NKX6.1 functions as a metastatic suppressor through epigenetic regulation of the epithelial-mesenchymal transition.

The transcription factor NKX6.1 (NK6 homeobox 1) is important in the development of pancreatic ß-cells and neurons. Although recent publications show that NKX6.1 is hypermethylated and downregulated during tumorigenesis, the function of NKX6.1 in carcinogenesis remains elusive. Here, we address the metastasis suppressor function of human NKX6.1 using cell, animal and clinical analyses. Our data show that NKX6.1 represses tumor formation and metastatic ability both in vitro and in vivo. Mechanistically, NKX6.1 suppresses cell invasion by inhibiting the epithelial-to-mesenchymal transition (EMT). NKX6.1 directly enhances the mRNA level of E-cadherin by recruiting BAF155 coactivator and represses that of vimentin and N-cadherin by recruiting RBBP7 (retinoblastoma binding protein 7) corepressor. Clinical cancer tumors with metastasis show low NKX6.1 protein expression coinciding with low E-cadherin and high vimentin expression. Our results demonstrate that NKX6.1 functions as an EMT suppressor by interacting with different epigenetic modifiers, making it a potential novel therapeutic option.

Heart disease in Asians and Pacific-Islanders, Hispanics, and Native Americans.

Heart disease is the leading cause of death for Asian-Americans and Pacific-Islanders, Hispanic-Americans, and Native Americans. Generally, heart disease death rates are lower in these population groups than in Caucasians, with the notable exception of Native Americans under the age of 35. Of particular interest are data for southwestern US Native Americans and Mexican-Americans, which indicate low CHD prevalence rates despite high rates of obesity, diabetes mellitus, increasing hypertension, and low socioeconomic status. Much more research is needed to explain these and other observations. Intervention in those risk factors already identified is necessary, particularly in prevention of obesity and diabetes.

Unstable angina pectoris.

The pathophysiology of unstable angina has been better elucidated in the past five years and has led to more rational therapy. Coronary arteries in patients with unstable angina have atherosclerotic plaques which are often complex and are the site of platelet activation and fibrin deposition. Nitrates, one of the oldest therapies, are efficacious and act not only by dilating coronary vessels but by reducing preload and afterload. Beta blockers have a salutary effect by decreasing myocardial oxygen demand. Calcium channel blockers attenuate smooth muscle contraction and thereby act to decrease coronary artery spasm. Beta blockers and calcium channel blockers are equally efficacious in unstable angina. The antiplatelet agent, aspirin, has been shown to reduce fatal or non-fatal myocardial infarction and probably overall mortality. The use of heparin acutely for unstable angina has been demonstrated to decrease refractory angina and myocardial infarction, and acutely is probably better than aspirin. For patients with reduced ejection fractions (0.30-0.49), a prospective randomized trial has shown that coronary artery bypass graft surgery offers an improved three-year survival compared with medical therapy; however, surgery does not prevent myocardial infarction. Percutaneous transluminal coronary angioplasty may be a reasonable therapeutic alternative for some patients with single-vessel disease who are refractory to medical therapy but there are as yet no controlled trials of this question. To date a clinical benefit from thrombolytic therapy has not been demonstrated.

Hemodynamic and respiratory effects of dezocine, ciramadol, and morphine.

The hemodynamic and respiratory effects of dezocine and ciramadol, two agonist-antagonist analgesics, were compared with those of morphine in 30 patients undergoing diagnostic cardiac catheterization. Each subject received a single intravenous dose of dezocine (0.125 mg/kg), ciramadol (0.6 mg/kg), or morphine (0.125 mg/kg) in a double-blind fashion. Hemodynamic and respiratory parameters were measured at baseline and 5, 10, and 20 minutes after dosing. Dezocine increased the cardiac index (CI; 2.67 to 2.92 L/min/m2), stroke volume index (SVI; 43.6 to 47.6 ml/beat/m2), left ventricular stroke work index (LVSWI; 57.4 to 64.7 gm-m/m2), and pulmonary vascular resistance (PVR; 105.6 to 154.0 dynes X sec/cm5). Ciramadol increased the CI (2.78 to 3.22 L/min/m2), SVI (40.9 to 48.2 ml/beat/m2), LVSWI (51.1 to 57.9 gm-m/m2), and mean pulmonary arterial pressure (PA; 14.7 to 18.9 mm Hg). Morphine had no effect on CI, SVI, LVSWI, PA, or PVR, but it significantly lowered systolic and diastolic blood pressures. There were no appreciable changes in heart rate, left ventricular end-diastolic pressure, mean arterial pressure, or mean pulmonary capillary wedge pressure after any of the drugs. All three drugs significantly decreased systemic vascular resistance. There were no clinically significant changes in respiratory parameters. We conclude that dezocine, ciramadol, and morphine have no clinically important adverse effects on cardiac performance.

