Myocardial Demand Research Articles

Impact of Atrial Fibrillation on Coronary Blood Flow: A Systematic Review.

Patients with atrial fibrillation (AF) frequently present with symptoms suggestive of myocardial isch- aemia, even in the absence of significant CAD, that seem to be attributable to abnormalities of myocardial perfusion and perfusion reserve. According to the results of recent human and previous experimen- tal studies the increase in coronary artery blood flow during AF is smaller, while the coronary vascular resistance during the arrhythmia does not decrease as much as we would expect, suggesting a mismatch between coronary blood flow and myocardial metabolic demand. AF itself diminishes coronary flow reserve, especially in the subendocardial layer, partly as a result of the increase in the myocardial com- ponent of coronary vascular resistance, and it is possible that irregular ventricular rhythm may play an important role. The mismatch of coronary blood flow and myocardial metabolic demand, especially in view of the severe reduction in coronary flow reserve, may have deleterious consequences that are not limited to patients with CAD.

Evaluation of Vasomera™, a Novel VPAC2-Selective Vasoactive Intestinal Peptide Agonist, in Rats With Doxorubicin-Induced Cardiomyopathy: Evidence for Chronic Cardio-Protection.

The natural vasoactive intestinal peptide (VIP) has been proposed as a therapeutic agent for heart failure triggering potent vasodilatation/inotropy via the activation of the G-protein-coupled VPAC1 and VPAC2 receptors; however, VIP's clinical utility is limited due to its short half-life and VPAC1-mediated side-effects. Vasomera™ is a novel long-acting biopolymer-based selective VPAC2-receptor agonist. Here, the chronic functional/geometrical effects of Vasomera when given daily to rats with doxorubicin-induced cardiomyopathy were evaluated.Sprague-Dawley rats were assigned to receive daily therapy with either Vasomera (9 mg/kg/day SQ; n = 15) or placebo (n = 10), and had heart failure induced via doxorubicin (3 mg/kg IP on M-W-F for 2 weeks; 18 mg/kg total); treatments started prior to HF induction (5 days) and continued until the end of the study. LV function/geometry were evaluated (via echocardiography) prior to the start of dosing, as well as weekly both during/after (for up to 3 weeks) HF induction. Animals were terminally studied in order to evaluate LV mechano-energetics.Doxorubicin lead to marked LV dysfunction/remodeling, characterized by depressed systolic function (e.g., FS: -18 ± 4 %, P < 0.05), myocardial dilatation (e.g., LVIDd: +12 ± 2, P < 0.05), and wall-thinning (WT: -15 ± 5 %, P < 0.05). Daily Vasomera therapy prevented doxorubicin-induced myocardial wasting/wall-thinning (WTs: +1 ± 4%, N.S.), ameliorating ventricular dysfunction (e.g., FS, -8 ± 2%, P < 0.05) and dilatation (LVIDd: +3 ± 3, N.S.). Vasomera treatment also tended to preserve the LV- to body-weight ratio (-2.4 ± 2.0% vs. time-controls, N.S.), when compared to un-treated animals (-7.5 ± 3.0% vs. time-controls, P = 0.1). Terminally, Vasometra-treated animals tended to have lower LV filling pressures (EDP: 13 ± 1 vs. 9 ± 1 mmHg).Daily treatment with Vasomera, a novel VPAC2 agonist, attenuated doxorubicin-induced myocardial remodeling/dysfunction in rats. In particular, Vasomera treatment prevented myocardial wall-thinning/muscular wasting. Moreover, acute Vasomera administration (IV) to rats with doxorubicin-induced cardiomyopathy, dose-dependently decreased myocardial loading and energetic demand, while improving LV systolic/diastolic function in a load-independent manner. The natural vasoactive intestinal peptide (VIP) has been proposed as a therapeutic agent for heart failure triggering potent vasodilatation/inotropy via the activation of the G-protein-coupled VPAC1 and VPAC2 receptors; however, VIP's clinical utility is limited due to its short half-life and VPAC1-mediated side-effects. Vasomera™ is a novel long-acting biopolymer-based selective VPAC2-receptor agonist. Here, the chronic functional/geometrical effects of Vasomera when given daily to rats with doxorubicin-induced cardiomyopathy were evaluated. Sprague-Dawley rats were assigned to receive daily therapy with either Vasomera (9 mg/kg/day SQ; n = 15) or placebo (n = 10), and had heart failure induced via doxorubicin (3 mg/kg IP on M-W-F for 2 weeks; 18 mg/kg total); treatments started prior to HF induction (5 days) and continued until the end of the study. LV function/geometry were evaluated (via echocardiography) prior to the start of dosing, as well as weekly both during/after (for up to 3 weeks) HF induction. Animals were terminally studied in order to evaluate LV mechano-energetics. Doxorubicin lead to marked LV dysfunction/remodeling, characterized by depressed systolic function (e.g., FS: -18 ± 4 %, P < 0.05), myocardial dilatation (e.g., LVIDd: +12 ± 2, P < 0.05), and wall-thinning (WT: -15 ± 5 %, P < 0.05). Daily Vasomera therapy prevented doxorubicin-induced myocardial wasting/wall-thinning (WTs: +1 ± 4%, N.S.), ameliorating ventricular dysfunction (e.g., FS, -8 ± 2%, P < 0.05) and dilatation (LVIDd: +3 ± 3, N.S.). Vasomera treatment also tended to preserve the LV- to body-weight ratio (-2.4 ± 2.0% vs. time-controls, N.S.), when compared to un-treated animals (-7.5 ± 3.0% vs. time-controls, P = 0.1). Terminally, Vasometra-treated animals tended to have lower LV filling pressures (EDP: 13 ± 1 vs. 9 ± 1 mmHg). Daily treatment with Vasomera, a novel VPAC2 agonist, attenuated doxorubicin-induced myocardial remodeling/dysfunction in rats. In particular, Vasomera treatment prevented myocardial wall-thinning/muscular wasting. Moreover, acute Vasomera administration (IV) to rats with doxorubicin-induced cardiomyopathy, dose-dependently decreased myocardial loading and energetic demand, while improving LV systolic/diastolic function in a load-independent manner.

