Safety and clinical activity of atezolizumab in head and neck cancer: results from a phase I trial.

Background: Head and neck cancer (HNC) has a poor prognosis at advanced stages. Given the immunosuppressive tumor microenvironment in HNC, inhibition of the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling pathway represents a promising therapeutic approach. Atezolizumab (anti-PD-L1) is efficacious against many tumor types. Here we report the clinical safety and activity from the HNC cohort of the phase Ia PCD4989g clinical trial. Patients and methods: Patients with previously treated, advanced HNC received atezolizumab i.v. every 3 weeks for 16 cycles, up to 1 year or until loss of clinical benefit. Patients were monitored for safety and tolerability and evaluated for response at least every 6 weeks. Baseline PD-L1 expression level and human papillomavirus (HPV) status were evaluated. Results: Thirty-two patients were enrolled; 7 patients (22%) had a primary tumor in the oral cavity, 18 (56%) in the oropharynx, 1 (3%) in the hypopharynx, 2 (6%) in the larynx, and 4 (13%) in the nasopharynx. Seventeen patients (53%) had ≥2 prior lines of therapy. Twenty-one patients (66%) experienced a treatment-related adverse event (TRAE), with three experiencing grade 3 TRAEs and one experiencing a grade 4 TRAE (per CTCAE v4.0). No grade 5 TRAEs were reported. Objective responses by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) occurred in 22% of patients, with a median duration of response of 7.4 months (range 2.8-45.8 months). Median progression-free survival was 2.6 months (range 0.5-48.4 months), and median overall survival was 6.0 months (range 0.5-51.6+ months). Responses showed no association with HPV status or PD-L1 expression level. Conclusions: In this heavily pre-treated advanced HNC cohort, atezolizumab had a tolerable safety profile and encouraging activity, with responses observed regardless of HPV status and PD-L1 expression level. These findings warrant further investigation of atezolizumab in HNC. ClinicalTrials.gov number: NCT01375842.

Unrelated donor hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis.

We report outcomes after unrelated donor hematopoietic cell transplantation (HCT) for 91 patients with hemophagocytic lymphohistiocytosis (HLH) transplanted in the US in 1989-2005. Fifty-one percent were <1 year at HCT and 29% had Lansky performance scores<90%. Most (80%) were conditioned with BU, CY, and etoposide (VP16) with or without anti-thymocyte globulin. Bone marrow was the predominant graft source. Neutrophil recovery was 91% at day-42. The probabilities of grades 2-4 acute GVHD at day-100 and chronic GVHD at 5 years were 41 and 23%, respectively. The overall mortality rate was higher in patients who did not receive BU/CY/VP16-conditioning regimen (RR 1.95, P=0.035). The 5-year probability of overall survival was 53% in patients who received BU/CY/VP16 compared to 24% in those who received other regimens. In the subset of patients with known disease-specific characteristics, only one of five patients with active disease at HCT is alive. For those in clinical remission at HCT (n=46), the 5-year probability of overall survival was 49%. Early mortality rates after HCT were high, 35% at day-100. These data demonstrate that a BU/CY/VP16-conditioning regimen provides cure in approximately 50% of patients and future studies should explore strategies to lower early mortality.

Effect of age on myocardial adaptation to volume overload in the rat.

To test the hypothesis that the capacity for left ventricular (LV) adaptation to volume overload might diminish with age, we examined the hemodynamics and degree of myocardial hypertrophy in response to aortic insufficiency in young adult (9 mo) and old (18 or 22 mo) Fischer rats. Before, immediately after, and at 2 and 4 wk after creating aortic insufficiency, LV and aortic pressures were measured using a catheterization technique. 4 wk after surgery, we measured aortic flow, and estimated the LV passive pressure-volume relationship and the degree of LV hypertrophy after killing. Immediately after the surgical creation of aortic insufficiency, both young and old rats showed similar elevation of LV end-diastolic pressure (from 4.8 +/- 0.6 to 12.0 +/- 1.5 mmHg in the young rats, P less than 0.01; from 4.9 +/- 0.4 to 11.0 +/- 0.7 mmHg in the old rats, P less than 0.01). In the young rats LV, end-diastolic pressure decreased to 8.0 +/- 1.0 and to 8.5 +/- 0.9 mmHg at 2 and 4 wk (P less than 0.05). In contrast, LV end-diastolic pressure at 2 (16.9 +/- 3.1 mmHg) and 4 wk (16.1 +/- 2.7 mmHg) in the old rats was even higher, compared with the values measured immediately after aortic insufficiency. At 4 wk, LV end-diastolic meridional wall stress (calculated from the in vivo LV end-diastolic pressure, and the pressure-volume relationship and muscle mass obtained after killing) was higher in the old rats than in the young rats. In the young rats, the diastolic pressure-volume relationship at 4 wk shifted to the right (P less than 0.01), and LV dry weight, LV dry weight/tibial length, and protein content of the LV myocardium increased by 26% (P less than 0.01), 24% (P less than 0.01), and 33% (P less than 0.01), respectively. However, old rats with aortic insufficiency did not show a significant change in the pressure-volume relationship, dry weight, or protein content at 4 wk. These results suggest that advanced age diminishes the capacity for LV hypertrophy in response to a volume overload, and this reduced LV hypertrophic response in the old rats resulted in persistent elevation of LV end-diastolic pressure and wall stress.

