Richmond W. Jeremy

Infarct artery perfusion and changes in left ventricular volume in the month after acute myocardial infarction

The relation between perfusion of the infarct-related artery and changes in left ventricular volume and function during the month after a first myocardial infarction was examined in 40 patients who did not receive thrombolytic therapy. Infarct artery perfusion was documented at predischarge coronary angiography, and left ventricular volume was measured by nongeometric analysis of radionuclide angiograms performed within 48 hours of infarction and at 1 month. Left ventricular dilation (greater than or equal to 20% increase in volume) developed in 16 patients, whereas 5 patients had a decrease in left ventricular volume of greater than or equal to 20% by 1 month. Left ventricular dilation occurred in all 14 patients without perfusion of the infarct-related artery, compared with only 2 of 26 patients with perfusion of this artery due to subtotal occlusion or collateral vessels. All five patients whose left ventricular volume decreased by greater than or equal to 20% had a perfused infarct artery. Multiple linear regression analysis confirmed that the degree of perfusion of the infarct artery (partial r = 0.58, p = 0.001) was a more important predictor of volume change than was infarct size measured by peak creatine kinase (partial r = 0.30, p = 0.009) or QRS score (partial r = 0.20, p = 0.087). Left ventricular ejection fraction decreased from 0.38 +/- 0.10 to 0.30 +/- 0.16 (p = 0.05) in 11 patients with an anterior infarct and ventricular dilation; it increased from 0.45 +/- 0.10 to 0.62 +/- 0.07 (p = 0.02) in the 5 patients with a greater than or equal to 20% decrease in volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Patterns of left ventricular dilation during the six months after myocardial infarction

Changes in left ventricular volume after a first myocardial infarction were studied in 50 patients. Serial radionuclide angiograms were obtained 48 h, 10 days and 1 and 6 months after infarction and left ventricular volume measured by a nongeometric method. Left ventricular dilation (greater than or equal to 20% increase in end-diastolic volume) occurred within 10 days of infarction in 11 patients, who had a mean volume increase of 34 +/- 15% (p = 0.002 versus 48 h) at 10 days and 61 +/- 43% (p = 0.01 versus 10 days) at 6 months. Ten other patients manifested left ventricular dilation between 10 days and 6 months with a lesser volume increase of 42 +/- 18% by 6 months. Among the 21 patients with ventricular dilation, progressive dilation (serial volume increases greater than or equal to 20% on two or more occasions) occurred in 8 patients, who all had a large anterior infarct. Mean volume increases at 10 days and 1 and 6 months were 27 +/- 20%, 49 +/- 40% (p = 0.03 versus 10 days) and 79 +/- 37% (p = 0.006 versus 1 month), respectively, in this group. In patients with progressive dilation, left ventricular ejection fraction decreased from 35 +/- 6% at 48 h to 24 +/- 10% at 1 month (p less than 0.001) and 27 +/- 10% (p = 0.006) at 6 months. Between 1 month and 2 years after infarction six patients died, of whom four had progressive dilation.(ABSTRACT TRUNCATED AT 250 WORDS)

RELATION BETWEEN AGE, ARTERIAL DISTENSIBILITY, AND AORTIC DILATATION IN THE MARFAN SYNDROME

This study examined the relations between age, arterial distensibility, and systemic hemodynamics in patients with the Marfan syndrome. The study group included 170 patients referred to a specialist clinic, of whom 55 (age 26 +/- 12 years) were diagnosed as having Marfan syndrome. The remaining 115 patients (age 25 +/- 14 years) formed a control group. Each patient underwent echocardiographic examination, with measurement of ascending aorta diameter at end-diastole and end-systole, and aortic flow velocities. The elastic properties of the aorta were indexed by calculation of aortic distensibility, wall stiffness, and systemic pulse wave velocity. Mean end-diastolic aortic diameter in the Marfan group (38 +/- 9 mm) was greater than that in the controls (26 +/- 4 mm, p < 0.01). Resting heart rate and aortic flow velocities were similar in the 2 groups, but systemic arterial pulse pressure was greater in the Marfan group (50 +/- 12 mm Hg) than in the controls (41 +/- 8 mm Hg, p < 0.01). Aortic diameter increased with age in both groups, but at all ages the Marfan group exhibited greater aortic diameters (p < 0.05). Aortic distensibility was less in the Marfan group (2.6 +/- 1.3 cm2.dynes-1 x10(-6)) than in the controls (6.2 +/- 2.1 cm2.dynes-1 x 10(-6), p < 0.01), and the aortic wall stiffness index was greater in the Marfan group (7.9 +/- 3.4) than in the controls (2.8 +/- 0.6, p < 0.01). Aortic wall stiffness increased with age and aortic diameter, but at all ages the Marfan group exhibited a stiffer aorta for a given diameter than did the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Dietary l-Arginine on Atherosclerosis and Endothelium-Dependent Vasodilatationin the Hypercholesterolemic Rabbit Response According to Treatment Duration, Anatomic Site, and Sex