Mechanism of myocardial ischemia with an anomalous left coronary artery from the right sinus of Valsalva

An ectopic coronary artery that courses between the aortic root and the pulmonary trunk may lead to sudden cardiac death, especially in athletes. It has been speculated that during exercise, compression of the coronary artery between the great vessels may impair coronary blood flow and produce myocardial ischemia and fatal arrhythmia. However, this hypothesis cannot be tested in humans, and little experimental data exist to explain this phenomenon. To this end, in a calf with an anomalous left coronary artery that coursed from the right sinus of Valsalva between the great vessels, we assessed for myocardial ischemia during pharmacologically induced tachycardia and hypertension. We identified a juvenile male calf (103 kg) with an anomalous left coronary artery from the right sinus of Valsalva that coursed between the great vessels. Via thoracotomy, the animal was instrumented for hemodynamic measurements. Intravenous dobutamine increased heart rate and myocardial metabolic demands. Intravenous phenylephrine produced arterial hypertension and increased myocardial metabolic demands. Fluorescent-labeled microspheres were used to map regional myocardial blood flow, and hemodynamics were recorded during each condition. Masson's trichrome staining for fibrosis, wheat-germ agglutinin staining for myocyte size, terminal deoxynucleotidyl transferase dUTP nick end-label staining for apoptosis, and isolectin-B4 staining for capillary density were performed. For the first time, empiric data documented that an ectopic coronary artery produced myocardial ischemia during elevated myocardial metabolic demands. Left coronary artery resistance increased in a cardiac cycle-dependent pattern that was consistent with systolic compression between the great vessels. Increased cardiac fibrosis, myocyte hypertrophy, cardiac apoptosis, and capillary density indicated that regional ischemic, inflammatory-mediated myocardial remodeling was present. These findings confirm the proposed mechanism of sudden death and support early surgical repair of coronary arteries that course between the aortic root and the pulmonary trunk.

Managing atrial fibrillation in the CRT patient: Controversy or consensus?

