Ventricular function curves from the cardiac response to angiographic contrast: a sensitive detector of ventricular dysfunction in coronary artery disease

Fifty cardiac catheterizations were performed in 44 patients undergoing evaluation for coronary artery disease. Ventricular function curves (VFC) were constructed by plotting the left ventricular end-diastolic pressure (LVEDP) and stroke work index (SWI) before and three to four minutes after a standard left ventricular angiogram. In an attempt to delineate the mechanism that produces changes in the post-angiogram LVEDP and SWI, 13 individuals (Group A) with no evidence of cardiac disease were compared to 14 patients with severe coronary artery disease (Group B). Cardiac output and LVEDP increased in both groups after angiogram. The increase in cardiac output was less and the increase in LVEDP greater in Group B. V_max. did not change significantly after angiogram in either group. Other measures of contractility ($\text{dp}\text{dt}$ max., peak Vce, and dp/dt/40 mm. developed pressure) changed appropriately for the large changes in preload seen after angiogram.Thirty-seven studies in patients with coronary artery disease demonstrated that VFC obtained from the cardiac response to contrast are more sensitive than resting LVEDP or ejection fraction in detecting left ventricular abnormality.VFC can be obtained from the ventricular response to angiographic contrast because of the increase in venous return produced by the hyperosmotic effect of contrast. Depressed curves occur in patients with coronary artery disease because of their stiff ventricles and not because of depression of myocardial contractility.     

Vectorcardiographic changes following coronary artery bypass surgery

Myocardial infarction (MI) has been reported to occur in about 15 per cent of patients following coronary artery bypass (CAB) surgery. Preoperative and postoperative electrocardiograms (ECG) were evaluated in 85 patients. Thirty-four of these patients also had pre- and postoperative vectorcardiograms (VCG). Fifteen additional patients undergoing open heart surgery were used as controls. These included aortic valve replacement (in 4), mitral valve commissurotomy (in 6), mitral valve replacement (in 1), atrial septal defect repair (in 3), and repair SVC to LA shunt (in 1). Pre- and postoperative VCG's were analyzed in three planes. The angle of each 10 msec. vector was measured. The maximal voltage was determined along each axis in each plane. Mean changes in these parameters were determined for the controls. Change exceeding two standard deviations from the control mean was considered abnormal and not explainable by trauma of open heart surgery itself. Excluding the six intraoperative deaths, $\text{19}\text{79}$ (24 per cent) had QRS changes of myocardial infarction by ECG. Changes were considered significant in the postoperative VCG if they occurred in at least two consecutive angles in one plane or in the maximum voltage in one axis. The postoperative VCG depicted MI in 34 per cent ($\text{12}\text{34}$). In the absence of classic criteria for MI a significant change in VCG angle occurred in 26.4 per cent ($\text{9}\text{34}$). The voltage in at least one axis changed significantly in 11.8 per cent ($\text{4}\text{34}$). A change in the postoperative VCG was demonstrated in 73.5 per cent ($\text{25}\text{34}$). The pre- and postoperative VCG is a sensitive method of detecting subtle changes in conduction or loss of myocardium seen in the majority of patients following CAB surgery.     

Laennec's cirrhosis and primary pulmonary hypertension

The association of cirrhosis and primary pulmonary hypertension has been rarely reported. This case report adds to the literature a case documented by liver biopsy and cardiac catheterization. The literature on this subject and potential pathophysiologic mechanisms of association are reviewed.     

Recent developments in thyroid hormone metabolism: interpretation and significance of measurements of reverse T3, 3,3'T2, and thyroglobulin

The development of specific radioimmunoassays has allowed measurements of 3,3',5'-triiodothyronine (reverse T3), 3,3'-diiodothyronine (3,3'T2), and thyroglobulin to be performed in serum and in various biological fluids both in normal and in altered states of thyroidal economy. The physiology, kinetics, and metabolic actions of reverse T3, 3,3'T2 and thyroglobulin are reviewed. Presently, it appears that reverse T3 and 3,3'T2 measurements in amniotic fluid and cord serum may potentially be useful in diagnosing fetal or neonatal thyroid dysfunction, and serum thyroglobulin measurements appear to be important as a measure of the efficacy of treatment of patients with differentiated thyroid carcinoma.     

Parameters of thyroid function in patients with active acromegaly.

