Group 2 Pulmonary Hypertension: Pulmonary Venous Hypertension: Epidemiology and Pathophysiology.

Pulmonary hypertension from left heart disease (PH-LHD) is the most common form of PH, defined as mean pulmonary artery pressure ≥25 mm Hg and pulmonary artery wedge pressure ≥15 mm Hg. PH-LHD development is associated with more severe left-sided disease and its presence portends a poor prognosis, particularly once right ventricular failure develops. Treatment remains focused on the underlying LHD and despite initial enthusiasm for PH-specific therapies, most studies have been disappointing and their routine clinical use cannot be recommended. More work is urgently needed to better understand the pathophysiology underlying this disease and to develop effective therapeutic strategies.

Correlation of Left Atrial Appendage Ejection Velocities with the CHADS2 and CHA2DS2-VASc Scores.

BACKGROUND: In patients with atrial fibrillation or flutter, a left atrial appendage ejection velocity measured via transesophageal echocardiography equal to or less than 40 cm/sec has been shown to correlate with an increased risk of developing left atrial appendage thrombus while velocities greater than 40 cm/sec are at lower risk. The CHADS2 and CHA2DS2-VASc scores calculated from clinical variables have been developed to risk stratify patients with atrial fibrillation/flutter in regard to the need for anticoagulation. This study was designed to assess whether a relationship exists between left atrial appendage ejection velocities and the respective CHADS2 and CHA2DS2-VASc scores, and whether this relationship is affected by the presence of atrial fibrillation or atrial flutter. METHODS: A retrospective chart review was performed on patients in the last 5 years who had undergone a transesophageal echocardiogram in which LAA velocity was measured. Once these patients were identified, relevant clinical information allowing for the calculation of the CHADS2 and CHA2DS2-VASc scores was also extracted from the medical record. RESULTS: Data from a total of 151 patients were included in the study. A statistically significant correlation between LAA velocity and CHADS2 score (P = 0.942) or between LAA velocity and CHA2DS2-VASc scores (P = 0.723) was not found. CONCLUSIONS: We could not identify a relationship between either the CHADS2 or CHA2DS2-VASc scores and LAA velocities. This was true regardless of whether patients were in sinus rhythm or AF at the time of the TEE. While reduced LAA velocities increase the risk of LAA thrombus, the development of stroke in patients with AF is secondary to a complex interplay of multiple clinical variables.

The nitric oxide synthase inhibitor N(G)-nitro-L-arginine decreases defibrillation-induced free radical generation.

OBJECTIVES: to demonstrate that nitric oxide (NO) contributes to free radical generation after epicardial shocks and to determinethe effect of a nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine (L-NNA), on free radical generation. BACKGROUND: Free radicals are generated by direct current shocks for defibrillation. NO reacts with the superoxide (O2*-) radical to for peroxynitrite (O = NOO-), which is toxic and initiates additional free radical generation. The contribution of NO to free radical generation after defibrillation is not fully defined. METHODS AND RESULTS: Fourteen open chest dogs were studied. In the initial eight dogs, 40 J damped sinusoidal monophasic epicardial shocks was administered. Using electron paramagnetic resonance, we monitored the coronary sinus concentration of ascorbate free radical (Asc*-), a measure of free radical generation (total oxidative flux). Epicardial shocks were repeated after L-NNA, 5 mg/kg IV. In six additional dogs, immunohistochemical staining was done to identify nitrotyrosine, a marker of reactive nitrogen species-mediated injury, in post-shock myocardial tissue. Three of these dogs received L-NNA pre-shock. After the initial 40 J shock, Asc*- rose 39 +/- 2.5% from baseline. After L-NNA infusion, a similar 40 J shock caused Asc*- to increase only 2 +/- 3% form baseline (P < 0.05, post-L-NNA shock versus initial shock). Nitrotyrosine staining was more prominent in control animals than dogs receiving L-NNA, suggesting prevention of O = NOO- formation. CONCLUSION: NO contributes to free radical generation and nitrosative injury after epicardial shocks; NOS inhibitors decrease radical generation by inhibiting the production of O = NOO-.

Stretch activation of GTP-binding proteins in C2C12 myoblasts.

