Aß Amyloid Pathology Affects the Hearts of Patients With Alzheimer's Disease: Mind the Heart.

BACKGROUND: Individually, heart failure (HF) and Alzheimer's disease (AD) are severe threats to population health, and their potential coexistence is an alarming prospect. In addition to sharing analogous epidemiological and genetic profiles, biochemical characteristics, and common triggers, the authors recently recognized common molecular and pathological features between the 2 conditions. Whereas cognitive impairment has been linked to HF through perfusion defects, angiopathy, and inflammation, whether patients with AD present with myocardial dysfunction, and if the 2 conditions bear a common pathogenesis as neglected siblings are unknown. OBJECTIVES: Here, the authors investigated whether amyloid beta (Aß) protein aggregates are present in the hearts of patients with a primary diagnosis of AD, affecting myocardial function. METHODS: The authors examined myocardial function in a retrospective cross-sectional study from a cohort of AD patients and age-matched controls. Imaging and proteomics approaches were used to identify and quantify Aß deposits in AD heart and brain specimens compared with controls. Cell shortening and calcium transients were measured on isolated adult cardiomyocytes. RESULTS: Echocardiographic measurements of myocardial function suggest that patients with AD present with an anticipated diastolic dysfunction. As in the brain, Aß40 and Aß42 are present in the heart, and their expression is increased in AD. CONCLUSIONS: Here, the authors provide the first report of the presence of compromised myocardial function and intramyocardial deposits of Aß in AD patients. The findings depict a novel biological framework in which AD may be viewed either as a systemic disease or as a metastatic disorder leading to heart, and possibly multiorgan failure. AD and HF are both debilitating and life-threatening conditions, affecting enormous patient populations. Our findings underline a previously dismissed problem of a magnitude that will require new diagnostic approaches and treatments for brain and heart disease, and their combination.

Human vasculogenic cells form functional blood vessels and mitigate adverse remodeling after ischemia reperfusion injury in rats.

Cell-based therapies to restore heart function after infarction have been tested in pre-clinical models and clinical trials with mixed results, and will likely require both contractile cells and a vascular network to support them. We and others have shown that human endothelial colony forming cells (ECFC) combined with mesenchymal progenitor cells (MPC) can be used to "bio-engineer" functional human blood vessels. Here we investigated whether ECFC + MPC form functional vessels in ischemic myocardium and whether this affects cardiac function or remodeling. Myocardial ischemia/reperfusion injury (IRI) was induced in 12-week-old immunodeficient rats by ligation of the left anterior descending coronary artery. After 40 min, myocardium was reperfused and ECFC + MPC (2 × 10(6) cells, 2:3 ratio) or PBS was injected. Luciferase assays after injection of luciferase-labeled ECFC + MPC showed that 1,500 ECFC were present at day 14. Human ECFC-lined perfused vessels were directly visualized by femoral vein injection of a fluorescently-tagged human-specific lectin in hearts injected with ECFC + MPC but not PBS alone. While infarct size at day 1 was no different, LV dimensions and heart weight to tibia length ratios were lower in cell-treated hearts compared with PBS at 4 months, suggesting post-infarction remodeling was ameliorated by local cell injection. Fractional shortening, LV wall motion score, and fibrotic area were not different between groups at 4 months. However, pressure-volume loops demonstrated improved cardiac function and reduced volumes in cell-treated animals. These data suggest that myocardial delivery of ECFC + MPC at reperfusion may provide a therapeutic strategy to mitigate LV remodeling and cardiac dysfunction after IRI.

The fire within: cardiac inflammatory signaling in health and disease.

Inflammatory mediators are operative in the pathogenesis of the most common forms of heart disease. Although in most cases the induction of these pathways is maladaptive and deleterious, there are notable exceptions when inflammatory pathways participate in healing or limiting the extent of injury. The appreciation of the role of these mechanisms in myocardial homeostasis and pathophysiology has led to increased efforts to elucidate the specific signaling pathways most relevant to the heart. Our goal in this introductory overview is to provide context for the five detailed reviews that follow by introducing the major relevant stimuli, the receptors, and pathways that mediate inflammatory signaling in the heart. We try to impart a sense of the scope and complexity of these pathways, as well as their interactions with signaling pathways regulating cell survival and metabolism. These complexities underscore the potential challenges of therapeutically targeting inflammatory mechanisms in heart disease and may help explain the mostly disappointing results of this approach to date.

IKKß regulates essential functions of the vascular endothelium through kinase-dependent and -independent pathways.

