Cardiac adaptation to obesity and hypertension after heart transplantation.

Obesity and hypertension frequently develop after heart transplantation. The cardiac adaptation to obesity and hypertension was studied by determining hemodynamic and echocardiographic indexes in 10 obese hypertensive patients (body mass index greater than or equal to 27.8 kg/m2 in men or greater than or equal to 27.3 kg/m2 in women) matched by mean arterial pressure, age and gender with 10 nonobese hypertensive patients 1 year after cardiac transplantation. Cardiac output was 30% greater (p less than 0.02) and systemic vascular resistance 25% lower (p less than 0.01) in the obese than in the nonobese patients. Right ventricular systolic and pulmonary artery systolic, diastolic and mean pressures were also significantly higher (p less than 0.05) in the obese patients. Left ventricular end-diastolic diameter was 25% greater (p less than 0.05), left ventricular mass 28% greater (p less than 0.02) and left ventricular end-diastolic volume 20% higher (p less than 0.01) in the obese subjects. Left ventricular ejection fraction was significantly lower in the obese than in the nonobese subjects (34% vs. 51%, p less than 0.05). These results indicate that the cardiac adaptation to obesity and hypertension after heart transplantation consists of left ventricular dilation and an increase in left ventricular mass associated with an increased cardiac output and lower peripheral vascular resistance. These adaptive changes that occur in obese hypertensive patients after heart transplantation might increase the long-term risk of graft failure, as suggested by their lower left ventricular ejection fraction 1 year after transplantation.

Predictive model to assess risk for cardiac allograft vasculopathy: an intravascular ultrasound study.

OBJECTIVES: This study was performed to assess the influence and interdependence of immunologic and nonimmunologic risk factors in the development of cardiac allograft vasculopathy. Another primary objective was to establish a clinically useful model for risk assessment of cardiac allograft vasculopathy that would facilitate identifying those heart transplant recipients likely to have severe intimal proliferation and thereby at greater risk for adverse clinical events. BACKGROUND: To our knowledge, no comprehensive intravascular ultrasound study has assessed the relative influences of both nonimmunologic and immunologic factors in the development of cardiac allograft vasculopathy, currently the major limitation to long-term cardiac allograft survival. METHODS: Using a computer-assisted model of stepwise logistic regression, immunologic and nonimmunologic risk factors were evaluated to help identify the development of severe intimal thickening in 101 subjects who underwent intravascular ultrasound. Prospective validation of the findings was performed in a separate consecutive cohort of 37 heart transplant recipients, and the accuracy of this model to predict a relative risk > 1 for the development of severe intimal hyperplasia was assessed. RESULTS: Significant independent predictors of severe intimal hyperplasia in this model included a donor age > 35 years, a first-year mean biopsy score > 1 (a measure not only of severity of rejection, but also of frequency of insidious rejection) and hypertriglyceridemia at two incremental levels of risk (150 to 250 mg/dl [1.70 to 2.83 mmol/liter] and > 250 mg/dl [2.83 mmol/liter]). Based on the absence (0) or presence (1) of these factors, 12 individual categories of risk were ascertained with increasing relative risks and predicted probabilities for severe intimal hyperplasia. Prospective validation of this model revealed a sensitivity and specificity of 70% and 90%, respectively, and the positive and negative predictive values were 85% and 80%, respectively. Additionally, subjects with severe intimal thickening had a four-fold higher cardiac event rate than those without severe intimal proliferation on intravascular ultrasound. CONCLUSIONS: This study establishes a clinically useful predictive model that can be applied to individual heart transplant recipients to assess their risk for developing significant cardiac allograft vasculopathy and, thus, aids in the identification of patients at risk for cardiac events in whom closer surveillance and risk factor modification may be warranted.

Coronary stenting in cardiac allograft vasculopathy.

