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Background: Hypertension after heart transplantation (HTx) is common. We investigated predictors of and mechanisms for hypertension development during the first year after HTx, with particular attention toward immunosuppressive agents, reinnervation processes, and donor/recipient sex., Methods: Heart transplant recipients (HTxRs) were consecutively enrolled 7 to 12 wk after surgery and followed prospectively for 12 mo. Ambulatory blood pressure recordings and autonomic cardiovascular control assessments were performed at baseline and follow-up. Possible predictors of posttransplant hypertension development were investigated in bivariate linear regression analyses followed by multiple regression modeling., Results: A total of 50 HTxRs were included; 47 attended the follow-up appointment at 12 mo. Mean systolic and diastolic blood pressure increased significantly during the observational period (systolic blood pressure from 133 to 139 mm Hg, P  = 0.007; diastolic blood pressure from 81 to 84 mm Hg, P  = 0.005). The blood pressure increment was almost exclusively confined to HTxRs with a female donor heart, doubling the cases of systolic hypertension (from 6 to 13/14; 46% to 93%, P  = 0.031) and diastolic hypertension (from 7 to 14/14; 54% to 100%, P  = 0.031) in this subgroup. Autonomic cardiovascular control assessments suggested tonically constricted resistance and capacitance vessels in recipients with female donor hearts. Immunosuppressive agents and reinnervation markers were not associated with hypertension development., Conclusions: Blood pressures increase during the first year after HTx, with female donor sex as a strong predictor of recipient hypertension development. The underlying mechanism seems to be enhanced peripheral vasoconstriction caused by attenuated cardiovascular homeostasis capabilities. Further studies are needed to confirm the results., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Heart transplantation (HTx) surgically transects all connections to the heart, including the autonomic nerves. We prospectively examined signs, timing and consequences of early sympathetic and parasympathetic sinoatrial reinnervation, as well as explored indirect evidence of afferent cardiopulmonary reinnervation., Methods: Fifty HTx recipients were assessed at 2.5, 6, and 12 mo after HTx. For comparison, 50 healthy controls were examined once. Continuous, noninvasive recordings of hemodynamic variables and heart rate variability indices were performed at supine rest, 0.2 Hz controlled breathing, 60° head-up-tilt, during the Valsalva maneuver and during handgrip isometric exercise., Results: In HTx recipients, supine low-frequency heart rate variability gradually increased; supine high-frequency variability did not change; heart rate variability indices during controlled breathing remained unaltered; heart rate responses during tilt and isometric exercise gradually increased; the tachycardia response during Valsalva maneuver increased, while the bradycardia response remained unchanged; and indices of baroreflex sensitivity improved. Responses remained low compared to healthy controls. A negative correlation between indices of preload and heart rate response during head-up tilt emerged at 12 mo., Conclusions: Results suggest that sympathetic reinnervation of the sinoatrial node starts within 6 mo after HTx and strengthens during the first year. No evidence of early parasympathetic reinnervation was found. Indirect signs of afferent reinnervation of cardiopulmonary low-pressure baroreceptors emerged at 12 mo. Better sympathetic sinoatrial control improved heart rate responsiveness to orthostatic challenge and isometric exercise, as well as heart rate buffering of blood pressure fluctuations., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: This article presents an update of the results achieved by modern surgery in congenital heart defects (CHDs) over the past 40 years regarding survival and the need for reoperations, especially focusing on the results from the past 2 decades., Methods and Results: From 1971 to 2011, all 7038 patients <16 years of age undergoing surgical treatment for CHD at Rikshospitalet (Oslo, Norway) were enrolled prospectively. CHD diagnosis, date, and type of all operations were recorded, as was all-cause mortality until December 31, 2012. CHDs were classified as simple (3751/7038=53.2%), complex (2918/7038=41.5%), or miscellaneous (369/7037=5.2%). Parallel to a marked, sequential increase in operations for complex defects, median age at first operation decreased from 1.6 years in 1971 to 1979 to 0.19 years in 2000 to 2011. In total, 1033 died before January 1, 2013. Cumulative survival until 16 years of age in complex CHD operated on in 1971 to 1989 versus 1990 to 2011 was 62.4% versus 86.9% (P<0.0001). In the comparison of patients operated on in 2000 to 2004 versus 2005 to 2011, 1-year survival was 90.7% versus 96.5% (P=0.003), and 5-year cumulative survival was 88.8% versus 95.0% (P=0.0003). In simple versus complex defects, 434 (11.6%) versus 985 (33.8%) patients needed at least 1 reoperation before 16 years of age. In complex defects, 5-year cumulative freedom of reoperation among patients operated on in 1990 to 1999 versus 2000 to 2011 was 66% versus 73% (P=0.0001)., Conclusions: Highly significant, sequential improvements in survival and reductions in reoperations after CHD surgery were seen. A future challenge is to find methods to reduce the need for reoperations and further reduce long-term mortality., (© 2014 American Heart Association, Inc.)