Alterations in lung volume and pulmonary function in relation to hemodynamic changes in acute myocardial infarction.

To characterize the changes in lung volumes after acute myocardial infarction (AMI), and the relationship of these changes to other alterations in lung function which correlate with the severity of pulmonary vascular congestion, we made measurements of pulmonary hemodynamics, lung volume, closing volume, frequency dependence of total pulmonary resistance to forced oscillation, and arterial PO2 in 18 subjects with AMI. The most consistent finding was reduced lung volume which correlated with the severity of pulmonary diastolic hypertension. Frequency dependence of resistance showed a small but significant correlation with pulmonary hemodynamics. Closing volume measurements by the resident gas method in nine subjects was not related to hemodynamics. Follow-up studies at the time of hospital discharge revealed a significant return toward normal for arterial PO2, all lung volumes, and total pulmonary resistance at 9 Hz. Based on measurements in healthy subjects, the reduced lung volume after AMI may explain the changes in resistance. In acute and follow-up studies the degree of lung volume reduction and the severity of hypoxemia were strongly correlated.

Effect of furosemide on hemodynamics and lung water in acute pulmonary edema secondary to myocardial infarction.

Hemodynamic studies were carried out in 19 patients with left ventricular failure complicating acute myocardial infarction. Fourteen patients were studied before and after the intravenous administration of 0.5 mg/kg of furosemide, and five patients served as a control group. Serial measurements included intracardiac pressures, cardiac output and lung water by a double isotope technique. A significant reduction was noted in right atrial (P less than 0.005), pulmonary arterial (P less than 0.0005) and pulmonary wedge pressures (P less than 0.0005) after administration of furosemide. Only the change in right atrial pressure was significantly different from that in the control group (P less than 0.05). Lung water was not changed in 4 patients studied 2 hours after administration of furosemide but was significantly changed in the remaining 10 patients studied 4 to 24 hours after furosemide (P = 0.0001). This change was also significantly different from values in the control group (P less than 0.05). The patients with no reduction in excess lung water also had a smaller reduction in pulmonary wedge pressure and a lower pretreatment stroke work index than the other patients. The mobilization of excess lung water in patients with acute myocardial infarction complicated by left ventricular failure has several features. Despite a prompt diuresis, the reduction in lung water is delayed for at least several hours after the administration of furosemide and may be related to the degree of left ventricular dysfunction. Venodilation may be a major result of treatment with furosemide.

Refractory ventricular arrhythmias in a patient with mitral valve prolapse. Successful control with mitral valve replacement.

A 35-year-old woman with proven mitral valve prolapse developed life threatening ventricular arrhythmias which were refractory to medical therapy. She had one episode of "cardiac arrest" presumably due to ventricular tachycardia or possibly ventricular fibrillation, and was successfully resuscitated with closed chest compression. Mitral valve replacement resulted in dramatic control of the ventricular arrhythmias. Over a period of three years following the operation, she has been able to resume an active life with occasional ventricular premature beats and no further episodes of ventricular tachyarrhythmias.

Hemodynamic and respiratory effects of morphine and butorphanol.

The hemodynamic effects of butorphanol, a potent synthetic narcotic-antagonist analgesic, were investigated and compared with those of morphine. A total of 20 patients were studied (8 butorphanol, 12 morphine) at the time of diagnostic cardiac catheterization. Butorphanol decreased pH, PCO2, and systemic artery pressure and increased PCO2, cardiac index, and pulmonary artery pressure. Morphine caused similar changes in pH, PO2, systemic artery pressure, and PCO2 but much smaller changes in cardiac index and no change in pulmonary artery pressure. The clinical implications and possible mechanisms are discussed.

The hemodynamic response to intra-aortic balloon counterpulsation in patients with cardiogenic shock complicating acute myocardial infarction.