Wall stress and patterns of hypertrophy in the human left ventricle.

It is generally recognized that chronic left ventricular (LV) pressure overload results primarily in wall thickening and concentric hypertrophy, while chronic LV volume overload is characterized by chamber enlargement and an eccentric pattern of hypertrophy. To assess the potential role of the hemodynamic factors which might account for these different patterns of hypertrophy, we measured LV wall stresses throughout the cardiac cycle in 30 patients studied at the time of cardiac catheterization. The study group consisted of 6 subjects with LV pressure overload, 18 with LV volume overload, and 6 with no evidence of heart disease (control). LV pressure, meridional wall stress (sigman), wall thickness (h), and radius (R) were measured in each patient throughout the cardiac cycle. For patients with pressure overload, LV peak systolic and end diastolic pressures were significantly increased (220 plus or minus 6/23 plus or minus 3 mm Hg) compared to control (117 plus or minus 7/10 plus or minus 1 mm Hg, P less than 0.01 for each). However, peak systolic and end diastolic (sigman) were normal (161 plus or minus 24/23 plus or minus 3 times 10-3 dyn/cm-2) compared to control (151 plus or minus 14/17 plus or minus 2 times 10-3 dyn/cm-2, NS), reflecting the fact that the pressure overload was exactly counterbalanced by increased wall thickness (1.5 plus or minus 0.1 cm for pressure overload vs. 0.8 plus or minus 0.1 cm for control, P less than 0.01). For patients with volume overload, peak systolic (sigman) was not significantly different from control, but end diastolic (sigmam) was consistently higher than normal (41 plus or minus 3 times 10-3 dyn/cm-2 for volume overload, 17 plus or minus 2 times 10-3 dyn/cm-2 for control, P less than 0.01). LV pressure overload was associated with concentric hypertrophy, and an increased value for the ratio of wall thickness to radius (h/R ratio). In contrast, LV volume overload was associated with eccentric hypertrophy, and a normal h/R ratio. These data suggest the hypothesis that hypertrophy develops to normalize systolic but not diastolic wall stress. We propose that increased systolic tension development by myocardial fibers results in fiber thickening just sufficient to return the systolic stress (force per unit cross-sectional area) to normal. In contrast, increased resting or diastolic tension appears to result in gradual fiber elongation or lengthening which improves efficiency of the ventricular chamber but cannot normalize the diastolic wall stress.

Comparison of acute alterations in left ventricular relaxation and diastolic chamber stiffness induced by hypoxia and ischemia. Role of myocardial oxygen supply-demand imbalance.