The understanding and control of the healing process after percutaneous transluminal coronary angioplasty (PTCA) and of the pathogenesis of restenosis are incomplete. To date, only stent implantation has been shown to successfully reduce the rate of restenosis. Calcium channel blockers have positive effects on a number of processes that may be associated with restenosis, including reduction of platelet aggregation, minimization of vasospasm, and inhibition of mitogens. Clinical trials have therefore been performed to assess the effect of calcium channel blockers on restenosis and ischemia. A meta-analysis of five restenosis trials investigating calcium channel blockers demonstrated a 30% reduction in the risk for restenosis. The Coronary Angioplasty Amlodipine Restenosis Study (CAPARES) is therefore assessing the effect of amlodipine, a long-acting, third-generation calcium channel blocker in angioplasty patients. Therapy (amlodipine 5 mg with a forced titration to 10 mg once daily, or placebo), is begun 2 weeks before angioplasty and is continued for 4 months after the procedure. The rationale of CAPARES is that amlodipine may offer anti-ischemic protection before, during, and after angioplasty, may have more beneficial effects on restenosis and various clinical end points than calcium channel blockers used in previous trials, and may improve the long-term outcome of PTCA therapy.

OBJECTIVE: To investigate whether the exercise systolic blood pressure predicts cardiovascular morbidity and mortality and in particular myocardial infarction beyond that prediction provided by the casual blood pressure at rest and independently of other cardiovascular risk factors. METHODS: We performed an average 16-year follow-up of 1999 middle-aged healthy men. RESULTS: We found that the systolic blood pressure during 6 min on a moderate load during a bicycle ergometer exercise test was a stronger predictor of total cardiovascular mortality and of morbidity and mortality from myocardial infarction than was the blood pressure of the subjects at rest. Furthermore, an early rise in systolic blood pressure during exercise seems to add prognostic information only when the systolic blood pressure of the subject at rest is elevated mildly (>/= 140 mmHg). Subjects whose systolic blood pressure increased to >/= 200 mmHg had a more than twofold greater risk of dying from cardiovascular causes and from myocardial infarction in particular within 16 years than did normotensives and men whose systolic blood pressure was >/= 140 mmHg when they were at rest whose systolic blood pressure did not increase to a similar extent, after we had adjusted for differences in age and a rather large number of traditional risk factors for cardiovascular disease. CONCLUSION: We suggest that systolic blood pressures recorded during standardized ergometer exercise testing may help one to distinguish between severe and less severe cases of hypertension among middle-aged men.

Background: Resting heart rate is directly associated and maximal exercise-induced heart rate inversely associated with cardiovascular mortality, and therefore their difference might contain prognostic information from both variables. The comparative long-term prognostic values of maximal exercise-induced heart rate and of the difference between it and resting heart rate were studied in apparently healthy middle-aged men., Methods: Resting heart rate and maximal exercise-induced heart rate were measured, and their difference calculated, in 1960 apparently healthy men aged 40-59 years, and mortality was recorded over a period of 16 years. Conventional coronary risk factors were assessed at baseline., Results: Both the difference between the two heart rates and the maximal exercise-induced heart rate were strongly, independently and inversely associated with cardiovascular mortality after adjustment for age, smoking, systolic blood pressure, lung function, glucose tolerance, serum cholesterol level, serum triglycerides level, physical fitness and exercise ECG findings. The adjusted relative risk of cardiovascular death in heart-rate difference quartiles 3 and 4 compared with that in quartile 1 (the lowest heart-rate difference quartile) was 0.54 (95% confidence interval 0.33-0.86; P = 0.009). The corresponding value for maximal exercise-induced heart rate was 0.56 (95% confidence interval 0.34-0.89; P = 0.018). Within the lowest heart-rate difference quartile, but not within the lowest maximal exercise-induced heart rate quartile, a further, strong, negative gradient in cardiovascular mortality was observed. In the high working capacity range, low heart-rate difference but not low maximal exercise-induced heart rate predicted very high cardiovascular disease mortality. Heart-rate difference and maximal exercise-induced heart rate were also inversely associated with non-cardiovascular disease mortality., Conclusions: Both heart-rate difference and maximal exercise-induced heart rate were strong, graded, long-term predictors of cardiovascular mortality among apparently healthy middle-aged men, independent of age, physical fitness and conventional coronary risk factors. However, low heart-rate difference was a better predictor than low maximal exercise-induced heart rate for recognizing individuals who were at particularly high risk of dying prematurely from cardiovascular diseases.