OBJECTIVE: The purpose of this study was to evaluate acute angiographic success, in-hospital complications and long-term outcome after intracoronary stenting in patients with cardiac allograft vasculopathy. BACKGROUND: The application of conventional interventional modalities to treat discrete lesions in patients with cardiac allograft vasculopathy is associated with higher procedural morbidity, mortality and higher restenosis compared to atherosclerotic coronary artery disease. Elective coronary stenting has been shown to lower restenosis rates and improve long-term outcome in selected patients with native coronary artery disease; however, its safety and efficacy in reducing restenosis in patients with cardiac allograft vasculopathy is unknown. METHODS: Ten patients with 19 discrete lesions in a major coronary artery without diffuse distal disease underwent intracoronary stenting using Palmaz-Schatz stents. The average stent size was 3.4 mm, and the stent/artery ratio was 0.99+/-0.07. Eight of ten (80%) patients received antiplatelet therapy (aspirin plus ticlopidine) only. RESULTS: Procedural success was 100% with no in-hospital stent thrombosis, Q-wave myocardial infarction or death. Minimal luminal diameter increased from 0.83+/-0.38 mm to 3.23+/-0.49 mm after stenting. Diameter stenosis decreased from 74.91+/-11.52% to 5.90+/-4.09% after stenting. Follow-up angiography was performed in 8 of 10 (80%) patients and 16 of 19 (84%) lesions. Target lesion revascularization was required in 2 of 10 (20%) patients and 3 of 16 (19%) lesions. Allograft survival was 7 of 10 (70%) at the end of 22+/-11 months follow-up. CONCLUSIONS: Intracoronary stenting can be performed safely with excellent angiographic success in selected patients with cardiac allograft vasculopathy. The restenosis rate appears to be low despite the aggressive nature of the disease. A multicenter study with a larger number of patients is required to assess its efficacy in reducing restenosis and improving allograft survival.

Heterogeneity of cardiac allograft vasculopathy: clinical insights from coronary angioscopy.

OBJECTIVES: With this study, we sought to examine the heterogeneity of cardiac allograft vasculopathy in vivo using coronary angioscopy as an adjunct to intravascular ultrasound, and we evaluated the clinical relations of immunologic and nonimmunologic risk factors with the different forms of cardiac allograft vasculopathy detected angioscopically. BACKGROUND: Intravascular ultrasound detects vascular intimal proliferation accurately but is limited in its ability to delineate morphologic characteristics. Coronary angioscopy can evaluate intimal surface morphology by direct visualization and can differentiate pathologically distinct forms of plaque topography on the basis of color and contour. METHODS: We studied 107 consecutive heart transplant recipients with intravascular ultrasound and angioscopy at the time of their annual angiogram, and we assessed the relation of nonimmunologic and immunologic risk factors to the development of cardiac allograft vasculopathy distinguished angioscopically into a pigmented (yellow) or nonpigmented (white) intimal thickening. We further evaluated the clinical differences in cardiac events among these two forms of angioscopically heterogeneous forms of cardiac allograft vasculopathy. RESULTS: Significant clinical predictors of nonpigmented intimal thickening were advanced donor age and lower mean cyclosporine levels, whereas hyperlipidemia, cumulative prednisone dose and time since transplantation correlated with pigmented intimal hyperplasia. In addition, comparisons between the two angioscopic groups revealed increased intimal thickening, serum cholesterol, low density lipoprotein cholesterol, acute allograft rejection and time since transplantation in the group with pigmented intimal thickening (p < 0.05). With regard to cardiac events, nonpigmented plaque was more frequently found in the sudden death group (53% vs. 20%, p = 0.05), whereas the nonsudden cardiac event group had a significantly higher prevalence of pigmented plaque (80% vs. 47%, p = 0.07). CONCLUSIONS: These findings indicate that cardiac allograft vasculopathy is a heterogeneous disease with varied morphologic expressions with different clinical implications. Furthermore, this investigation provides insight into the cohesive, yet diverse influences of various factors, particularly immunosuppression, in these forms of cardiac allograft vasculopathy.

Renal involvement follows cardiac enlargement in essential hypertension.

To assess the relationship between early clinically detectable involvement of hypertensive vascular disease in heart and kidneys, we obtained systemic and renal hemodynamic and M-mode echocardiographic measurements in 65 patients with essential hypertension. The results indicate that patients with and without left ventricular hypertrophy had similar renal hemodynamic findings. In contrast, patients with altered renal hemodynamic measurements (ie, reduced renal distribution of cardiac output and, therefore, absolute renal blood flow with increased renal vascular resistance) and increased serum uric acid levels also had increased left ventricular posterior and septal wall thicknesses and mass index. Moreover, these data also demonstrated that in patients with altered renal hemodynamics, the lower the renal distribution of cardiac output and the higher the serum uric acid levels, the greater were the indexes of cardiac enlargement. These results demonstrated that the pathophysiological and hemodynamic effects of essential hypertension in the heart precede those in the kidneys.