To clarify conflicting reports concerning the effects of ischemia on left ventricular chamber stiffness, we compared the effects of hypoxia at constant coronary perfusion with those of global ischemia on left ventricular diastolic chamber stiffness using isolated, perfused rabbit hearts in which the left ventricle was contracting isovolumically. Since chamber volume was held constant, increases in left ventricular end diastolic pressure (LVEDP) reflected increases in chamber stiffness. At a control coronary flow rate (30 ml/min), 2 min of hypoxia and pacing tachycardia (4.0 Hz) produced major increases in postpacing LVEDP (10+/-1 to 24+/-3 mm Hg, P < 0.01) and the relaxation time constant, T, (40+/-4 to 224+/-37 ms, P < 0.001), while percent lactate extraction ratio became negative (+ 18+/-2 to -48+/-15%, P < 0.001). Coronary perfusion pressure decreased (72+/-5 to 52+/-3 mm Hg, P < 0.01), and since coronary flow was held constant, the fall in coronary perfusion pressure reflected coronary dilation and a decrease in coronary vascular resistance. Following an average of 71+/-6s reoxygenation and initial heart rate (2.0 Hz), LVEDP and relaxation time constant T returned to control. Hypoxia alone (without pacing tachycardia) produced similar although less marked changes (LVEDP, 10+/-1 to 20+/-3 mm Hg; and T, 32+/-3 to 119+/-22 ms; P < 0.01 for both) and there was a strong correlation between LVEDP and T (r = 0.82, P < 0.001). When a similar degree of coronary vasodilatation was induced with adenosine, no change in LVEDP occurred, indicating that the increase in end diastolic pressure observed during hypoxia was not secondary to vascular engorgement, but due to an acute effect of hypoxia on the diastolic behavior of the ventricular myocardium. In contrast, global ischemia produced by low coronary flow (12-15 ml/min) resulted in a decrease in LVEDP, as well as a marked fall in left ventricular systolic pressure. In 14 global ischemia experiments, pacing tachycardia led to a further decline in left ventricular systolic pressure, and no increase was noted in postpacing LVEDP. Changes in lactate extraction ratio were much smaller in magnitude than with hypoxia and constant coronary perfusion. In two experiments (one at normal coronary flow and one at 15 ml/min), left ventricular systolic pressure did not change markedly from control when tachycardia was superimposed, and postpacing LVEDP showed a marked rise (to > 25 mm Hg), which gradually recovered over 1-2 min at the control heart rate. From these results, we conclude that left ventricular chamber stiffness increases when myocardial O(2) demand exceeds supply. This change is usually masked in ischemic (reduced coronary flow) preparations, perhaps because of reduced turgor of the coronary vascular bed, marked reductions in systolic work (and therefore myocardial O(2) requirements), and local accumulation of hydrogen ion and metabolites following acute severe reduction of coronary flow. The increased chamber stiffness during hypoxia is accompanied by marked slowing of relaxation, with increased diastolic pressure relative to volume persisting throughout diastole.

Effects of sodium nitroprusside on left ventricular diastolic pressure-volume relations.

The effect of sodium nitroprusside on the relationship between left ventricular pressure and volume during diastole was studied in 11 patients with congestive heart failure. Nitroprusside was infused to lower mean arterial pressure approximately 20-30 mm Hg. High fidelity left ventricular pressures were recorded in all patients simultaneously with left ventricular cineangiography (biplane in eight and single plane in three patients), allowing precise measurement of pressure and volume throughout the cardiac cycle. Left ventricular diastolic pressure-volume curves were constructed in each patient from data obtained before and during nitroprusside infusion. In 9 of 11 patients there was a substantial downward displacement of the diastolic pressure-volume curve during nitroprusside infusion, with left ventricular pressure being lower for any given volume with nitroprusside. Serial left ventricular cineangiograms performed 15 min apart in six additional subjects who did not receive sodium nitroprusside showed no shift in the diastolic pressure-volume relation, indicating that the shift seen with nitroprusside was not due to the angiographic procedure itself. A possible explanation for the altered diastolic pressure-volume relationships with nitroprusside might be a direct relaxant effect of nitroprusside on ventricular muscle, similar to its known relaxant effect on vascular smooth muscle. Alternatively, nitroprusside may affect the diastolic pressure-volume curve by affecting viscous properties or by altering one or more of the extrinsic constraints acting upon the left ventricle.

Chronic exercise training protects aged cardiac muscle against hypoxia.

To test the hypothesis that chronic exercise may improve tolerance to hypoxia in aged hearts, we compared cardiac function of exercised rats to that of their age-matched, nonexercised controls. Right ventricular papillary muscles were removed from young adult (9 mo) and old (24-26 mo) male Fischer 344 rats that were chronically exercised on a rodent treadmill and from their age-matched, nonexercised controls. During isometric contraction, hypoxia depressed contraction and relaxation in all muscles, but to a lesser extent in the exercised groups. A significant exercise effect was observed in the following variables: the maximum developed tension, the maximum rate of tension development, the maximum rate of tension decline, and the time required for the hypoxia to reduce maximum tension by 20%. The maximum rate of tension decline was more sensitive to hypoxia than was the maximum rate of tension development in all groups. Exercise also had an effect on the temperature dependence of cardiac performance during hypoxia. Thus, chronic exercise results in the preservation of both contraction and relaxation during hypoxia for aged as well as young adult hearts.