Background Nitric oxide (NO) may protect arteries against atherosclerosis. In the present study, we examined whether di-etary l-arginine, the precursor of NO, could chronically preserve endothelium-dependent vasodilatation in vivo and/or limit atherogenesis. Methods and Results Rabbits were randomized according to sex to receive 2% dietary cholesterol, with or without l-arginine (2.25% solution), for 7 or 14 weeks. Hindlimb vasodilator responses to acetylcholine and nitroprusside were measured with an electromagnetic flow probe. Atherosclerosis was measured with planimetry of aortic lesions stained with Oil-Red-O. In rabbits administered l-arginine, plasma arginine levels increased to 483±30 μmol/L at 3 weeks (mean±SEM, P<.0001 versus control animals) but declined to 224±25 μmol/L at 7 weeks (P=.02) and to 100±23 μmol/L at 14 weeks (NS versus control animals). At 7 weeks, peak hindlimb conductance in response to acetylcholine in cholesterol-fed males was 249±49% of baseline compared with 332±9% in control...

Relation Between Ischemia Time, Infarct Size, and Left Ventricular Function in Humans

BACKGROUND Experimental studies indicate that duration of ischemia is a major determinant of myocardial infarct size, but only limited information is available about the relation between ischemia time and infarct size in individual patients. This prospective study sought to document the role of ischemia time as a determinant of infarct size in humans. METHODS AND RESULTS We studied 61 patients (50 men, 11 women) 57 +/- 11 years old admitted with a first infarct (31 anterior, 30 inferior) who underwent continuous 12-lead ECG monitoring to document ischemia time. Infarct size (32-point QRS score on day 7) and changes in regional myocardial wall motion (echocardiography) during the following month were related to ischemia time. Among patients with < 3 hours of ischemia (n = 16), mean infarct size on day 7 was 21 +/- 13% of potential infarct size; in patients with 3 to 6 hours of ischemia (n = 23), infarct size was 38 +/- 18% of potential (P < .05 versus 0 to 3 hours of ischemia); and in patients with 6 to 9 hours of ischemia (n = 10), infarct size was 66 +/- 14% of potential (P < .05 versus 3 to 6 hours). In contrast, the 12 patients with an ischemia time > 9 hours had a final infarct size of 77 +/- 10% of potential (P < .01 versus 3 to 6 hours). Multivariate regression identified size of risk region, duration of ischemia, and degree of initial ST-segment elevation as independent predictors of infarct size, of which the most important variable was ischemia time. The regression models accurately predicted both individual absolute infarct size (R2 = .83) and individual infarct/risk ratio (R2 = .74). Patients with < 6 hours of ischemia exhibited significant recovery of myocardial wall motion by day 7 (wall motion score, 2.1 +/- 1.4 versus 5.7 +/- 3.2 on day 1, P < .01). Patients with 6 to 9 hours of ischemia had some recovery by 1 month (score, 6.3 +/- 4.4 versus 10.9 +/- 3.8 on day 1, P < .01), but patients with > 9 hours of ischemia had little recovery of wall motion by 1 month (score, 10.3 +/- 4.5 versus 12.8 +/- 3.1 on day 1, P < .05). CONCLUSIONS Measurement of ischemia time allows improved prediction of infarct size in humans. Significant myocardial salvage and functional recovery may be achieved by reperfusion up to 9 hours after coronary occlusion. Continuous ST-segment monitoring should be used to measure ischemia time and guide interventions to reperfuse the infarct artery.

Electrocardiographic measurement of infarct size after thrombolytic therapy.

OBJECTIVES We examined the utility of the 32-point QRS score from the 12-lead electrocardiogram (ECG) for measurement of the ischemic risk region and infarct size in patients receiving thrombolytic therapy. BACKGROUND The QRS score offers a means of evaluating the therapeutic benefit of thrombolytic therapy by comparing final infarct size with the initial extent of ischemic myocardium. METHODS The study included 38 patients (34 men, 4 women; mean [+/-SD] age 54 +/- 10 years) with a first infarction (18 anterior, 20 inferior). The maximal potential QRS score (QRS0) was assigned to all leads with >/= 100-microV ST elevation on the initial ECG. The QRS scores were calculated at 7 and 30 days after infarction. Left ventricular ejection fraction was measured by radionuclide ventriculography at 1 month. Twenty-eight patients had thallium (Tl)-201 and technetium (Tc)-99m pyrophosphate tomographic measurement of the ischemic region and infarct size. RESULTS The QRS0 was 10.3 +/- 3.1 (mean +/- SD) for anterior and 10.4 +/- 3.5 for inferior infarcts. The QRS scores were similar at 7 and 30 days for both anterior (5.6 +/- 3.4 vs. 5.5 +/- 3.4) and inferior infarcts (3.7 +/- 2.6 vs. 2.9 +/- 2.2). The day 7 QRS score and ejection fraction at 1 month were inversely correlated (r = -0.74, p < 0.01). The Tl-201 perfusion defect was 34 +/- 11% of the left ventricle for anterior and 32 +/- 7% for inferior infarcts. Subsequent Tc-99m pyrophosphate infarct size was 15 +/- 9% of the left ventricle for anterior and 17 +/- 9% for inferior infarcts. The QRS0 was correlated with the extent of the Tl-201 perfusion defect (r = 0.79, p < 0.001), and the day 7 QRS score was correlated with Tc-99m pyrophosphate infarct size (r = 0.79, p < 0.005). CONCLUSIONS The 32-point QRS score can provide useful immediate measurements of the ischemic risk region and subsequent infarct size.