The cumulative incidence of new onset atrial fibrillation (AF) in patients undergoing cardiac resynchronization therapy (CRT) is substantial, exceeding 25% in multiple recent studies. Although AF patients undergoing CRT show improved echocardiographic parameters, functional status, and quality of life in, they benefit to a lesser degree than do patients in normal sinus rhythm. They also exhibit a trend toward increased mortality. Understanding the barriers to response from CRT among AF patients is critical to addressing the needs of growing populations of patients with AF and HF. Foremost among these are suboptimal biventricular pacing, often characterized by fusion or pseudo-fusion complexes, leading to inefficient CRT delivery. Furthermore, AF increases the risk of inappropriate shocks, which lead to substantial psychiatric morbidity, increased risk of heart failure hospitalization, and may also increase mortality. Assiduous rate control is reasonable for all AF patients receiving CRT, but there is a paucity of data regarding specific antiarrhythmic drug therapy recommendations. For patients with permanent AF and severe symptoms, atrioventricular junction ablation appears effective in improving response by ensuring biventricular capture and reducing implantable cardioverter-defibrillator shock burden in selected patients. Catheter-based techniques such as pulmonary vein isolation appear more attractive and in the future may offer further advantages and lower risks, particularly for patients with paroxysmal AF.

Aortic reservoir function, estimated myocardial demand and coronary perfusion pressure following steady‐state and interval exercise

Aortic reservoir function is a measure of the aorta's ability to distribute blood during diastole, attenuating the pulsatility of blood flow, and is important in balancing cardiac flow. Effects of acute high versus moderate exercise intensity on reservoir function and cardiac energetics is unknown. Eighteen athletes completed a interval (INT) and steady-state (SS) cycling bout at 60% of VO(2) peak. Reservoir function was calculated as the ratio of diastolic run-off to stroke volume and expressed as a percentage. Coronary perfusion pressure was derived from tissue Doppler imaging and echocardiography. Systolic tension-time integral (TTI) from the aortic pressure waveform served as a measure of myocardial oxygen consumption. All measures were made at rest, 30-min postexercise and 60-min postexercise. Average reservoir function before SS was 76%, which was reduced to 62% 30-min post-SS and 67% 60-min post-SS (P<0.05). Significantly greater reductions in reservoir function were seen following INT (from 71% pre-INT to 45% 30-min post-INT and 53% 60-min INT, P<0.05). Estimated coronary perfusion pressure was reduced 30min following INT but not SS; both bouts reduced coronary perfusion pressure at 60-min postexercise (P<0.05). TTI increased following both INT and SS at 30- and 60-min postexercise with greater increases following INT (P<0.05). Following exercise, reservoir function was associated with TTI (P<0.05), but not coronary perfusion pressure (P>0.05). We conclude that reservoir function is attenuated following acute SS and INT, but these reductions were greater post-INT, suggesting that exercise intensity affects reservoir function. Reduction of reservoir function following exercise is related to TTI, a reflection of myocardial oxygen consumption but apparently not associated with coronary perfusion pressure.

Cardioprotection of electroacupuncture against myocardial ischemia-reperfusion injury by modulation of cardiac norepinephrine release

Augmentation of cardiac sympathetic tone during myocardial ischemia has been shown to increase myocardial O(2) demand and infarct size as well as induce arrhythmias. We have previously demonstrated that electroacupuncture (EA) inhibits the visceral sympathoexcitatory cardiovascular reflex. The purpose of this study was to determine the effects of EA on left ventricular (LV) function, O(2) demand, infarct size, arrhythmogenesis, and in vivo cardiac norepinephrine (NE) release in a myocardial ischemia-reperfusion model. Anesthetized rabbits (n = 36) underwent 30 min of left anterior descending coronary artery occlusion followed by 90 min of reperfusion. We evaluated myocardial O(2) demand, infarct size, ventricular arrhythmias, and myocardial NE release using microdialysis under the following experimental conditions: 1) untreated, 2) EA at P5-6 acupoints, 3) sham acupuncture, 4) EA with pretreatment with naloxone (a nonselective opioid receptor antagonist), 5) EA with pretreatment with chelerythrine (a nonselective PKC inhibitor), and 6) EA with pretreatment with both naloxone and chelerythrine. Compared with the untreated and sham acupuncture groups, EA resulted in decreased O(2) demand, myocardial NE concentration, and infarct size. Furthermore, the degree of ST segment elevation and severity of LV dysfunction and ventricular arrhythmias were all significantly decreased (P < 0.05). The cardioprotective effects of EA were partially blocked by pretreatment with naloxone or chelerythrine alone and completely blocked by pretreatment with both naloxone and chelerythrine. These results suggest that the cardioprotective effects of EA against myocardial ischemia-reperfusion are mediated through inhibition of the cardiac sympathetic nervous system as well as opioid and PKC-dependent pathways.