Age-related differences in the expression of proto-oncogene and contractile protein genes in response to pressure overload in the rat myocardium.

Cardiac adaptation to hemodynamic stress involves both quantitative (hypertrophy) and qualitative (pattern of gene expression) changes. Our previous studies have shown that advancing age in the rat is associated with diminished capacity to develop left ventricular hypertrophy in response to either ascending aortic constriction (AoC). In this study, we examined whether the expression of protooncogenes and contractile protein genes in response to AoC differs between adult (9-mo-old) and old (18-mo-old) rats. RNA was isolated from the left ventricles of AoC animals of both age groups subjected to a similar hemodynamic stress. Immediately after AoC, the levels of the ventricular expression of c-fos and c-jun protooncogenes were markedly lower in the old rats than in the adult animals. 5 d after the operation, the ratio of beta- to alpha-myosin heavy chain mRNAs increased significantly after AoC in both age groups. In contrast, AoC was associated with a marked reduction in the levels of mRNAs encoding sarcoplasmic reticulum Ca(2+)-ATPase (by 69%) and cardiac calsequestrin (by 49%) in the old rats but not in the adults. The mRNAs encoding atrial natriuretic factor and skeletal alpha-actin increased in response to AoC only in the adult rats. There were no significant differences in expression of the cardiac alpha-actin mRNA among the experimental groups. These data suggest that (a) the expression of protooncogenes in response to acute pressure overload is significantly reduced in the aged rats and (b) the pattern of expression of the contractile protein gene in response to AoC in the old rats differs qualitatively as well as quantitatively from that in younger animals. These age-related differences may play a role in the higher frequency of heart failure in the aged during hemodynamic stress.

Intracellular calcium and ventricular function. Effects of nisoldipine on global ischemia in the isovolumic, coronary-perfused heart.

Ischemia-induced ventricular dysfunction has been shown to be associated with increased diastolic and systolic intracellular concentrations of free, ionized calcium ([Ca2+]i). The present study was designed to determine the effects of the Ca2+ antagonist nisoldipine on the relationship between [Ca2+]i and left ventricular contraction and relaxation during ischemia and reperfusion on a beat-to-beat basis. Nine isovolumic coronary-perfused ferret hearts were made globally ischemic for 3 min and reperfused for 10 min. Ischemia and reperfusion were repeated during perfusion with a buffer containing 10(-8) M nisoldipine. From left ventricular developed pressure, time to peak pressure and time to 50% pressure decline were obtained. [Ca2+]i was determined with the bioluminescent protein aequorin. Global ischemia caused a rapid decline in contractile function and a significant increase in diastolic [Ca2+]i, from 0.35 to 0.81 microM, and in systolic [Ca2+]i, from 0.61 to 0.96 microM. During reperfusion, [Ca2+]i returned to baseline while ventricular function was still impaired. Relaxation was more affected than systolic contractile function. Nisoldipine significantly reduced the ischemia-induced rise in diastolic [Ca2+]i to 0.62 microM, and in systolic [Ca2+]i to 0.77 microM, and lessened the decrease in contractile function. Nisoldipine significantly accelerated the decline in [Ca2+]i during reperfusion and improved recovery of contractility and relaxation. These effects were associated with a significant diminution in ischemic lactate production. Taken together, our results provide direct quantitative evidence on a beat-to-beat basis that the calcium antagonist nisoldipine can ameliorate ischemia-induced abnormalities in [Ca2+]i handling, an effect that was associated with improved myocardial function during early reperfusion.

Diastolic dysfunction in hypertrophic cardiomyopathy. Effect on active force generation during systole.

We tested the hypothesis that intracellular Ca++ [( Ca++]i) overload underlies the diastolic dysfunction of patients with hypertrophic cardiomyopathy. Myocardial tissue was obtained at the time of surgery or transplantation from patients with hypertrophic cardiomyopathy and was compared with control myocardium obtained from patients without heart disease. The isometric contractions and electrophysiologic properties of all myocardial specimens were recorded by standard techniques and [Ca++]i was measured with the bioluminescent calcium indicator aequorin. In contrast to the controls, action potentials, Ca++ transients, and isometric contraction and relaxation were markedly prolonged in the hypertrophic myocardium, and the Ca++ transients consisted of two distinct components. At 38 degrees C and 1 Hz pacing frequency, a state of relative Ca++ overload appeared develop, which produced a rise in end-diastolic [Ca++]i, incomplete relaxation, and fusion of twitches with a resultant decrease in active tension development. We also found that drugs with increase [Ca++]i, such as digitalis, exacerbated these abnormalities, whereas drugs that lower [Ca++]i, such as verapamil, or agents that increase cyclic AMP, such as forskolin, prevented them. These results may explain why patients with hypertrophic cardiomyopathy tolerate tachycardia poorly, and may have important implications with regard to the pharmacologic treatment of patients with hypertrophic cardiomyopathy.

