neomycin (0.5 × 10 −3 m), an inhibitor of phosphoinositidase specific phospholipase C. In both events neomycin restored the Ins(1,4,5)P 3 levels to control values. For correlation of tissue Ins(1,4,5)P 3 levels with mechanical events, noradrenaline (3 × 10 −5 m), in the presence of 10 m m LiCl, 10 −7 m propanolol and 10 −7 m atropine, was administered to isolated perfused rat hearts and the mechanical performance recorded over a period of 20 mins. Noradrenaline caused a significant increase in peak systolic pressure and work performance which was maintained for at least 10 mins, suggesting that the positive inotropic effects of noradrenaline may be provoked by Ins(1,4,5)P 3. Furthermore, the finding that 20 min NICA followed by 30 s reperfusion causes an immediate significant increase in Ins(1,4,5)P 3 content suggests a role for the phosphatidylinositol pathway in the intracellular Ca 2+ overloading, characteristic of ischaemia-reperfusion.

Inotropic and metabolic effects of dibutyryl cyclic adenosine 3', 5'-monophosphate in the perfused rat heart.

AbstractThe isolated, working rat heart preparation was used to study whether dibutyryl cyclic adenosine 3′,5′‐monophosphate could reproduce the inotropic and nietabolic effects of catecholamines in the heart. The effects of dibutyryl cyclic AMP and adrenaline were studied in absence and presence of aβ‐receptor blocking agent (propranolol). Heart rate, cardiac output, peak systolic pressure, glycogen content, lactate production and concentrations of ATP and creatine‐phosphate were measured.Dibutyryl cyclic AMP (5×10‐3 M and higher concentrations) evoked a positive inotropic effect as measured by an increase in peak systolic pressure, when the heart rate was kept constant by electrical stimulation. The nucleotide also produced a marked and concentration dependent (10‐5 to10‐3) glycogenolytic effect. Propranolol (10‐5M) blocked the inotropic and glycogenolytic effects of adrenaline, but did not reduce the effects of dibutyryl cyclic AMP. The effects of adrenaline were seen already 1 min after its addition to the perfusion medium, while the effects of dibutyryl cyclic AMP were not seen until 3–5 min after addition of the nucleotide. In time course studies, no dissociation was observed between mechanical and metabolic effects of the nucleotide.