Vascular endothelium provides a selective barrier between the blood and tissues, participates in wound healing and angiogenesis, and regulates tissue recruitment of inflammatory cells. Nuclear factor (NF)-κB transcription factors are pivotal regulators of survival and inflammation, and have been suggested as potential therapeutic targets in cancer and inflammatory diseases. Here we show that mice lacking IKKß, the primary kinase mediating NF-κB activation, are smaller than littermates and born at less than the expected Mendelian frequency in association with hypotrophic and hypovascular placentae. IKKß-deleted endothelium manifests increased vascular permeability and reduced migration. Surprisingly, we find that these defects result from loss of kinase-independent effects of IKKß on activation of the serine-threonine kinase, Akt. Together, these data demonstrate essential roles for IKKß in regulating endothelial permeability and migration, as well as an unanticipated connection between IKKß and Akt signalling.

Left atrial appendage exclusion using an Amplatzer device.

Patients with atrial fibrillation are at an increased risk of having a cardioembolic stroke. Most of the thrombi responsible for these ischemic events originate in the left atrial appendage (LAA). Several surgical and percutaneous endovascular techniques have been explored to occlude the LAA. As an alternative of the surgical closure, percutaneous exclusion of the LAA is a new approach used to prevent strokes in high-risk patients with AF and contraindication to long-term oral anticoagulant therapy. Currently, two devices have been developed specifically for percutaneous occlusion of the LAA the PLAATO system and the WATCHMAN filter system. Although the Amplatzer septal occluder device was not originally intended to occlude the LAA it has been used with success in our centre for this purpose. We present an illustrative case of a patient with AF no longer suitable for chronic OCA referred for percutaneous exclusion of the LAA. She was treated successfully with an Amplatzer septal occluder. Although our experience with this device holds promise, future trials will be necessary to explore this strategy.

Nitric oxide in the pulmonary vasculature.

Homeostasis in the pulmonary vasculature is maintained by the actions of vasoactive compounds, including nitric oxide (NO). NO is critical for normal development of the pulmonary vasculature and continues to mediate normal vasoregulation in adulthood. Loss of NO bioavailability is one component of the endothelial dysfunction and vascular pathology found in pulmonary hypertension (PH). A broad research effort continues to expand our understanding of the control of NO production and NO signaling and has generated novel theories on the importance of pulmonary NO production in the control of the systemic vasculature. This understanding has led to exciting developments in our ability to treat PH, including inhaled NO and phosphodiesterase inhibitors, and to several promising directions for future therapies using nitric oxide-donor compounds, stimulators of soluble guanylate cyclase, progenitor cells expressing NO synthase (NOS), and NOS gene manipulation.

Role of collateral blood flow in the apparent disparity between the extent of abnormal wall thickening and perfusion defect size during acute myocardial infarction and demand ischemia.

OBJECTIVES: The aim of this study was to test the hypothesis that the apparent disparity between the circumferential extent of abnormal wall thickening (WT) and that of infarct size (IS) at rest or size of ischemic zone (IZ) during demand ischemia (DI) is principally due to the effects of collateral blood flow (CollBF). BACKGROUND: A disparity has been reported between the circumferential extent of abnormal WT and that of IS at rest or IZ size during DI. METHODS: Wall thickening and CollBF were measured in 18 dogs: at 6 h after coronary occlusion (Group 1, n = 6), and during 40 microg x kg x min(-1) of dobutamine in the presence of either one-vessel (Group 2, n = 6) or two-vessel stenosis (Group 3, n = 6). RESULTS: The apparent overestimation of the IS by the circumferential extent of abnormal WT was due to intermediate levels of CollBF in border zones within the risk area that had escaped necrosis. Although reduced, WT in these regions was commensurate with the level of flow. Similarly, during DI, regions within the IZ exhibiting the worst WT in Group 2 and 3 dogs were those not supplied by CollBF. The regions supplied by CollBF had intermediate WT, which was also commensurate with the level of flow. Only in two Group 3 dogs was tethering seen in small, normally perfused regions that were interspersed between two large IZ. Excluding these few tethered regions, data from different myocardial regions (infarcted, ischemic, CollBF dependent, and normal) were described by a single relation: y = 57(1 - e([-0.72(x - 0.06)])) (r = 0.80, p < 0.001). CONCLUSIONS: Myocardial regions at the margins of ischemic territories contribute to the apparent disparity between the circumferential extent of abnormal WT and IS or IZ during DI. In most circumstances, these regions are supplied by collaterals and their WT is commensurate with the degree of myocardial blood flow. The apparent disparity between the circumferential extent of WT and ischemia is rarely due to myocardial tethering, which is seen only in some instances of multi-vessel disease where a small normal region is interspersed between two large IZs.

Direct effects of dobutamine on the coronary microcirculation: comparison with adenosine using myocardial contrast echocardiography.