Expression of dihydropyridine receptor (Ca2+ channel) and calsequestrin genes in the myocardium of patients with end-stage heart failure.

Cytoplasmic free calcium ions (Ca2+) play a central role in excitation-contraction coupling of cardiac muscle. Abnormal Ca2+ handling has been implicated in systolic and diastolic dysfunction in patients with end-stage heart failure. The current study tests the hypothesis that expression of genes encoding proteins regulating myocardial Ca2+ homeostasis is altered in human heart failure. We analyzed RNA isolated from the left ventricular (LV) myocardium of 30 cardiac transplant recipients with end-stage heart failure (HF) and five organ donors (normal control), using cDNA probes specific for the cardiac dihydropyridine (DHP) receptor (the alpha 1 subunit of the DHP-sensitive Ca2+ channel) and cardiac calsequestrin of sarcoplasmic reticulum (SR). In addition, abundance of DHP binding sites was assessed by ligand binding techniques (n = 6 each for the patients and normal controls). There was no difference in the level of cardiac calsequestrin mRNA between the HF patients and normal controls. In contrast, the level of mRNA encoding the DHP receptor was decreased by 47% (P less than 0.001) in the LV myocardium from the patients with HF compared to the normal controls. The number of DHP binding sites was decreased by 35-48%. As reported previously, expression of the SR Ca(2+)-ATPase mRNA was also diminished by 50% (P less than 0.001) in the HF group. These data suggest that expression of the genes encoding the cardiac DHP receptor and SR Ca(2+)-ATPase is reduced in the LV myocardium from patients with HF. Altered expression of these genes may be related to abnormal Ca2+ handling in the failing myocardium, contributing to LV systolic and diastolic dysfunction in patients with end-stage heart failure.

Depression of systolic and diastolic myocardial reserve during atrial pacing tachycardia in patients with dilated cardiomyopathy.

Previous reports have shown that increases in heart rate may result in enhanced left ventricular (LV) systolic and diastolic performance. To assess whether this phenomenon occurs in the presence of depressed LV function, the effects of pacing on LV pressure and volume were compared in seven patients with dilated cardiomyopathy (LV ejection fraction 0.19 +/- 0.11) and six patients with no or minimal coronary artery disease (LV ejection fraction 0.69 +/- 0.11). Patients with normal LV function demonstrated significant increases in LV peak-positive dP/dt, LV end-systolic pressure-volume ratio, LV peak filling rate, and a progressive leftward and downward shift of their pressure-volume diagrams, compatible with increased contractility and distensibility in response to pacing tachycardia. There was no change in LV peak-negative dP/dt or tau. Patients with dilated cardiomyopathy, in contrast, demonstrated no increase in either LV peak-positive dP/dt or the end-systolic pressure-volume ratio, and absence of a progressive leftward shift of their pressure-volume diagrams. Moreover, cardiomyopathy patients demonstrated no increase in LV peak-negative dP/dt or LV peak filling rate and a blunted downward shift of the diastolic limb of their pressure-volume diagrams. Tau, as determined from a derivative method, became abbreviated although never reaching control values. We conclude that patients with dilated cardiomyopathy may demonstrate little or no significant enhancement in systolic and diastolic function during atrial pacing tachycardia, suggesting a depression of both inotropic and lusitropic reserve.

Basic fibroblast growth factor improves myocardial function in chronically ischemic porcine hearts.