In order to determine if acromegaly per se may be associated with abnormalities in thyroidal economy, serum thyroxine-binding globulin (TBG), resin T3 uptake, total and free T4, T3, and reverse T3 concentrations were measured in 21 patients with active acromegaly. Mean (+/- SE) total T4, T3, and reverse T3 levels were 7.1 +/- 0.2 microgram/dl, 111 +/- 4 ng/dl, and 45 +/- 2 ng/dl, respectively, and the mean TBG concentration was 3.6 +/- 0.2 mg/dl. Similarly, mean free T4, T3, and reverse T3 concentrations were 2.4 +/- 0.09 ng/dl, 383 +/- 22 pg/dl, and 118 +/- 7 pg/dl, respectively. None of these values is significantly different from normal and the thyrotropin response to thyrotropin-releasing hormone was also normal. In contrast to several earlier reports, these data suggest that parameters of thyroid function are generally normal in patients with active acromegaly.     

Glucose modulation of alterations in serum iodothyronine concentrations induced by fasting.

In order to investigate the process by which dietary composition may regulate T4 conversion to T3 and reverse T3, iodothyronine levels were measured in the sera of seven obese subjects during consecutive study periods. These study periods included the ingestion of an approximate weight-maintaining diet (40% carbohydrate, 40% fat, 20% protein) during a control period of 4 days, a fast of 7 days thereafter, and then a 5-day period of glucose ingestion (50 g/day) only. The mean (±SE) serum T3 concentration was 117 ± 8 ng/dl on day 4 of the control period, and gradually decreased to 66 ± 11 ng/dl (p < 0.01) on the last day of fasting. The subsquent administration of glucose was associated with an increase in the mean serum T3 level to 94 ± 10 ng/dl (p < 0.01). Mean (±SE) serum levels of reverse T3 varied reciprocally and were 52 ± 9 ng/dl, 82 ± 12 ng/dl (p < 0.005), and 65 ± 9 ng/dl (compared to fasting, p < 0.05) during the fed and fasting states and during glucose administration, respectively. Furthermore, employing a similar protocol in a different group of subjects, serum sampled during the administration of 100 g of fructose orally during days 8–12 of fasting also was associated with an increase in mean serum T3 and a decrease in mean serum reverse T3, as compared to values obtained on day 6 or day 7 of fasting (T3: 83 ± 6 ng/dl, fasting vs. 111 ± 10, fructose (p < 0.05); rT3: 56 ± 9, fasting vs. 42 ± 6 ng/dl, fructose (p < 0.025)). Serum T4 concentrations were not significantly altered in any study period either during glucose or fructose ingestion. Despite the decrement in serum T3 levels observed during fasting, the mean peak TSH in response to TRH stimulation in a group of 15 obese subjects was decreased during fasting as compared to the fed state (8.1 ± 1.2 μU/ml, fast vs. 12.8 ± 2.0 μU/ml, fed). These observations suggest that both glucose and fructose are capable of modulating serum T3 and reverse T3 levels and that administration of these hexoses in doses of only 100–200 g/day for 5 days may be effective in altering T4 degradative pathways. Furthermore, despite the decreased serum T3 levels, the TSH response to TRH stimulation is decreased, paradoxically, during fasting.     

Failure of 3,3'-diiodothyronine administration to alter TSH and prolactin responses to TRH stimulation.

In order to determine whether elevations in serum 3,3'-diiodothyronine (3,3'T2) concentrations influence the hypothalamic-pituitary--thyroid axis, thyrotropin (TSH) and prolactin responses to thyrotropin-releasing hormone (TRH) were assessed in five patients both prior to and during 3,3'T2 administration. Mean (+/- SE) peak TSH responses to TRH were 168 +/- 64 microU/ml during 3,3'T2 administration and 168 +/- 65 muU/ml during 3,3'T2 administration. Mean basal and peak prolactin concentrations after TRH were 6 +/- 3 ng/ml and 54 +/- 26 ng/ml, whereas during 3,3'T2 administration the basal and peak prolactin levels were 6 +/- 2 ng/ml and 55 +/- 28 ng/ml, respectively. Hypothyroid rats administered triiodothyronine (10 migrogram b.i.d.) for 5 days had a mean TSH response to TRH stimulation of 0.051 +/- 0.003 mU/ml, whereas rats to whom saline or 3,3'T2 (50 microgram b.i.d.) had been given for the same time interval had mean TRH-induced TSH responses of 1.127 +/- 0.179 mU/ml and 1.324 +/- 0.286 mU/ml, respectively. None of the TSH or prolactin responses to TRH, in either human or rat studies, were apparently altered by 3,3'T2. These observations suggest that elevation of serum 3,3'T2 levels are not associated with alterations in the hypothalamic--pituitary--thyroid axis in the experimental systems employed.     

The effect of T3 and reverse T3 administration on muscle protein catabolism during fasting as measured by 3-methylhistidine excretion.