Overweight and sudden death. Increased ventricular ectopy in cardiopathy of obesity.

Obesity has been documented to be an independent risk factor for sudden death and other cardiovascular mortality. The present study was designed to monitor and quantify cardiac arrhythmias in obese subjects with and without eccentric left ventricular hypertrophy, who were matched with regard to arterial pressure, age, sex, and height with lean subjects. Prevalence of premature ventricular (but not atrial) contractions was 30 times higher in obese patients with eccentric left ventricular hypertrophy compared with lean subjects. Similarly, obese patients with left ventricular hypertrophy scored higher with regard to the classification of Lown and Wolf than those without left ventricular hypertrophy and lean subjects having the same level of arterial pressure. Patients' class in the Lown and Wolf system correlated with ventricular diastolic diameter and left ventricular mass. Thus, heart enlargement of the eccentric type as a consequence of obesity predisposes to excessive ventricular ectopy. Echocardiographic assessment and electrocardiographic monitoring allow us to identify the patients who are at highest risk of more serious arrhythmias or possibly sudden death and to subject them to the most specific preventive and therapeutic measures.

Hypertension and sudden death. Disparate effects of calcium entry blocker and diuretic therapy on cardiac dysrhythmias.

This study was designed to evaluate the impact of antihypertensive therapy on cardiac dysrhythmias in 13 hypertensive patients who received calcium entry blockers and in 10 hypertensive patients who received hydrochlorothiazide. Mean arterial pressure fell to a similar extent in both treatment groups; however, left ventricular mass index decreased (from 102 +/- 4 to 95 +/- 2 g/m2) only in patients receiving calcium entry blockers, but not in those taking hydrochlorothiazide. The prevalence of premature ventricular contractions decreased 74% from 21 +/- 14/h to 5.7 +/- 6/h in the calcium entry blocker group, but did not change in the hydrochlorothiazide group (15 +/- 17/h to 16 +/- 13/h). Couplets, multiform contractions, ventricular tachycardia, and supraventricular tachycardia were completely abolished after calcium entry blocker therapy, whereas the prevalence of these arrhythmias remained unchanged during treatment with hydrochlorothiazide. We conclude that antihypertensive therapy with calcium entry blockers (but not with thiazide diuretics) reduces left ventricular mass and the prevalence and severity of ventricular dysrhythmias. Whether this reduction will improve the ominous prognosis of left ventricular hypertrophy and diminish the risk of sudden death remains unknown.

Clinical and hemodynamic determinants of left ventricular dimensions.

This study was designed to quantitate the influence of 20 clinical, hemodynamic, and volume determinants of left ventricular (LV) structure. Systemic hemodynamics, intravascular volume, and LV echocardiographic measurements were collected in a heterogeneous population of 171 patients. Stepwise multiple-regression analysis indicated that body weight and body-surface area were the most powerful determinants of LV chamber size, wall thickness, and muscle mass. Age, a pressure independent determinant of myocardial mass, had no influence on chamber size or LV function. Arterial pressure correlated best with the relative wall thickness and chamber volume. Intravascular volume was a major discriminator for chamber volume, LV mass, and velocity of circumferential fiber shortening. It is concluded that body weight, arterial pressure, intravascular volume, and age are each independent determinants of the LV dimension. Systolic pressure most closely correlated with relative wall thickness and thereby is the best predictor of degree of concentric LV hypertrophy.

Study of arterial and autonomic effects of cyclosporine in humans.