The effect of basic fibroblast growth factor (bFGF) administration on regional myocardial function and blood flow in chronically ischemic hearts was studied in 26 pigs instrumented with proximal circumflex coronary artery (LCX) ameroid constrictors. In 13 animals bFGF was administered extraluminally to the proximal left anterior descending (LAD) and LCX arteries with heparin-alginate beads and 13 other animal served as controls. bFGF-treated pigs showed a fourfold reduction in left ventricular infarct size compared to untreated controls (infarct size: 1.2 +/- 0.4% vs. 5.1 +/- 1.3% of LV mass, mean +/- SEM, P < 0.05). Percent fractional shortening (% FS) in the LCX area at rest was reduced compared with the LAD region in both bFGF and control pigs. However, there was better recovery in the LCX area after rapid pacing in bFGF-treated pigs (% FSLCX/% FSLAD, 22.9 +/- 7.3%-->30.5 +/- 8.5%, P < 0.05 vs. prepacing) than in controls (16.0 +/- 7.8%-->14.3 +/- 7.0%, P = NS). Furthermore, LV end-diastolic pressure rise with rapid pacing was less in bFGF-treated than control pigs (pre-pacing; pacing; post-pacing, 10 +/- 1; 17 +/- 3; 11 +/- 1* mmHg vs 10 +/- 1; 24 +/- 4; 15 +/- 1 mmHg, *P < 0.05 vs. control). Coronary blood flow in the LCX territory (normalized for LAD flow) was also better during pacing in bFGF-treated pigs than in controls. Thus, periadventitial administration of bFGF in a gradual coronary occlusion model in pigs results in improvement of coronary flow and reduction in infarct size in the compromised territory as well as in prevention of pacing-induced hemodynamic deterioration.

Human lung carcinoma monoclonal antibody specific for the Thomsen-Friedenreich antigen.

A monoclonal antibody, RS1-114, was raised against the human adenocarcinoma of the lung cell line A549. By studying the reactivity of RS1-114 with A549 cells following chemical and enzymatic treatments, it was shown that the epitope is a galactose-containing carbohydrate, which is devoid of sialic acid. Hemagglutination of desialylated RBCs, enzyme-linked immunosorbent assay studies with glycoprotein antigens before and after desialylation, and competition studies using peanut agglutinin indicate that monoclonal antibody RS1-114 recognizes the Thomsen-Friedenreich antigen, a cryptic determinant on human erythrocytes which can be exposed by neuraminidase treatment. It is expressed in an unhidden form on a large percentage of carcinomas and is therefore an important human tumor marker. RS1-114 is reactive with cryptic determinants of the Thomsen-Friedenreich antigen on white blood cells as well as red blood cells, and it reacts with unhidden determinants on human tumor cell lines. The number of binding sites on carcinoma cells is further increased by neuraminidase treatment. By immunohistochemical staining, it was shown that 75% of the human tumors tested are reactive with RS1-114. These include tumors of the breast, colon, lung, kidney, ovary, and rectum.

Diastolic dysfunction as a cause of heart failure.

Diastolic dysfunction is an important cause of symptoms in patients with various types of cardiac disease. Increased left ventricular diastolic pressure may lead to pulmonary congestion, even in the setting of normal left ventricular systolic function. Although the physiology of diastolic function is complex, left ventricular diastolic pressure may become elevated through one of three broad mechanisms. Abnormalities intrinsic to the left ventricle may include 1) impaired left ventricular relaxation, a finding that is common in most cardiac diseases and may be particularly important during ischemia; 2) increased left ventricular wall thickness relative to cavity volume, which will shift the diastolic pressure-volume relation such that the same volume is associated with a higher pressure; and 3) increased myocardial stiffness, which is thought to be associated with interstitial fibrosis or scar tissue formation. In addition, diastolic pressures may become elevated because of factors extrinsic to the left ventricle. These may include 1) increased central blood volume, which will increase left ventricular pressure without altering the left ventricular pressure-volume relation; and 2) ventricular interaction mediated by pericardial restraint, which may cause a parallel upward shift of the diastolic pressure-volume relation. Treatment of the factors extrinsic to the left ventricle tends to be much more successful than treating abnormalities that are intrinsic to the ventricle. Improved understanding of myocardial relaxation at the cellular level and delineation of the molecular regulation of myocyte hypertrophy and fibroblast proliferation may lead to new and innovative approaches to the treatment of heart failure.

Regional diastolic mechanics of ischemic and nonischemic myocardium in the pig heart.