Molecular pathology of familial hypertrophic cardiomyopathy caused by mutations in the cardiac myosin binding protein C gene.

DNA studies in familial hypertrophic cardiomyopathy (FHC) have shown that it is caused by mutations in genes coding for proteins which make up the muscle sarcomere. The majority of mutations in the FHC genes result from missense changes, although one of the most recent genes to be identified (cardiac myosin binding protein C gene, MYBPC3) has predominantly DNA mutations which produce truncated proteins. Both dominant negative and haploinsufficiency models have been proposed to explain the molecular changes in FHC. This study describes two Australian families with FHC caused by different mutations in MYBPC3. The first produces a de novo Asn755Lys change in a cardiac specific domain of MYBPC3. The second is a Gln969X nonsense mutation which results in a truncated protein. Neither mutation has previously been found in the MYBPC3 gene. The consequences of DNA changes on the function of cardiac myosin binding protein C are discussed in relation to current molecular models for this disorder.

Modifications of myosin-regulatory light chain correlate with function of stunned myocardium

The precise molecular basis for myocardial stunning remains unresolved, but protein damage within the myofibril is a likely mechanism. We used two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) to identify protein modifications in stunned myocardium. In isolated, perfused rabbit hearts, low-flow ischemia (1 ml/min) and reperfusion resulted in impaired left-ventricular function (rate-pressure product (RPP) after 15-min ischemia: 65 +/- 5% pre-ischemia). We have characterised the sequence of ventricular myosin-regulatory light chain (MLC-2, 18 kDa) in rabbit myocardium and identified two non-phosphorylated (P(1) and P(2)) and two phosphorylated (P(3) and P(4) at Ser-14) isoelectric point variants. MS revealed that the acidic isoelectric point post-translational modification of P(1) and P(3), resulting in P(2) and P(4) respectively, was due to deamidation of asparagine to aspartate at residue 13, adjacent to Ser-14 phosphorylation site. After 15-min ischemia and reperfusion, a 15-kDa MLC-2 fragment was detected (MLC-2(14-165)), resulting from N-terminal cleavage between Asn/Asp-13 and Ser-14 of non-phosphorylated MLC-2, which accounted for 9.8% of visible non-phosphorylated MLC-2. Subsequent 2-DE of subcellular fractions showed that the fragment was lost from the myofilament. Treatment with an OH radical scavenger, N-(2-mercaptopropionyl) glycine (MPG, 3 mmol/l), preserved contractile function (RPP: 106 +/- 9% pre-ischemia) and prevented cleavage of MLC-2. Proteolytic damage to MLC-2, related to presence of OH radicals during reperfusion, correlates with myocardial stunning and may contribute to impaired contractility.

Rheumatic Heart Disease in Indigenous Populations

Rates of acute rheumatic fever and chronic rheumatic heart disease in Aboriginal people, Torres Strait Islanders and Māori continue to be unacceptably high. The impact of rheumatic heart disease is inequitable on these populations as compared with other Australians and New Zealanders. The associated cardiac morbidity, including the development of rheumatic valve disease, and cardiomyopathy, with possible sequelae of heart failure, development of atrial fibrillation, systemic embolism, transient ischaemic attacks, strokes, endocarditis, the need for interventions including cardiac surgery, and impaired quality of life, and shortened life expectancy, has major implications for the individual. The adverse health and social effects may significantly limit education and employment opportunities and increase dependency on welfare. Additionally there may be major adverse impacts on family and community life. The costs in financial terms and missed opportunities, including wasted young lives, are substantial. Prevention of acute rheumatic fever is dependent on the timely diagnosis and treatment of sore throats and skin infections in high-risk groups. Both Australia and New Zealand have registries for acute rheumatic fever but paradoxically neither includes all cases of chronic rheumatic heart disease many of whom would benefit from close surveillance and follow-up. In New Zealand and some Australian States there are programs to give secondary prophylaxis with penicillin, but these are not universal. Surgical outcomes for patients with rheumatic valvular disease are better for valve repair than for valve replacement. Special attention to the selection of the appropriate valve surgery and valve choice is required in pregnant women. It may be necessary to have designated surgical units managing Indigenous patients to ensure high rates of surgical repair rather than valve replacement. Surgical guidelines may be helpful. Long-term follow-up of the outcomes of surgery in Indigenous patients with rheumatic heart disease is required. Underpinning these strategies is the need to improve poverty, housing, education and employment. Cultural empathy with mutual trust and respect is essential. Involvement of Indigenous people in decision making, design, and implementation of primary and secondary prevention programs, is mandatory to reduce the unacceptably high rates of rheumatic heart disease.

Uteroplacental blood flow and placental vascular endothelial growth factor in normotensive and pre-eclamptic pregnancy

Objective To determine whether placental vascular endothelial growth factor (VEGF) is increased in pre‐eclampsia.