Amlodipine (5-10 mg, once daily) and enalapril (10-40 mg, once daily) were compared in terms of quality of life, efficacy, and tolerability, in a multicenter, double-blind trial lasting for 50 weeks in 461 mild or moderate hypertensive patients. Both drugs were similarly effective in lowering blood pressure while maintaining quality of life. Apart from class-typical effects, such as edema for calcium antagonists, and cough for angiotensin-converting enzyme inhibitors, both drugs were equally well tolerated, with few adverse effects of clinical significance. Only a few patients [eight amlodipine (4%); nine enalapril (4%)] were withdrawn from the trial due to drug-related adverse events, demonstrating that tolerability was good. Neutral to slightly beneficial effects were found in blood lipid concentrations after treatment with amlodipine. Both drugs reduced the calculated risk of coronary heart disease over the next 10 years. It was concluded that amlodipine compared favorably with enalapril as an effective and well-tolerated antihypertensive drug.

Mortality rises as resting heart rate increases. Patients who are less able to increase their heart rate while exercising are more likely to die than those whose heart rate does rise. The occurrence of silent ischaemic events shows a circadian distribution, with increased mortality, heart rate and systolic blood pressure early in the morning. Treatment with beta-blockers reduces the number of asymptomatic ischaemic episodes, and lowers heart rate during exercise and at rest. The ischaemic myocardium of the dog loses the ability to undergo wall thickening during exercise. Moreover, blood flow in the ischaemic subendocardium is reduced during exercise. These effects can be overcome using beta-blockers. The effects of beta-blockers in reducing heart rate are less pronounced during mental stress. Furthermore, changes in wall motion abnormalities during mental stress are not improved by beta-blockers. Treatment of patients with beta-blockers after a myocardial infarction reduces the mortality rate. The greater the reduction in heart rate, the greater the reduction in mortality.

Background: Experimental animal and clinical studies indicate that blood platelets have an important role in atherosclerosis and formation of thrombi. Prospective studies presenting evidence of an association between blood platelet count and cardiovascular mortality have not been performed., Methods and Results: From 1973 to 1975, blood platelets were counted, and their responsiveness to aggregating agents was studied in healthy middle-aged men. The aim was to assess the possible association between these variables and coronary heart disease. At 13.5 years of follow up, a significantly higher coronary heart disease mortality was observed among the 25% of subjects with the highest platelet counts. Platelet aggregation performed in a random subsample (150 of the 487 men), moreover, revealed that the 50% with the most rapid aggregation response after ADP stimulation had significantly increased coronary heart disease mortality compared with the others. These associations could not be explained by differences in age, lipids, blood pressure, or smoking habits., Conclusions: The present study is the first to present conclusive, prospective evidence of an association between platelet concentration and aggregability and long-term incidence of fatal coronary heart disease in a population of apparently healthy middle-aged men.