Mechanical stimulation has been proposed as a fundamental determinant of muscle physiology. The mechanotransduction of strain and strain rate in C2C12 myoblasts were investigated utilizing a radiolabeled GTP analogue to detect stretch-induced GTP-binding protein activation. Cyclic uniaxial strains of 10% and 20% at a strain rate of 20% s(-1) rapidly (within 1 min) activated a 25-kDa GTPase (183 +/- 17% and 186 +/- 19%, respectively), while 2% strain failed to elicit a response (109 +/- 11%) relative to controls. One, five, and sixty cycles of 10% strain elicited 187 +/- 20%, 183 +/- 17%, and 276 +/- 38% increases in activation. A single 10% stretch at 20% s(-1), but not 0.3% s(-1), resulted in activation. Insulin activated the same 25-kDa band in a dose-dependent manner. Western blot analysis revealed a panel of GTP-binding proteins in C2C12 myoblasts, and tentatively identified the 25-kDa GTPase as rab5. In separate experiments, a 40-kDa protein tentatively identified as Galpha(i) was activated (240 +/- 16%) by 10% strain at 1 Hz for 15 min. These results demonstrate the rapid activation of GTP-binding proteins by mechanical strain in myoblasts in both a strain magnitude- and strain rate-dependent manner.

Coronary vascular dysfunction associated with direct current shock injury.

OBJECTIVE: To determine if cardiac injury following DC shocks includes impairment of coronary vascular reactivity. METHODS: 36 dogs (18-32 kg) were anesthetized and a thoracotomy was performed. Either antioxidant enzymes, superoxide dismutase (SOD, 15,000 U/kg) plus catalase (55,000 U/kg) or the NO synthase inhibitor N(G)-nitro-L-arginine (L-NNA, 5 mg/kg) was administered IV prior to sham (no shocks) or DC shock treatment, and the results were compared to dogs which did not receive SOD/catalase or L-NNA. In sham dogs, electrodes cradled the heart, but no shocks were delivered. In shock dogs, three 20 Joule DC shocks were delivered to the epicardium using hand-held paddles. Other dogs were allowed a 3-hour recovery period after the shocks. Epicardial microvessels and conduit rings were studied in vitro. Antagonists were not added to the bath of the study vessel. Internal diameter was measured in microvessels after constriction with endothelin. Tension of conduit arteries was measured after constriction with PGF(2alpha). Responses to acetylcholine (Ach, 10(-10)-10(-4) M), bradykinin (10(-14)-10(-6) M), the calcium ionophore A23187 (A23187, 10(-12)-10(-4) M) or nitroprusside (SNP, 10(-10)-10(-4) M) were measured. RESULTS: Bradykinin, A23187 and SNP dependent dilation was not different between vessels from sham and shocked animals. Dilation to Ach was attenuated in vessels from shocked dogs. Superoxide production probably contributed to the impaired dilation to Ach since treatment with SOD/catalase improved dilation. Treatment with L-NNA also improved vascular function after DC shock. CONCLUSION: DC shocks cause endothelial dysfunction, as demonstrated by impaired dilation to acetylcholine, in both canine coronary microvascular and conduit arteries. Since pretreatment with either SOD/catalase or L-NNA protects against this damage, a free radical mechanism, possibly involving eNOS, may contribute to endothelial dysfunction.DC shocks for cardioversion and defibrillation cause myocardial injury that may be free radical mediated.

The nitric oxide synthase inhibitor N(G)-nitro-L-arginine decreases defibrillation-induced free radical generation.

OBJECTIVES: To demonstrate that nitric oxide (NO) contributes to free radical generation after epicardial shocks and to determine the effect of a nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine (L-NNA), on free radical generation. BACKGROUND: Free radicals are generated by direct current shocks for defibrillation. NO reacts with the superoxide (O(2).(-)) radical to form peroxynitrite (O=NOO(-)), which is toxic and initiates additional free radical generation. The contribution of NO to free radical generation after defibrillation is not fully defined. METHODS AND RESULTS: Fourteen open chest dogs were studied. In the initial eight dogs, 40 J damped sinusoidal monophasic epicardial shocks was administered. Using electron paramagnetic resonance, we monitored the coronary sinus concentration of ascorbate free radical (Ascz.(-)), a measure of free radical generation (total oxidative flux). Epicardial shocks were repeated after L-NNA, 5 mg/kg IV. In six additional dogs, immunohistochemical staining was done to identify nitrotyrosine, a marker of reactive nitrogen species-mediated injury, in post-shock myocardial tissue. Three of these dogs received L-NNA pre-shock. After the initial 40 J shock, Ascz.(-) rose 39+/-2.5% from baseline. After L-NNA infusion, a similar 40 J shock caused Ascz.(-) to increase only 2+/-3% from baseline (P<0.05, post-L-NNA shock versus initial shock). Nitrotyrosine staining was more prominent in control animals than dogs receiving L-NNA, suggesting prevention of O=NOO(-) formation. CONCLUSIONS: NO contributes to free radical generation and nitrosative injury after epicardial shocks; NOS inhibitors decrease radical generation by inhibiting the production of O=NOO(-).