Since recent studies have indicated that measurement in urine of the amino acid, 3-methylhistidine, accurately reflects the extent of muscle catabolism, and because it has been suggested that thyroid hormones may influence muscle breakdown, especially during fasting, the effect of T3 and reverse T3 (rT3) administration on the excretion of 3-methylhistidine was examined in obese subjects during fasting. The mean (+/- SE) 3-methylhistidine excretion in patients fed an egg protein diet (devoid of meat protein) was 256 +/- 35 mumoles/day and decreased to 190 +/- 14 mumoles/day during fasting. T3 administration (100 microgram/day x 5 days) increased 3-methylhistidine excretion to 304 +/- 37 mumoles/day during its ingestion and to 485 +/- 46 mumoles/day in the T3 posttreatment interval. T3 doses of 10 microgram every 4 hr (q4h) for the first 6 days of fasting also appeared capable of increasing 3-mehis excretion whereas 5 microgram T3 q4h administered during the first 6 days of fasting did not increase 3-mehis excretion. Reverse T3 administration (80 microgram q6h) during fasting was associated with a mean 3-methylhistidine of 130 +/- 13 mumoles/day, a value no higher than in patients fasted alone. These observations suggest that: (1) skeletal muscle catabolism decreases during fasting: and (2) pathophysiologic doses of T3 (60 microgram/day or more), but not reverse T3, enhance muscle catabolism during fasting.     

Hypocalcemia with osteoblastic metastases in a patient with prostate carcinoma: A cause of secondary hyperparathyroidism

A 68 year old man with prostatic carcinoma and extensive painful osteoblastic metastases was discovered to have hypocalcemia (serum calcium 7.1 mg/dl) without evidence of hypoalbuminemia, renal failure or malabsorption. Baseline studies revealed hypocalciuria (24 hour urine calcium <5 mg/day), normal serum phosphate (3.4 mg/dl), low tubular reabsorption of phosphate (68 percent), undetectable serum calcitonin, normal serum 25-hydroxyvitamin D, slightly elevated serum parathyroid hormone level and increased urinary cyclic AMP (8.87 μmol/g creatinine). These studies were compatible with secondary hyperparathyroidism. The intravenous administration of parathyroid extract produced no further change in urinary phosphate but a 25-fold increase in nephrogenous cyclic AMP. Three days administration of intramuscular parathyroid extract slowly and temporarily restored serum calcium to normal levels while increasing urinary cyclic AMP and phosphate. Chemotherapy with cyclophosphamide and 5-fluorouracil rendered the patient free of pain while reducing serum acid and alkaline phosphatase levels and restoring serum total and ionized calcium and urinary cyclic AMP excretion to normal.     

Nature of suppressed TSH secretion during undernutrition: Effect of fasting and refeeding on TSH responses to prolonged TRH infusions

TSH responses to 4-hr continuous TRH infusions of approximately 0.8 μg/min were assessed during feeding (1500 Kcal), fasting, and refeeding (1500 Kcal) intervals in 9 euthyroid obese subjects. The total area under the TSH response curve was 1854 ± 322 μU/ml · 4-hr during feeding, decreased to 1359 ± 199 μU/ml · 4-hr (p < 0.01) on the 10th day of fasting, and remained low, being 1405 ± 185 μU/ml · 4-hr, despite refeeding a 1500 Kcal diet (40% carbohydrate, 40% fat, 20% protein) for 5 days. Baseline serum T3 concentrations were 167 ± 11 ng/dl during feeding, 86 ± 8 ng/dl during fasting, and 119 ± 12 ng/dl during refeeding. The observed decreases in TSH release appeared to correlate with decreased biologic action on the thyroid gland since the net rise in T3 during the infusion was less in fasting and refeeding than in the control (fed) period. Basal serum rT3 levels were 42 ± 5 ng/dl during feeding, rose as expected to 56 ± 5 ng/dl during fasting (p < 0.005), and were completely restored to normal during refeeding (36 ± 5 ng/dl). These data suggest that: (1) TSH responsiveness to prolonged TRH infusion is diminished during fasting and does not return to control (fed) values despite 5 days of refeeding a 1500 Kcal diet; (2) net T3 increases observed during the TRH infusion are greater in the fed period than in the fasting or refeeding periods; and (3) 5 days of refeeding a 1500 Kcal diet (40% carbohydrate, 40% fat, 20% protein) did not return the T3 to its original fed value whereas rT3 was completely restored to control values. Lastly, since the TSH response was lower both during the early and late phases of the infusion, the decrease in ΔTSH to a bolus of TRH during fasting appears to represent one manifestation of a more general suppression of TSH neogenesis associated with caloric deprivation.     