Aging attenuates the coronary blood flow response to cold air breathing and isometric handgrip in healthy humans

The purpose of this echocardiography study was to measure peak coronary blood flow velocity (CBV(peak)) and left ventricular function (via tissue Doppler imaging) during separate and combined bouts of cold air inhalation (-14 ± 3°C) and isometric handgrip (30% maximum voluntary contraction). Thirteen young adults and thirteen older adults volunteered to participate in this study and underwent echocardiographic examination in the left lateral position. Cold air inhalation was 5 min in duration, and isometric handgrip (grip protocol) was 2 min in duration; a combined stimulus (cold + grip protocol) and a cold pressor test (hand in 1°C water) were also performed. Heart rate, blood pressure, O(2) saturation, and inspired air temperature were monitored on a beat-by-beat basis. The rate-pressure product (RPP) was used as an index of myocardial O(2) demand, and CBV(peak) was used as an index of myocardial O(2) supply. The RPP response to the grip protocol was significantly blunted in older subjects (Δ1,964 ± 396 beats·min(-1)·mmHg) compared with young subjects (Δ3,898 ± 452 beats·min(-1)·mmHg), and the change in CBV(peak) was also blunted (Δ6.3 ± 1.2 vs. 11.2 ± 2.0 cm/s). Paired t-tests showed that older subjects had a greater change in the RPP during the cold + grip protocol [Δ2,697 ± 391 beats·min(-1)·mmHg compared with the grip protocol alone (Δ2,115 ± 375 beats·min(-1)·mmHg)]. An accentuated RPP response to the cold + grip protocol (compared with the grip protocol alone) without a concomitant increase in CBV(peak) may suggest a dissociation between the O(2) supply and demand in the coronary circulation. In conclusion, older adults have blunted coronary blood flow responses to isometric exercise.

A novel clinical method for quantification of regional left ventricular pressure–strain loop area: a non-invasive index of myocardial work

AimsLeft ventricular (LV) pressure–strain loop area reflects regional myocardial work and metabolic demand, but the clinical use of this index is limited by the need for invasive pressure. In this study, we introduce a non-invasive method to measure LV pressure–strain loop area.Methods and resultsLeft ventricular pressure was estimated by utilizing the profile of an empiric, normalized reference curve which was adjusted according to the duration of LV isovolumic and ejection phases, as defined by timing of aortic and mitral valve events by echocardiography. Absolute LV systolic pressure was set equal to arterial pressure measured invasively in dogs (n = 12) and non-invasively in patients (n = 18). In six patients, myocardial glucose metabolism was measured by positron emission tomography (PET). First, we studied anaesthetized dogs and observed an excellent correlation (r = 0.96) and a good agreement between estimated LV pressure–strain loop area and loop area by LV micromanometer and sonomicrometry. Secondly, we validated the method in patients with various cardiac disorders, including LV dyssynchrony, and confirmed an excellent correlation (r = 0.99) and a good agreement between pressure–strain loop areas using non-invasive and invasive LV pressure. Non-invasive pressure–strain loop area reflected work when incorporating changes in local LV geometry (r = 0.97) and showed a strong correlation with regional myocardial glucose metabolism by PET (r = 0.81).ConclusionsThe novel non-invasive method for regional LV pressure–strain loop area corresponded well with invasive measurements and with directly measured myocardial work and it reflected myocardial metabolism. This method for assessment of regional work may be of clinical interest for several patients groups, including LV dyssynchrony and ischaemia.