Altered sympathetic activity and peripheral vascular function are suspected as a mechanism of the development of arterial hypertension in organ transplantation recipients treated with cyclosporine. We assessed whether cyclosporine might alter peripheral vascular properties or autonomic modulation of the sinus node and the vasculature during rest and standing. We examined 17 orthotopic heart transplantation recipients, 8 solid organ transplantation recipients, 17 patients with essential hypertension, and 42 normotensive control subjects. All except the normotensive control subjects were treated with a long-acting dihydropyridine calcium entry blocker; transplantation recipients also received cyclosporine-based immunosuppression. Radial artery compliance was reduced in patients with essential hypertension and in patients with heart and solid organ transplantation as compared with normotensive control subjects, with this reduction being more marked in heart transplantation recipients. At rest, R-R variance was lowest in heart transplantation recipients, denoting denervation. The spectral profile of both R-R and systolic blood pressure variability as well as the index of baroreflex gain was normal at rest in patients with solid organ transplantation. On standing, both transplantation groups demonstrated reduced responsiveness in markers of autonomic modulation. The decrease in arterial compliance in cyclosporine-induced hypertension seems to imply a degree of ventricular vascular uncoupling more apparent in heart transplantation recipients. These changes are associated with alterations in autonomic modulation that are evidenced by an orthostatic stimulus.

Hypertension and sudden death. Increased ventricular ectopic activity in left ventricular hypertrophy.

The present study was designed to detect and quantify cardiac arrhythmias in hypertensive patients with left ventricular hypertrophy. Continuous ambulatory electrocardiographic tracings and arterial pressure were recorded for 24 hours in 14 normotensive subjects, 10 patients with established essential hypertension without left ventricular hypertrophy, and 16 hypertensive patients with left ventricular hypertrophy by electrocardiographic criteria. Urinary excretion of norepinephrine was simultaneously measured over four successive four-hour and one eight-hour period. Patients with left ventricular hypertrophy had significantly more ventricular (but not atrial) premature contractions than those without left ventricular hypertrophy or than normotensive subjects. Five patients with left ventricular hypertrophy had episodes of more than 30 premature ventricular contractions per minute. Higher-grade ventricular ectopic activity such as coupled premature ventricular contractions was seen in two, and multifocal premature ventricular contractions were seen in three in the group with left ventricular hypertrophy. No difference in urinary catecholamine excretion rates among the three groups was seen. Left ventricular hypertrophy has been shown to be an independent risk factor for sudden death and acute myocardial infarction. Electrocardiographic monitoring of patients with left ventricular hypertrophy allows identification of those who have the highest risk and, therefore, require the most aggressive therapeutic intervention.

Immediate regional blood flow distribution following angiotensin converting enzyme inhibition in patients with essential hypertension.

The increased total peripheral resistance that characterizes essential hypertension is generally reversed by antihypertensive drugs, but the reduction may not be uniform in all regions of the body. In this study, regional blood flow was investigated immediately after the oral administration of 25 mg of captopril in 11 patients with mild to moderate essential hypertension. Within 90 minutes, the total vascular resistance decreased significantly, and the decrease was significant in the kidney. It decreased but not significantly in the splanchnic organs, the skeletal musculature, and the skin. In no region was the blood flow reduced. As captopril has no direct effect on smooth muscle, these effects are likely to have been due to angiotensin converting enzyme inhibition.

Renal haemodynamic studies in obesity hypertension.

Previous investigations have reported the systemic haemodynamic characteristics of obese hypertensive patients; however, their renal haemodynamics have not been explored. This report compares the renal and systemic haemodynamic findings in obese and lean normotensive and hypertensive patients. Our results demonstrate that both normotensive and hypertensive obese subjects had an increased renal blood flow, total blood volume and cardiac output, with decreased total peripheral and renal vascular resistances in comparison with lean normotensive and hypertensive patients. Body weight correlated directly and significantly with total blood volume, cardiac output and renal blood flow but indirectly with total peripheral resistance. Therefore, the elevated cardiac output and volume expansion found in obese patients were associated with increased renal perfusion; this increased renal blood flow accounts for the reduced renal vascular resistance in patients with obesity hypertension. Thus, we suggest that this effect of volume expansion in obesity could counteract the opposing effect of active vasoconstriction produced by the hypertensive disease and may account for the difference in prognosis of obese and lean hypertensive patients.

Norepinephrine-induced hypertension in Guillain Barré syndrome.