To study the effect of selective alpha 1- or alpha 2-adrenergic blockade on the myocardial contractile and chronotropic response to exercise, 29 dogs were chronically instrumented with a sonomicrometer for measuring myocardial wall thickness and a micromanometer for measuring left ventricular pressure. During treadmill exercise, either the selective alpha 1-blocker prazosin (80 micrograms/kg, n = 12) or the alpha 2-blocker idazoxan (80 micrograms/kg, n = 8) was infused into the left atrium beginning 2-3 minutes after the onset of exercise. alpha 1-Adrenoceptor blockade, like alpha 2-adrenoceptor blockade, was found to cause significant increases in systolic wall thickening, thickening velocity, heart rate, and left ventricular contractility, indicating an increase in inotropic state that was comparable to that with alpha 2-adrenoceptor blockade. Preventing the decrease in aortic blood pressure after selective alpha 1-blockade by using either systemic angiotensin II infusion (n = 6) or inflation of an intra-aortic balloon (n = 6) did not prevent the observed increases in wall thickening, heart rate, and left ventricular contractility. In four of the dogs treated with prazosin, the norepinephrine concentration in the coronary sinus was found to more than double after alpha 1-blockade. beta-Adrenergic blockade (propranolol, 1.0 mg/kg) prevented the increased contractile and chronotropic state caused by alpha 1- or alpha 2-blockade. Selective alpha-adrenergic blockade during adrenergic activation by intravenous norepinephrine infusion, in contrast to exercise, had no effect on wall thickening, heart rate, or left ventricular contractility. These data indicate that selective alpha 1-adrenergic blockade, like selective alpha 2-adrenergic blockade, causes a significant augmentation of heart rate and left ventricular contractility in the dog during dynamic exercise. These data are consistent with the hypothesis that this occurs through a presynaptic disinhibition of neural norepinephrine release mediated by a prejunctional alpha 1-adrenoceptor.

Determination of the effect of inotropic stimulation on regionally ischemic and hypokinetic myocardium is complicated when intravenous administration of the inotropic agent also causes stimulation of nonischemic adjacent and distant regions, thereby altering global ventricular hemodynamics. To obviate such events, 16 anesthetized swine were studied during regional inotropic stimulation by infusion of dobutamine hydrochloride (2.5 +/- 1 microgram/min) into the cannulated left anterior descending coronary artery. Coronary inflow was controlled by a pump in an extracorporeal circuit. Two groups of swine with different degrees of ischemia were studied. In the first group of animals (n = 8), reduction in coronary inflow to produce a fall in coronary artery pressure (CAP) from 114 +/- 7 mm Hg to 62 +/- 2 mm Hg caused a decrease in percent systolic wall thickening (%WTh) from 34.6 +/- 8.1% to 25.4 +/- 5.8% (p less than 0.005). In the second group of animals (n = 8), CAP was decreased to 46 +/- 5 mm Hg (control: 115 +/- 8 mm Hg) and % WTh decreased from 34.1 +/- 16.4% to 10.4 +/- 6.9% (p less than 0.001). Subendocardial blood flow was reduced from 1.41 +/- 0.38 ml/min/g to 0.65 +/- 0.13 ml/min/g (group 1, p less than 0.001) and from 1.08 +/- 0.22 ml/min/g to 0.24 +/- 0.08 ml/min/g (group 2, p less than 0.001). Regional infusion of dobutamine caused asynchronous ventricular contraction with early systolic augmentation in wall thickening followed by late systolic thinning. Therefore, during hypoperfusion regional myocardial function assessed by %WTh remained unchanged (26.2 +/- 5.8%, p = NS) in group 1 and decreased significantly to 1.6 +/- 5.1% (p less than 0.041) in group 2. Subendocardial blood flow decreased to 0.44 +/- 0.15 ml/min/g in group 1 (p less than 0.005) and to 0.15 +/- 0.07 ml/min/g in group 2 (p less than 0.012). To account for the augmented early systolic thickening that occurred during asynchronous contraction, a myocardial work index was developed in which the sum of the instantaneous left ventricular pressure-wall thickness product was calculated for estimation of regional myocardial work. Increases in this work index were apparent with the addition of dobutamine at both levels of hypoperfusion. This significant enhancement in regional myocardial function in group 2 caused a significant increase of 16% (p less than 0.009) in overall left ventricular power during ejection. Thus, regional inotropic stimulation with dobutamine caused enhancement of maximum work of the ischemic myocardium in the steady state despite a further decrease in subendocardial blood flow.

Disopyramide exerts a quinidinelike effect on the heart and is a valuable drug for treating atrial and, especially, ventricular tachyarrhythmias. The therapeutic plasma concentration of disopyramide is thought to be 2.0-4.0 (5.0) microgram/ml. We here report the cardiac effects of a high dose of disopryamide in a patient with extensive coronary artery disease complicated by ventricular extrasystoles. At plasma levels above approximately 7.0 micrograms/ml, heart rate was decreased, while PQ interval, width, and QT interval were increased. At concentrations above approximately 6.0 micrograms/ml, disopyramide exerted negative intropic effects as judged by increases in mean right atrial, pulmonary arteriolar, and pulmonary capillary venous pressures and a decrease in cardiac output.