Strain and strain rate activation of G proteins in human endothelial cells.

The endothelium is known to sense and respond to its physical environment, but the underlying mechanisms and early events of endothelial cell mechanotransduction are not well understood. The present study measured G protein activation by mechanical strain in human umbilical vein endothelial cells (HUVEC) directly by photoincorporation of a hydrolysis resistant, radiolabeled GTP analog. Ten percent uniaxial strain at a strain rate of 20% s(-1) over 1min activated a 38kDa Galpha subunit 167+/-17% relative to controls, while 2% cyclic strain failed to significantly activate the protein (117+/-19%). A single cycle of 10% strain at 20% s(-1) strain rate activated the Galpha subunit 152+/-25%, while activation at the same strain but lower strain rate (0.3% s(-1)) was not significantly different from controls (116+/-12%). Western blot analysis identified the 38kDa protein as Galpha(q/11). These results demonstrate the rapid activation of G proteins in HUVEC by cyclic uniaxial strain in a strain- and strain rate-dependent manner.

Body weight is a predictor of biphasic shock success for low energy transthoracic defibrillation.

BACKGROUND: Transthoracic impedance and current flow are determinants of defibrillation success with monophasic shocks. Whether transthoracic impedance, either independently or via its association with body weight, is a determinant of biphasic waveform shock success has not been determined. METHODS AND RESULTS: We studied 22 swine, weighing 18-41 kg. After 15 s of ventricular fibrillation, each pig received transthoracic truncated exponential biphasic shocks (5/5 ms), 70-360 J. Shock success was strongly associated individually with body weight, leading-edge transthoracic impedance and current at low energy levels (70 and 100 J, all P<0.001). Multiple logistic regression analysis showed a significant association of body weight with shock success after adjusting for the effect of leading-edge impedance (odds ratio of success for 1 kg decrease in weight at 70 J was 1.29, 95% CI: 1.05-1.59, P=0.02; and at 100 J was 1.30, 95% CI: 1.14-1.49, P<0.0001). The same result was observed after adjusting for the effect of leading-edge current. At 150 J or higher energy levels, no significant association was observed. CONCLUSIONS: Body weight is a determinant of shock success with biphasic waveforms at low energy levels in this swine model.

Transthoracic biphasic waveform defibrillation at very high and very low energies: a comparison with monophasic waveforms in an animal model of ventricular fibrillation.

The purpose of this study was to compare truncated exponential biphasic waveform versus truncated exponential monophasic waveform shocks for transthoracic defibrillation over a wide range of energies. Biphasic waveforms are more effective than monophasic shocks for defibrillation at energies of 150-200 Joules (J) but there are few data available comparing efficacy and safety of biphasic versus monophasic defibrillation at energies of <150 J or >200 J. Thirteen adult swine (weighing 18-26 kg, mean 20 kg) were deeply anesthetized and intubated. After 15 s of electrically-induced ventricular fibrillation (VF), each pig received truncated exponential monophasic shocks (10 ms) and truncated exponential biphasic shocks (5/5 ms) in random order. Energy doses ranged from 70 to 360 J. Success was defined as termination of VF at 5 s post-shock. For both biphasic and monophasic waveforms success rate rose as energy was increased. Biphasic waveform shocks (5/5 ms) were superior to 10 ms monophasic waveform shocks at the very low energy levels (at 70 J, biphasic: 80+/-9%, monophasic; 32+/-11% and at 100 J, biphasic; 96+/-3% and monophasic 39+/-11%, both P < 0.01). No significant differences in shock success were seen between biphasic and monophasic waveform shocks at 200 J or higher energy levels. Shock success of > 75% was achieved with 200 J (10 J/kg) for both waveforms. Pulseless electrical activity (PEA) or ventricular asystole occurred in 4 animals receiving monophasic shocks and 1 animal receiving biphasic shocks. Biphasic waveform shocks (5/5 ms) for transthoracic defibrillation were superior to monophasic shocks (10 ms) at low energy levels. Percent success increased with increasing energies. PEA occurred infrequently with either waveform.