Sixteen patients with cardiogenic shock complicating acute myocardial infarction underwent serial hemodynamic studies during intra-aortic balloon counterpulsation (IABC) at an assist frequency of 1:1. Significant increase was noted during the first 12 hours of IABC in the systemic artery peak diastolic pressure (assisted), cardiac index, stroke index, and stroke work index. During the second 12 hours further significant improvement was noted in the latter three parameters and, in addition, the systemic artery systolic pressure increased significantly. The pulmonary wedge pressure fell as did the total systemic resistance (TSR) during the first 24 hours of IABC. Patients found to be balloon independent after reduction in balloon assist frequency demonstrated significantly greater increase in systemic artery peak diastolic pressure during the first 12 hours of IABC than did those patients found to be balloon dependent. Likewise, the improvement noted in CI, SI, and SWI during the second 12 hours of IABC was of greater magnitude in balloon-independent than in balloon-dependent patients. The data suggest late hemodynamic deterioration after 48 hours of IABC. It is concluded that IABC is effective in improving the deranged hemodynamics of cardiogenic shock. Maximum response is noted between 24 and 48 hours. It is suggested that patients who are balloon independent may be distinguished from those who are balloon dependent by the hemodynamic response within the first 24 hours of IABC.

Hypoxemia and lung water in acute myocardial infarction.

Pulmonary extravascular volume or lung water (PEV), arterial blood gases, and cardiac hemodynamics were measured in 88 patients with acute myocardial infarction. A progressive increase in PEV and a decrease in arterial oxygen tension (PaO2) were observed from Class I (uncomplicated) patients to Class III (frank pulmonary edema) patients. Heart rate and pulmonary wedge pressure (Pw) rose and cardiac index declined with increasing severity of heart failure by clinical classification. There was a significant correlation between PEV and Pw independent of clinical class (r = 0.47, p less than 0.01). PaO2 had a negative correlation with Pw (r = -0.28, p less than 0.01) as well as PEV (r = -0.26, p less than 0.02). We conclude therefore that increased pulmonary hydrostatic pressure secondary to pulmonary venous hypertension in patients with acute myocardial infarction is a major determinant of interstitial edema. At higher values of PEV, PaO2 was lower. The mechanism of hypoxemia in the presence of excessive lung water may be due to multiple factors, including small airway dysfunction and intrapulmonary shunting.

ST-segment variations after acute myocardial infarction. Relationship to clinical status.

The degree of vectorcardiographic ST-segment elevation was employed as an index of myocardial ischemic injury in a study of 27 patients after acute myocardial infarction (AMI). The ST-segment vector magnitude (STVM) was derived from the continuously recorded modified Frank vectorcardiogram and was plotted serially by hours after onset of AMI. The STVM in normal subjects was 51.1 +/- 7.1 muV (mean +/- SE). A standard deviation of the pooled variance of 15.2 muV was obtained in a group of control patients and a change of more than 2 SD (greater than 30 muV) in an individual STVM was considered to be significant. The STVM progressively decreased in patients who survived without clinical complications while it remained elevated in those with congestive heart failure. A modest, sustained re-elevation of STVM was observed in patients who developed pericarditis, and a significant late average increase of 64 muV occurred in survivors with infarct extension. In contrast, STVM underwent a major increase in patients who died. In five of these six patients without associated pericarditis a mean increase of 164 muV was recorded in the last 5-12 hours of life. While death was clinically predictable in two patients with cardiogenic shock, it was not so for the four other patients who died. Thus, major increases in STVM frequently suggested significant new ischemic injury and were often premonitory to sudden death after AMI. The increases preceding death implied that not only ventricular extopy but also lethal conduction abnormalities after AMI might be ischemia-related.

Early care of acute myocardial infarction.

A fixed life support station (LSS) was established in the emergency department of a community hospital in order to provide early care for patients with suspected acute myocardial infarction (MI). Prospective studies were conducted on 154 patients with verified acute MI. Median time from onset of symptoms to electrocardiographic monitoring was 164 minutes. Overall hospital mortality for these patients was 15.6%. Of 112 patients less than 70 years old, 51 arrived within two hours; only three (6%) of the 51 died. Patients arriving within two hours of the onset of symptoms in clinical class I had an incidence of cardiogenic shock (CS) of 2%, while those arriving two hours or more after the onset of symptoms in clinical class II had an incidence of CS of 26% (P less than .005). A fixed LSS in a community hospital is feasible and effective for early care of patients with acute MI and may facilitate identification of patients at highest risk for development of CS.

Long-term survival following aortic valve replacement.

Study was made of 95 survivors of aortic valve replacement during the early years of this procedure (1964 to 1970). The average follow-up time was 50.2 months. Survival was not related to hemodynamic parameters, such as cardiac index or left ventricular pressure, and did not appear to be influenced by the type of preoperative valve lesion. A history of angina pectoris and a New York Heart Association Class IV grouping were associated with shorter survival. Associated coronary artery disease was a leading cause of death in those patients surviving less than 2 years and angina pectoris the leading cause of morbidity in the long-term survivors. Sudden death occurred in five patients. Once a patient survived 36 months after the operation, the prognosis was excellent.