Investigations into the etiology of elevated serum T3 levels in protein-malnourished rats

Thyroid function studies and the peripheral metabolism of thyroid hormone were examined in rats fed a low protein diet (9% casein) for 4-8 wk. Compared to animals fed a normal protein diet ad libitum, both the low protein rats and a pair-fed control group weighed less at the end of the study. However, serum total T3 levels were significantly higher only in the protein deficient rats. The elevated serum T3 was not explainable by enhanced peripheral T4 to T3 conversion, as there was no evidence of any change in hepatic or renal 5'-deiodinase activity when homogenates were examined for conversion of T4 to T3, reverse T3 to 3,3'-diiodothyronine, or 3',5'-diiodothyronine to 3'-monoiodothyronine. Neither was there an effect on hepatic T3 receptor maximal binding capacity (204 +/- 24 versus 168 +/- 15 fmol/mg DNA control) or binding affinity (2.07 +/- 0.38 versus 2.49 +/- 0.24 x 10(-10) M control). In two separate experiments the dialyzable fraction of T3 was significantly lower in the low protein group while free T3 concentrations were unchanged or reduced. In contrast, serum total and free T4 were either normal or reduced and dialyzable T4 was unaffected by protein deficiency. We conclude that while serum total T3 is elevated in rats chronically fed a low protein diet, this elevation is not due to enhanced T4 to T3 conversion. Rather, the increased T3 levels can be accounted for by a striking alteration in protein binding to T3. Moreover, the failure to demonstrate similar changes in serum total and dialyzable T4 suggests that in the rat, protein deficiency has different effects on binding to the two major thyroid hormones. Dietary induced changes in serum thyroid hormone binding must be kept in mind in nutrition studies in the rat.     

Skeletal responsiveness in pseudohypoparathyroidism. A spectrum of clinical disease

Three cases of pseudohypoparathyroidism with roentgenographic evidence of hyperparathyroid bone disease are described. Renal resistance to exogenous parathyroid hormone (PTH), the hallmark of pseudohypoparathyroidism, was documented by markedly blunted or absent urinary phosphate and cyclic AMP responses to parathyroid extract. At the time of diagnosis all patients were hypocalcemic and hyperphosphatemic with elevated serum alkaline phosphatase levels and subperiosteal resorption noted on skeletal films. Bone biopsy in one patient revealed a histologic appearance consistent with hyperparathyroidism. Serum PTH levels, measured in two patients while they were hypocalcemic, were elevated. None of the patients had short stature, brachydactyly, subcutaneous calcification or mental deficiency. These cases are compared to the 15 well-documented cases previously reported. The presently available information on pseudohypoparathyroidism indicates a variable skeletal response to PTH mediated by several factors extrinsic to bone and suggests that pseudohypoparathyroidism with hyperparathyroid bone disease is one extreme of a clinical spectrum of skeletal responsiveness to PTH. This disorder is part of an expanding clinical picture which makes pseudohypoparathyroidism a diagnostic consideration in any patient with unexplained hypocalcemia, hyperphosphatemia, elevated alkaline phosphatase levels or metabolic bone disease.     

Normal valine disposal in obese subjects with impaired glucose disposal: Evidence for selective insulin resistance

Insulin has major effects on both glucose and branched chain amino acid metabolism. To determine whether the insulin resistance of obesity equally affects both glucose and branched chain amino acid metabolism, we measured the ability of obese and normal subjects to dispose of intravenous bolus doses of glucose (25 g) or L-valine (4 g). Basal plasma glucose levels were the same in the 18 normal and 17 obese (163 ± 8% of ideal body weight) subjects, but basal plasma insulin levels were higher in the obese group (15 ± 2 vs 6 ± 1 μU/ml; p < 0.001). The obese group had a slower glucose disappearance rate after glucose challenge (0.84 ± 0.06 vs 1.11 ± 0.07 hr^?1; p < 0.01) despite having a greater serum insulin response to the glucose load (26 ± 4 vs 11 ± 1 insulin area units; p < 0.01), confirming insulin resistance. In contrast, disposal of a valine load was the same in normal and obese subjects, as assessed by initial and second phase exponential disappearance rates, metabolic clearance rates of valine, and volumes of distribution. In normal men, disposal rates of glucose and valine after simultaneous administration of both substances were slower than corresponding disposal rates determined when each substance was given alone. We conclude that obese subjects with impaired glucose disposal have normal valine disposal, suggesting that the insulin resistance of obesity can be selective in its effect on different metabolic systems. Glucose and valine also appear to mutually antagonize each other's disposal.