To assess the role of segmental dyssynchrony as a determinant of ischemic diastolic dysfunction, systolic and diastolic mechanics of ischemic and nonischemic myocardium were compared in the open chest pig heart (n = 7). Pacing tachycardia (1.8 x heart rate at rest) was imposed for 3 to 5 min in the presence of a single critical stenosis of the left anterior descending artery (demand ischemia, n = 7). After 30 min of recovery, the left anterior descending artery was totally occluded for 1.5 min in the same pigs (primary ischemia, n = 6). Both demand and primary ischemia increased left ventricular end-diastolic pressure and prolonged the time constant of left ventricular pressure decline. Percent systolic shortening of ischemic segments (perfused by the left anterior descending artery) decreased by 32% during demand ischemia and by 120% during primary ischemia, but that of nonischemic segments (perfused by the left circumflex artery) did not change significantly during either type of ischemia. During demand ischemia (but not during primary ischemia), left ventricular diastolic pressure increased relative to segment length so that a higher diastolic pressure was needed to stretch the ischemic segment to the same length (decreased distensibility). In nonischemic areas, diastolic pressure and segment length increased commensurately during both types of ischemia, indicating no change in diastolic distensibility. During demand ischemia, peak early diastolic lengthening rates increased in nonischemic segments but remained unchanged in ischemic segments. Diastolic segmental dyssynchrony developed during both types of ischemia, but was more pronounced during primary ischemia. Therefore, segmental dyssynchrony is unlikely to account for the rise in diastolic pressure relative to segment length seen during demand ischemia.

Effect of zatebradine on contractility, relaxation and coronary blood flow.

OBJECTIVES: The purpose of this study was to compare the effects of zatebradine on heart rate, contractility and relaxation with those of its structural analog verapamil. We used isoproterenol, a potent beta-agonist, to see how these effects were modulated by sympathetic activation. We also compared the effects of zatebradine and verapamil on coronary blood flow and coronary blood flow reserve. BACKGROUND: Zatebradine, previously called UL-FS 49, is a new bradycardic agent believed to act selectively at the sinoatrial node. METHODS: Isolated isovolumetric pig hearts were prepared and left ventricular pressure, its first derivative (dP/dt), tau and heart rate were measured both before and after administration of either 0.975 mg of zatebradine (Group I, n = 8) or 125 micrograms of verapamil (Group II, n = 8). After the effects of each drug reached a plateau, a continuous infusion of isoproterenol was started and measurements were obtained again and compared with a third group of measurements from control hearts infused with isoproterenol after receiving only saline solution (n = 8). We also assessed the effects of zatebradine and verapamil on coronary vascular tone by measuring flow in the left anterior descending coronary artery in intact anesthetized open chest pigs both before and after the intracoronary administration of these drugs (n = 8 for each). All preparations were atrially paced to negate any bradycardiac effects of the drugs. RESULTS: In the group that received zatebradine, mean (+/- SE) heart rate decreased from 143 +/- 8 to 99 +/- 4 beats/min (p < 0.01) and there was no significant change in either peak left ventricular systolic pressure, dP/dt or tau. In contrast, verapamil produced a lesser decrease in heart rate (136 +/- 7 to 120 +/- 7 beats/min, p < 0.05) but produced substantial decreases in peak left ventricular pressure (100 +/- 3 to 45 +/- 4 mm Hg, p < 0.01) and dP/dt (68% decrease, p < 0.01) and an increase in tau (+26%, p < 0.05). Isoproterenol restored these variables toward normal values in the hearts treated with verapamil, although left ventricular systolic pressure and dP/dt were restored to control values only at the highest isoproterenol concentrations. In the hearts treated with zatebradine, isoproterenol significantly increased left ventricular pressure and contractility and decreased tau; however, heart rate remained unchanged at peak effect. Zatebradine had no effect on coronary blood flow and there was a 100% increase in flow with reactive hyperemia. Conversely, verapamil increased coronary flow by 100%, with no subsequent further increase by reactive hyperemia compared with control values. CONCLUSIONS: Although structurally similar to verapamil, zatebradine is a highly specific bradycardic agent. It has little direct effect on left ventricular developed pressure, contractility, relaxation and coronary vascular tone. Furthermore, the bradycardic effect of zatebradine unlike that of verapamil, is not overcome by doses of isoproterenol that increase developed pressure and contractility and improve relaxation. Because of its highly specific bradycardic effect, this drug may potentially be useful in treating patients with ischemic heart disease or congestive heart failure.

Atherectomy of the subclavian artery for patients with symptomatic coronary-subclavian steal syndrome.