Competitive flow and arterial graft a word of caution

Competitive flow is a common finding in arterial grafting. Flow competition results from an equilibrium between the residual flow through the native coronary artery and the flow provided by the bypass graft at the anastomosis. This situation occurs when conductance of the graft closely matches that of the native circulation and is mainly dependent on stenosis severity and on graft diameter and length. The phenomenon is nearly inexistent with the saphenous vein graft (SVG) whose large conduit generally opposes very few resistance to blood flow; consequently, the pressure at the ostium of SVG is nearly equivalent to that provided at the distal anastomosis even in conditions of high myocardial flow demand [1]. Conversely, the conductance of arterial grafts is generally lower due to smaller diameter and greater length, resulting in some pressure drop along the graft [2]. The longer the arterial assembly, the lower the pressure at the distal anastomosis, a phenomenon aggravated by the anatomic distal tapering of arteries. Therefore competitive flow is more frequent at the right coronary anastomosis of composite Y grafts due to the lower pressure in the distal portion of the Y branch [3]. Another important parameter in the phenomenon of flow competition well described in this issue by Nakajima et al. [4] is the sequential grafting versus single grafting. The mechanism of competitive flow is more complex than in the individual graft in which the interaction is only between the proximal inflow and the distal anastomosis outflow. In sequential composite bypass, the interaction is also between all the anastomosed branches within the composite graft. This leads to a phasic delay between the pressure wave in the grafts, and in the coronary arteries, especially in the more distal ones such as the right coronary artery [5]. The success of the CABG has been assessed by the ‘patency’ of grafts, predominantly using the Fizgabon classification [6]. This system was appropriate for a period when the predominant bypass conduit was the SVG. SVGs are minimally reactive and as such can be classified as either patent or not. The increasing use of arterial conduits represents a paradigm shift in bypass surgery. In contrast to SVG, arterial grafts are dynamic and may adapt their luminal diameter both at short interval through vasomotion and at long-term through anatomic adaptation. As such, Nakajima as [4] well as others [7] sought to define a classification system more representative of the functional status rather than the anatomical patency of the graft. A graft is defined ‘not functional’ when occluded, when the flow from the native coronary artery is dominant or when flow supply from the native coronary and from the graft is balanced. A graft is defined ‘functional’ when the native coronary is fully opacified by the graft or when the native coronary is fully opacified by the graft only (occluded or sub-occluded coronary native vessel). On the other hand, Nakajima et al. [4] have used the classic methodology for assessing the severity of target vessel stenosis, namely percentage stenosis by visual inspection, which may be inappropriate when considering the use of arterial conduits. We have demonstrated that the minimal luminal diameter correlates far better with arterial graft functionality than the percent stenosis [3–6]. We believe that this measure is a more relevant predictor of the degree of competitive flow, which is known to be a critical determinant in long-term arterial graft functionality. Studies designed to select the most appropriate graft configuration for each individual case will certainly contribute to optimize myocardial revascularization in the future. More accurate assessments of graft function and of the pre-operative status with the help of new objective evaluation tools such as quantitative angiography or fractional flow reserve could contribute to reach this objective.

Altered coronary vascular control during cold stress in healthy older adults

Cardiovascular-related mortality increases in the cold winter months, particularly in older adults. Previously, we reported that determinants of myocardial O(2) demand, such as the rate-pressure product, increase more in older adults compared with young adults during cold stress. The aim of the present study was to determine if aging influences the coronary hemodynamic response to cold stress in humans. Transthoracic Doppler echocardiography was used to noninvasively measure peak coronary blood velocity in the left anterior descending artery before and during acute (20 min) whole body cold stress in 10 young adults (25 ± 1 yr) and 11 older healthy adults (65 ± 2 yr). Coronary vascular resistance (diastolic blood pressure/peak coronary blood velocity), coronary perfusion time fraction (coronary perfusion time/R-R interval), and left ventricular wall stress were calculated. We found that cooling (via a water-perfused suit) increased left ventricular wall stress, a primary determinant of myocardial O(2) consumption, in both young and older adults, although the magnitude of this increase was nearly twofold greater in older adults (change of 9.1 ± 3.5% vs. 17.6 ± 3.2%, P < 0.05, change from baseline in young and older adults and young vs. older adults). Despite the increased myocardial O(2) demand during cooling, coronary vasodilation (decreased coronary vascular resistance) occurred only in young adults (3.22 ± 0.23 to 2.85 ± 0.18 mmHg·cm(-1)·s(-1), P < 0.05) and not older adults (3.97 ± 0.24 to 3.79 ± 0.27 mmHg·cm(-1)·s(-1), P > 0.05). Consistent with a blunted coronary vascular response, absolute coronary perfusion time tended to decrease (P = 0.13) and coronary perfusion time fraction decreased (P < 0.05) during cooling in older adults but not young adults. Collectively, these data suggest that older adults demonstrate an altered coronary hemodynamic response to acute cold stress.