Systemic haemodynamics, plasma catecholamine levels and diurnal variation of arterial pressure were studied in a 20-year-old patient with hypertension during Guillain Barré syndrome after complete resolution of the illness. Transient arterial hypertension during the course of Guillain Barré syndrome is characterized by an increased total peripheral resistance associated with elevated circulating norepinephrine levels, suggesting an over-activity of the sympathetic nervous system as the underlying mechanism of the elevated blood pressure.

Body composition and its relation to systemic haemodynamics, fluid volume partitions and energy utilization in rats with bilateral ventromedial hypothalamic lesions.

Body composition and its relationship with intra-arterial pressure, fluid volume partitions and oxygen consumption were studied in male rats four months following ventromedial hypothalamic (VMH) destruction during the static phase of the development of obesity. Compared with sham-operated controls, rats with VMH lesions had a greater body weight which was related to an increased body lipid content and an elevated arterial pressure and total peripheral resistance. Fluid volume distribution was normal and total body oxygen consumption (per unit of body weight) was reduced. Bilateral destruction of the ventromedial hypothalamus was confirmed in each of the rats studied and no relationship could be demonstrated between the lesion size and the magnitude of haemodynamic changes. It is concluded that the increased arterial pressure observed in obese VMH lesioned rats was directly related to an elevated total body lipid content.

The signal-averaged electrocardiogram in cardiac transplantation. A noninvasive marker of acute allograft rejection.

Cardiac allograft rejection represents a major cause of morbidity and mortality in transplanted patients. Noninvasive markers of rejection have been sought, though transvenous endomyocardial biopsy remains the "gold standard" for the diagnosis of rejection. Sixty-one signal-averaged electrocardiograms (five in patients with rejection and 56 in patients without rejection) were obtained on 41 patients and prospectively analyzed in frequency domain via fast Fourier transform (FFT). Patients with acute allograft rejection demonstrate a significant increase in the high-frequency components of the QRS complex upon FFT analysis (QRS area ratio 203 +/- 57 vs. 66 +/- 10, P = 0.0007) compared with patients without rejection. Thus, frequency domain analysis may be a useful noninvasive marker of acute cardiac allograft rejection.

Colles-Stokes contributions to the concept of heart failure.

"Colles fracture," "Colles law," "Stokes-Adams syndrome," "Cheyne-Stokes respiration," and "Corrigan pulse" are some of the contributions of the Irish school that are utilized for teaching purposes in medical schools and training programs, as well as in daily practice of medicine. We wish to add an important description by Drs. Colles and Stokes that personifies the considerable personal contributions of these 2 physicians in our understanding of the pathophysiologic expression of the syndrome of heart failure. The clinical-pathologic correlation of the disease that affected Dr. Colles is well described by Dr. Stokes in his treatise Diseases of the Heart and the Aorta. He recognized the cyclical nature of frequent decompensations in heart failure, the relation of clinical worsening in conjunction with reduced urine output, as well as the importance of reestablishing urinary flow to achieve a decrease in dyspnea. Dr. Colles also demonstrated a profound clinical insight when he noticed, first, that his affliction was "eventually a fatal disease and that remedies that work may lose effect over time," illustrating an observation that has stood the test of time and, secondly, when he told Dr. Smith "... I would direct particular attention to the heart and the lungs ... and the swelling in the right hypochondrium ... I suspect that there is some connexion between this swelling of the hypochondrium and the diseased state of the heart." We believe that the Colles-Stokes contributions, both in the clinical as well as the clinical-pathologic arenas, are one of the landmark descriptions that helped to evolve the concept of the syndrome of heart failure.

Safety and clinical utility of long-term intravenous milrinone in advanced heart failure.