The direct effects of dobutamine on capillary blood volume (VOL) and blood flow velocity (VEL) are not known. We hypothesized that these would be more similar to that of adenosine because of its effects on the beta(2) receptors on the coronary circulation. A total of 9 open-chest anesthetized dogs were studied after placement of 2 noncritical stenoses at rest and during separate intracoronary administrations of 5 microg/kg(-1)/min(-1) of adenosine and 2 microg/kg(-1)/min(-1) of dobutamine. VOL and VEL were measured using myocardial contrast echocardiography, wall thickening with 2-dimensional echocardiography, and myocardial blood flow (MBF) with radiolabeled microspheres. Dobutamine increased the rate-pressure product significantly, whereas adenosine had no effect on the rate-pressure product. In the normal myocardium, adenosine had no effect on VOL and increases in MBF were all a result of increases in VEL. Dobutamine also caused mostly an increase in VEL and only a 30% increase in VOL indicating modest capillary recruitment. In the bed with stenosis both drugs attenuated increase in MBF by the same amount, which was associated with an attenuation in the increase in VEL secondary to a 15% increase in capillary resistance because of capillary derecruitment. The MBF-wall thickening relation was described for both drugs by the same function: y = 1 - exp(x) with wall thickening being significantly higher for dobutamine compared with adenosine for each level of MBF. We conclude that the increase in MBF in the normal myocardium with intracoronary dobutamine occurs mostly from an increase in VEL rather than from an increase in VOL. In the bed with a noncritical stenosis, the increases in MBF and VEL are similar for both drugs. Similar to intracoronary adenosine, intracoronary dobutamine also caused capillary derecruitment distal to a noncritical coronary stenosis.

Relation between myocardial oxygen consumption and myocardial blood volume: a study using myocardial contrast echocardiography.

Myocardial blood volume (MBV) is the volume of blood residing in myocardial vessels, 90% of which is in capillaries. MBV can be measured in vivo using myocardial contrast echocardiography (MCE). It has been shown that when increases in coronary blood flow (CBF) are not associated with increase in myocardial oxygen consumption (MVO(2)), MBV does not increase. We hypothesized that MBV would increase when increases in CBF are associated with an increase in MVO(2). The atrioventricular node was ablated in 18 dogs and dual-chamber pacing was instituted. In group 1 dogs (n = 9), heart rate was altered from 50 to 150 bpm(-1) in increments of 20 bpm(-1) in random order. In group 2 dogs (n = 9), heart rate was kept constant, and dobutamine was infused at doses of 5, 10, 20, 30, and 40 microg/kg(-1)/min(-1). During each intervention, hemodynamic parameters and MVO(2) were measured, and MCE was performed. MVO(2) increased more (P <.01) with inotropic compared with chronotropic stimulation, resulting in a parallel increase in CBF. MBV fraction and MCE-derived myocardial blood flow increased significantly with increases in MVO(2) (P <.05 and P <.001, respectively) when dobutamine was infused, but remained unchanged when heart rate alone was increased. We conclude that when MVO(2) is increased substantially, the resulting increase in CBF and MCE-derived myocardial blood flow is mediated, in part, by an increase in MBV. Thus, capillary recruitment plays an important role in the physiologic regulation of CBF. Lack of increase in MBV during dobutamine stress may indicate the presence of coronary stenosis or microvascular disease.

Mechanism of inducible regional dysfunction during dipyridamole stress.

BACKGROUND: We hypothesized that increased myocardial oxygen demand resulting from hypotension and reflex tachycardia unmasking a reduced endocardial myocardial blood flow (MBF) reserve is the mechanism of dipyridamole-induced regional dysfunction in chronic coronary artery disease. METHODS AND RESULTS: Ameroid constrictors were placed around the proximal coronary arteries and their major branches in 15 dogs to create chronic coronary stenosis. Seven days later, radiolabeled microsphere-derived MBF and 2-dimensional echocardiography-derived percent wall thickening (%WT) were measured at rest and after 0.56 mg/kg dipyridamole. Dipyridamole caused an increase (mean, 21%) in the rate-pressure product secondary to reflex tachycardia resulting from mild systemic hypotension. %WT in myocardial segments with an endocardial MBF reserve (dipyridamole/resting MBF) of 1.5 to 2.5 (n=35) did not change after dipyridamole, whereas it decreased in segments with an endocardial MBF reserve of <1.5 (n=30) and increased in those with an endocardial MBF reserve of > or =2.5 (n=45) (P<0.05). Most (80%) segments with endocardial MBF reserve of <1.5 and 14% with an endocardial MBF reserve of 1.5 to 2.5 showed inducible dysfunction after dipyridamole, whereas none of the segments with an endocardial MBF reserve of > or =2.5 showed this finding. A sigmoid relation (y=-6.74/[1+exp (19.9. [x-1.84])]+1.35. x, r=0.93, P<0.0001) was noted between endocardial MBF reserve and Delta%WT. In contrast, neither the epicardial MBF reserve nor the endocardial/epicardial MBF ratio during hyperemia was associated with inducible regional dysfunction. CONCLUSIONS: Increased myocardial oxygen demand resulting from hypotension and reflex tachycardia unmasking a reduced endocardial MBF reserve is the primary mechanism of dipyridamole-induced regional dysfunction in chronic coronary artery disease.