Arterial Pulse Wave Dynamics After Percutaneous Aortic Valve Replacement

Background— Aortic stenosis causes angina despite unobstructed arteries. Measurement of conventional coronary hemodynamic parameters in patients undergoing valvular surgery has failed to explain these symptoms. With the advent of percutaneous aortic valve replacement (PAVR) and developments in coronary pulse wave analysis, it is now possible to instantaneously abolish the valvular stenosis and to measure the resulting changes in waves that direct coronary flow. Methods and Results— Intracoronary pressure and flow velocity were measured immediately before and after PAVR in 11 patients with unobstructed coronary arteries. Using coronary pulse wave analysis, we calculated the intracoronary diastolic suction wave (the principal accelerator of coronary blood flow). To test physiological reserve to increased myocardial demand, we measured at resting heart rate and during pacing at 90 and 120 bpm. Before PAVR, the basal myocardial suction wave intensity was 1.9±0.3×10 −5 W · m −2 · s −2 , and this increased in magnitude with increasing severity of aortic stenosis ( r =0.59, P =0.05). This wave decreased markedly with increasing heart rate (β coefficient=−0.16×10 −4 W · m −2 · s −2 ; P &lt;0.001). After PAVR, despite a fall in basal suction wave (1.9±0.3 versus 1.1±0.1×10 −5 W · m −2 · s −2 ; P =0.02), there was an immediate improvement in coronary physiological reserve with increasing heart rate (β coefficient=0.9×10 −3 W · m −2 · s −2 ; P =0.014). Conclusions— In aortic stenosis, the coronary physiological reserve is impaired. Instead of increasing when heart rate rises, the coronary diastolic suction wave decreases. Immediately after PAVR, physiological reserve returns to a normal positive pattern. This may explain how aortic stenosis can induce anginal symptoms and their prompt relief after PAVR. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01118442.

Risk Factors and Consequences of Atrial Fibrillation with Rapid Ventricular Response in Patients with Ischemic Stroke Treated with Intravenous Thrombolysis

Atrial fibrillation (AF) is associated with rapid ventricular response (RVR) that increases myocardial demand and blood pressure instability. We investigated the incidence, risk factors, and outcomes of RVR among patients with ischemic stroke receiving treatment with intravenous (IV) recombinant tissue plasminogen activator (rtPA). Consecutive patients with AF who received IV rtPA within 3 hours of symptom onset were included. Vascular risk factors, stroke characteristics, and outcome measures were compared between patients who developed RVR and those who did not. Eighty patients with AF (mean age, 79 years; 46% men) who underwent rtPA treatment were studied. Nineteen (24%) of these patients developed RVR and were treated with IV rate-controlling medications. A bimodal pattern of distribution was observed in the occurrence of RVR, with the first peak occurring within 12 hours of stroke onset and the second peak occurring 24-48 hours after onset. Compared with the patients without RVR, those with RVR stayed a median duration of 1.2 days longer in the intensive care unit (P = .048). There were no differences in functional recovery and hemorrhagic outcomes between the patients with RVR and those without RVR. We observed a 16-hour delay in the resumption of antiarrhythmic medications (either at previous or reduced dosage) in the patients who subsequently developed RVR (median time from stroke onset, 29 hours vs 13 hours; P = .040). Our findings suggest that a delay in the resumption of rate-control medications in patients with AF may result in RVR and prolong the use of intensive care resources.

Pilot Evaluation of a Novel Intra-Atrial Valved-Shunt (V-Wave Device) for Pressure-Dependent Cardiac Unloading in a Chronic Model of Ischemic Heart Failure

Increased left-ventricular (LV) diastolic pressures, occurring during heart failure (HF), can increase myocardial energy demand and facilitate maladaptive remodeling. We hypothesized that LV unloading during periods of volume overload can mitigate remodeling/functional deterioration in HF. Therefore, we studied a novel intra-atrial one-way (left-to-right) valve (V-Wave) designed to act as a selective/pressure dependent shunt, implanted in animals with chronic ischemic heart (HF).