OBJECTIVES: This study addresses the efficacy of directional atherectomy in the subclavian artery for the relief of angina in patients with the coronary-subclavian steal syndrome. In addition, we review the histologic findings from the atherectomy specimens. BACKGROUND: The coronary-subclavian steal syndrome may occur after internal mammary-coronary artery bypass grafting. It is due to a stenosis in the subclavian artery proximal to the origin of the internal mammary artery and causes frank ischemia to the area supplied by the graft. Currently, surgery is the corrective procedure of choice. METHODS: In three patients with severe subclavian artery stenoses and unstable angina, directional atherectomy was performed using a peripheral atherectomy catheter through a percutaneous femoral approach. The patients ranged from 43 to 71 years of age and had undergone internal mammary-coronary artery bypass grafting 3 to 10 years previously. Each patient had severe peripheral vascular and cerebrovascular disease. RESULTS: All three patients had immediate symptomatic relief after the atherectomy, and postprocedure exercise testing demonstrated improved cardiac function. Two patients remain asymptomatic at 7 and 8 months, respectively; the third patient developed unstable angina 9 months later because of severe restenosis that was again successfully treated with atherectomy. Histologic examination of the specimens revealed atherosclerotic plaque, occasionally with adventitia. The specimen from the repeat atherectomy showed severe intimal hyperplasia. CONCLUSIONS: Directional atherectomy appears to be a safe and effective treatment for coronary-subclavian steal syndrome. This procedure may be the treatment of choice for patients in whom a vascular bypass operation is not feasible.

Regional myocardial blood flow and left ventricular diastolic properties in pacing-induced ischemia.

The relation between left ventricular diastolic abnormalities and myocardial blood flow during ischemia was studied in eight open chest dogs with critical stenoses of the proximal left anterior descending and circumflex coronary arteries. The heart was paced at 1.7 times the heart rate at rest for 3 min. In dogs with coronary stenoses, left ventricular end-diastolic pressure increased from 8 +/- 1 to 14 +/- 2 mm Hg during pacing tachycardia (p less than 0.01) and 16 +/- 3 mm Hg (p less than 0.01) after pacing, with increased end-diastolic and end-systolic segment lengths in the ischemic regions. Left ventricular diastolic pressure-segment length relations for ischemic regions shifted upward during and after pacing tachycardia in dogs with coronary stenoses, indicating decreased regional diastolic distensibility. In dogs without coronary stenoses, the left ventricular diastolic pressure-segment length relation was unaltered. Pacing tachycardia without coronary stenoses induced an increase in anterograde coronary blood flow (assessed by flow meter) in both the left anterior descending and circumflex coronary arteries, and a decrease in regional vascular resistance. In dogs with coronary stenoses, regional vascular resistance before pacing was decreased by 18%; myocardial blood flow (assessed by microspheres) was unchanged in both the left anterior descending and circumflex coronary artery territories. During pacing tachycardia with coronary stenoses, regional coronary vascular resistance did not decrease further; subendocardial myocardial blood flow distal to the left anterior descending coronary artery stenosis decreased (from 1.03 +/- 0.07 to 0.67 +/- 0.12 ml/min per g, p less than 0.01), as did subendocardial to subepicardial blood flow ratio (from 1.04 +/- 0.09 to 0.42 +/- 0.08, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

First-pass nuclear magnetic resonance imaging studies using gadolinium-DTPA in patients with coronary artery disease.

Nuclear magnetic resonance (NMR) imaging has been shown to accurately portray cardiac anatomy and function. To investigate the potential of NMR imaging for the assessment of coronary stenosis in patients with chest pain, ultrafast NMR imaging in conjunction with a T1 (longitudinal relaxation time) contrast agent was performed in 17 patients with chest pain who had undergone cardiac catheterization. These included 12 patients with significant coronary artery stenoses and 4 who underwent repeat NMR study after myocardial revascularization. Cardiac images at rest were obtained during rapid intravenous injection of gadolinium-DTPA (0.04 mM/kg). Electrocardiographic-gated images were acquired over 380 ms, with repetitive images obtained every 3 to 4 s. After contrast injection, there was pronounced signal enhancement in the right ventricular cavity, followed by enhancement in the left ventricular cavity and myocardium. Regional myocardium perfused by a diseased vessel demonstrated a lower peak signal intensity (p = 0.001) and lower rate of signal increase (p = 0.001) than did myocardium perfused by coronary arteries without stenosis. Repeat NMR study after revascularization showed an increase in peak signal intensity (p less than 0.002). These results demonstrate the clinical potential of dynamic gadolinium-DTPA-enhanced NMR imaging for the assessment of coronary artery disease in patients with chest pain. In combination with anatomic and functional NMR imaging, this technique has the potential to provide a comprehensive noninvasive cardiac evaluation of patients with suspected coronary artery disease.