Few data are available on the long-term safety or clinical utility of the inodilator agent milrinone. We designed a prospective, nonrandomized, observational trial in a cohort of 71 patients who had demonstrated dependence on inotropic therapy, had been clinically stable on an inotropic regimen (milrinone, dobutamine, or both) for > or = 72 hours, and had been given intravenous milrinone for > 72 hours. Group I (n = 22) patients required treatment with both milrinone and dobutamine to achieve stability; group II (n = 49) patients attained stability initially with either milrinone (subgroup IIA) or dobutamine (subgroup IIB), but later required adjunctive therapy with the other inotropic agent for continued hemodynamic support. Of the 71 patients, 38% required mechanical intervention to achieve hemodynamic stability, and 68% were successfully bridged to heart transplantation. Patients were maintained on milrinone therapy for as long as 8 weeks and demonstrated a low incidence of adverse cardiac (7%) or noncardiac (4%) events. Subgroup IIA (28%) had significantly less need than subgroup IIB (52%) for mechanical intervention using an intraaortic balloon pump (p = 0.05), although mortality rates while awaiting transplantation were statistically similar in subgroups IIA (28%) and IIB (35%). Significant improvements from baseline values were noted at the time of transplantation for all aspects of systemic hemodynamics, indicating sustained long-term hemodynamic effects. Long-term intravenous milrinone therapy is safe and well tolerated, and it provides hemodynamic and metabolic support as a pharmacologic bridge to transplantation. The findings also suggest that milrinone as primary inodilator therapy may be associated with less need for mechanical ventricular support.

Immediate hemodynamic effects of a new calcium-channel blocking agent (nitrendipine) in essential hypertension.

The immediate hemodynamic effects of a new calcium-channel blocking agent nitrendipine were studied in 12 patients with mild established essential hypertension. According to the response to mean arterial pressure, patients were classified into responders (decrease greater than 10 mm Hg, 7 patients) and nonresponders (less than or equal to 10 mm Hg, 5 patients). The decrease in arterial pressure in responders was associated with a significant (p less than 0.01) decrease in total peripheral resistance and a significant (p less than 0.05) increase in heart rate, cardiac index, and left ventricular ejection rate. The plasma norepinephrine level was significantly (p less than 0.05) increased in the responders. The response to upright tilt was qualitatively similar to pretreatment values. Thus, nitrendipine lowered arterial pressure as a result of arteriolar dilatation associated with a reflexive increase in heart rate and cardiac index. These hemodynamic properties make the drug particularly apt for use in combination with beta-adrenergic blockade for the treatment of arterial hypertension.

Cardiovascular effects and regional blood flow distribution associated with angiotensin converting enzyme inhibition (captopril) in essential hypertension.

Systemic and regional hemodynamics and cardiac structural changes were studied in 12 patients with mild to moderately severe essential hypertension before and then 90 minutes and 12 weeks after administration of captopril. Mean arterial pressure was reduced from 111 mm Hg to 96 mm Hg (p less than 0.001), and this was mediated through a fall in total peripheral resistance from 26 +/- 2 units to 23 +/- 2 units (p less than 0.01). The decreased total peripheral resistance was distributed to all circulations studied: kidney, skeletal muscle, skin and the splanchnic organs. Furthermore, left ventricular (LV) mass index diminished without altering myocardial contractility at rest. Thus, captopril lowered arterial pressure through systemic arteriolar dilatation in patients with mild to moderately severe essential hypertension and also reduced LV mass even in patients without evidence of LV hypertrophy.

Enalapril improves systemic and renal hemodynamics and allows regression of left ventricular mass in essential hypertension.

Enalapril, a new angiotensin-converting enzyme inhibitor, is an effective antihypertensive agent for both renovascular and essential hypertension. It is structurally different from captopril in that it does not possess a sulfhydryl group. The systemic and renal hemodynamic, biochemical and cardiac adaptive changes induced by enalapril were studied in 8 patients with essential hypertension before and after 12 weeks of therapy. Mean arterial pressure decreased from 110 to 90 mm Hg (p less than 0.01), and this was mediated through a decrease in total peripheral resistance from 42 +/- 3 to 32 +/- 3 U (p less than 0.01). Cardiac index and heart rate did not change. Renal plasma flow was increased in 6 of 8 patients and renal vascular resistance decreased from 123 +/- 6 to 91 +/- 7 U (p less than 0.001). Left ventricular mass index decreased from a mean of 166 +/- 29 to 117 +/- 8 g/m2 (p less than 0.05) without impaired myocardial contractility. Thus, enalapril lowers arterial pressure by reducing total peripheral resistance without reflexive cardiac effects. It also has favorable hemodynamic effects on the kidney. This is the first report of regression of LV mass with this agent in man.