Vascular Dysfunction in Sleep Apnea

See related article, pp 417–424 Cardiovascular disease remains one of the leading causes of morbidity and mortality. Obstructive sleep apnea (OSA) has been increasingly implicated in a breadth of cardiovascular diseases, including systemic hypertension, heart failure, stroke, arrhythmias, myocardial ischemia, and pulmonary arterial hypertension.1 The importance of this association, especially in the context of OSA as an etiologic factor, is compellingly relevant to disease management strategies, given the high prevalence of OSA and its likely rising trajectory secondary to the ongoing obesity epidemic.2 OSA may be present in approximately 20% of American adults, only a minority of whom have ever been diagnosed; this is true even for patients with established cardiovascular disease3 and despite the widespread availability of several effective treatment modalities (including continuous positive airway pressure [CPAP]). It is only over the past 2 decades that serious investigative interest has been paid to the interactions between OSA and cardiac and vascular disease and dysfunction. Deciphering the mechanisms, causal relationships, and potential therapeutic targets in the links between OSA and cardiovascular morbidity has not been an easy task, in part because of the constellation of comorbidities that characterize a large proportion of sleep apnea patients. OSA leads to multiple sources of cardiovascular stress, including nocturnal hypoxemia and hypercapnia, precipitous intrathoracic pressure changes, repetitive arousals, and poor sleep quality with consequent sleep deprivation. These, in turn, have been linked to endothelial dysfunction,4 systemic inflammation, sympathetic activation,5 metabolic dysregulation, hypercoagulability, and atrial enlargement, the combination of which may contribute to the initiation and progression of a range of cardiovascular diseases. Of these, endothelial dysfunction …

Progress in perioperative myocardial ischaemia and myocardial infarction

Background Many perioperative factors may result in myocardial ischaemia and myocardial infarction. Better understanding of the mechanism and effective prevention of it are all essential to decrease the incidence of perioperative cardiac event. Purpose To investigate the mechanism of perioperative myocardial ischaemia and myocardial infarction and their effective preventive measures. Content The change of the responsiveness of coronary atherosclerosis endodermis to sympathetic and parasympathetic stimulius along with the special pathophysiologic states may contribute to perioperative myocardial ischaemia and myocardial infarction. For patients with coronary artery disease, enhancing the monitor and diagnose of perioperative myocardial ischaemia and myocardial infarction, maintaining the stabilization of plaque and the banlance of myocardial oxygen supply and demand, improving postoperative analgesia, keeping normothermia and the avoidance of high blood glucose can decrease the incidence of perioperative myocardial infarction. Trend The relationship between the treatment duration of preoperative prophylactic drug therapy and the advantage as well as the value of preoperative coronary artery reconstitution for patients with coronary artery disease undergoing noncardiac operation still need to be researched. Key words: Perioperative; Myocardial ischaemia; Myocardial infarction; Prevention

Acute Intermittent Hypoxia Inhibits Triglycerides Clearance And Has a Tissue‐Specific Effect on Lipoprotein Lipase Activity

Background We have recently shown that chronic intermittent hypoxia (IH) decreases triglycerides (TG) clearance due to the inhibition of lipoprotein lipase (LPL) activity in adipose tissue. However, the impact of acute IH on TG clearance and LpL activity remains unknown. Methods Male C57BL/6J mice were exposed to 7hs of IH with FiO2 decreasing from 20.9% to 5% once per minute or to intermittent air (IA). During the exposure, intralipid (20%, 7.5 ml/kg) was administered and serum triglyceride levels were measured over the 2 hr time course. In a separate batch of mice, fasting (5 hrs) LPL activity was measured in the epididymal fat pads, heart and skeletal muscle. Results Compared to IA, IH increased TG levels throughout the 2 hr time course of intralipid (p <0.01). Exposure to IH for 7 hrs resulted in a significant decrease in adipose LPL activity (IA: 5.83±0.51 vs. IH: 4.40±0.29 umol FFA released/g/hr; P<0.05) and a significant increase in the heart LPL activity (IA: 42.61±2.28 vs. IH: 60.70±3.05 umol FFA released/g/hr; P<0.01). No difference was observed in the skeletal muscle. Conclusions Acute IH inhibits TG clearance, possibly by suppressing adipose LpL activity. A simultaneous increase in heart LpL may be attributable to the heightened myocardial demand in fatty acids as a source of energy. Research Support: R01 HL80105, AHA 10GRNT3360001, 5P50HL084945, FAPESP 2010/11681-0

Evidence for a Role for the Cytoskeleton in Communication Between the L-Type Calcium Channel and the Mitochondria in Isolated Cardiac Myocytes

Cytoskeletal proteins stabilize cell structure but also regulate subcellular distribution of mitochondria and cardiac L-type Ca2+ channel (LTCC) activity. We have previously demonstrated that mitochondrial function can be regulated by alterations in LTCC activity. This effect was attenuated when the cytoskeleton was disrupted with latrunculin A. To further explore this, we determined whether regulation of mitochondrial function by the LTCC is altered in a murine model of Duchenne Muscular Dystrophy(mdx). Mitochondrial membrane potential (Ψm) and metabolic activity was assessed after activation of the LTCC in cardiac myocytes isolated from C57BL/10ScSn-Dmdmdx/Arc (mdx) and C57BL/10ScSnArc (control) mice. Exposure of control myocytes to 10μM BayK(-) (LTCC agonist) caused a 11.4±1.7% increase in Ψm assessed as alterations in JC-1 compared to myocytes exposed to inactive BayK(+) (n=8, p<0.05). The response was attenuated when myocytes were exposed to LTCC antagonist nisoldipine (n=7). However BayK(-) did not induce any significant alteration in JC-1 signal in myocytes from mdx mice (n=6). In control myocytes BayK(-) caused a 105.4±7.4% increase in metabolic activity assessed using an MTT assay (n=8, p<0.05). The response was attenuated when myocytes were exposed to nisoldipine (n=8) or mitochondrial calcium uniporter inhibitor Ru360 (n=8) but unaltered when exposed to ryanodine receptor antagonist dantrolene (n=4). Exposure of mdx myocytes to BayK(-) did not induce any significant alteration in metabolic activity (n=8). These data confirm that alterations in LTCC activity can modulate mitochondrial function and that the cytoskeleton plays an important role in mediating this response. Since the LTCC is the initiator of contraction it has been proposed that a functional coupling between the LTCC and mitochondria may assist in meeting myocardial energy demand on a beat to beat basis.

Levosimendan in trauma patients with acute cardiac failure

Acute heart failure (AHF) is common among trauma patients with pre-existing coronary artery disease (CAD) and myocardial perfusion defect. The therapy is aimed at increased contractility while decreasing afterload and includes β1-adrenergic agents and phosphodiesterase III inhibitors, which act by increasing the intracellular calcium (Ca) concentration, thus markedly increasing myocardial energy consumption and risk of arrhythmias. The new Ca sensitizer levosimendan enhances cardiac performance without increasing myocardial energy demand and oxygen consumption. We report new use of levosimendan in polytrauma victims with AHF.

PII: S8756-3282(10)01794-1

The traditional concept of myocardial ischemia precipitated by increases in the myocardial demand for oxygen is well accepted for patients with fixed coronary atherosclerosis. Recently, however, observations of abnormal vasomotor tone in the coronary artery bed have suggested that vasoconstriction at an atherosclerotic site may be a primary cause of decreases in the myocardial supply of oxygen. This has led to a classification of mixed ischemic subsets characterized by the superimposition of an increased myocardial oxygen demand on a decreased myocardial oxygen supply. The subsets are defined by several clinical parameters, including unstable angina pectoris, acute myocardial infarction, malignant ventricular arrhythmias, mixed angina pectoris, and asymptomatic or silent ischemia. Holter monitoring, electrocardiography, and evaluations of wall motion have confirmed the existence of asymptomatic ischemic episodes that far outnumber episodes of angina in patients with stable angina pectoris. This concept has considerable diagnostic and therapeutic implications.

Enhancing the metabolic substrate: PPAR-alpha agonists in heart failure

The prognosis for patients diagnosed with heart failure has significantly improved over the past three decades; however, the disease still confers a high degree of morbidity and mortality. Current treatments for chronic heart failure have focused primarily on blocking neurohormonal signaling and optimizing hemodynamic parameters. Although significant resources have been devoted toward the development of new pharmaceutical therapies for heart failure, few new drugs have been designed to target myocardial metabolic pathways despite growing evidence that on a fundamental level chronic heart failure can be characterized as an imbalance between myocardial energy demand and supply. Disruptions in myocardial energy pathways are evident as the myocardium is unable to generate sufficient amounts of ATP with advancing stages of heart failure. Down-regulation of fatty acid oxidation likely contributes to the phenotype of the "energy starved" heart. Fibrates are small molecule agonists of PPARα pathways that have been used to treat dyslipidemia. Although never used therapeutically in clinical heart failure, PPARα agonists have been shown to enhance fatty acid oxidation, improve endothelial cell function, and decrease myocardial fibrosis and hypertrophy in animal models of heart failure. In light of their excellent clinical safety profile, PPARα agonists may improve outcomes in patients suffering from systolic heart failure by augmenting myocardial ATP production in addition to targeting maladaptive hypertrophic pathways.