Influence of the force--frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy

In isolated human myocardium it was shown that a positive force-frequencyrelationship occurs in non-failing myocardium; however, theforce-frequency relationship was found to be inverse in myocardiumfrom failing human hearts. In order to investigate the clinicalrelevance of these experimental findings, the influence of heartrate changes on haemodynamics and left ventricular functionwas studied in eight patients without heart failure and in ninewith failing dilated cardiomyopathy (NYHA II–III). Rightventricular pacing was performed at a rate slightly above sinusrate and at 100, 120 and 140 beats. min^–1 Haemodynamicparameters were obtained by right heart catheterization andby high-fidelity left ventricular pressure measurements. Leftventricular angiography was performed at basal pacing rate andat 100 and 140 beats. min^–1 With increasing heart rate,cardiac index increased in patients with normal left ventricularfunction from 2·9 ± 0·2 to 3·5 ±0·21. min^–1. m^–2 (P<0·01) and decreasedcontinuously in patients with dilated cardiornyopathy from 2·6± 0·1 to 2·2 ± 0·11. min^–1. m^–2 (P<0·05). With increasing heart rate,the maximum rate of left ventricular pressure rise increasedin non-failing hearts from 1388 ± 86 to 1671 ±88 mmHg. s^–1 (P<0·01) and did not change infailing hearts. Ejection fraction decreased from 27 ± 3% to 19 ±2% in patients with dilated cardiomyopathy (P<0·05)when the pacing rate was changed from 84 ± 2 beats. min^–1to 140 beats. min^–1, which was associated with a significantlyincrease in end-systolic volume without significantly changesin end-diastolic volume. In patients with normal left ventricularfunction, when the pacing rate was changed from 85 ±3 beats. min^–1 to 140 beats. min^–1, end-diastolicvolume decreased significantly by 13%, whereas left ventricularend-systolic volume and ejection fraction did not significantlychange. Left ventricular systolic and end-diastolic pressuresdid not significantly change with pacing tachycardia in eithergroup. The frequency-related changes in left ventricular volumesand pressures indicate that the differrent haemodynamic effectsof pacing tachycardia in both groups of patients result predominantlyfrom frequency effects on myocardial function and not from frequencyeffects on preload or afterload. These data indicate that recentexperimental findings of positive force-frequency effects innon-failing and negative force-frequency effects in failinghuman myocardium are relevant for the intact heart.     

Clinical cardiac electrophysiologic evaluation of the positive inotropic agent, DPI 201-106

DPI 201–106 is a new positive inotropic agent. The cardiacelectrophysiology of 16 patients was studied before and duringDPI 201–106 administration (loading dose of intravenousDPI 201–106, 1·8 mg kg^–1 h^–1 administeredover 10 min, followed by a maintenance dose of 0·2 mgkg^–1 h^–1). DPI 201–106 had no effect on thesinus node. The AH interval during fixed-rate atrial pacingbecame prolonged during DPI 201–106 infusion. There wasa significant prolongation of the QT interval [QT (corrected),417 ± 22 to 502 ± 35 ms, P<0·05; QT(atrial pacing at 600 ms), 374 ±17 to 419 ± 23ms, P<0·05; QT (ventricular pacing at 600 ms), 409± 37 to 449 ± 30 ms, P<0·05]. The ventriculareffective refractory period significantly prolonged during DPI201–106 administration (242 ± 21 to 287 ±56 ms, P < 0·05), but the supernormal-period durationdecreased. The atrial effective refractory period was shortenedin four patients and prolonged in one (261 ± 67 to 240± 53 ms, NS). The corrected atrial repolarization time(PT_ac) shortened significantly during DPI 210–106 infusion(479 ± 26 to 445 ± 22 ms at 20 min of the maintenancedose, P<0·05). Atrial fibrillation was initiated infive patients during DPI infusion, but no ventricular arrhythmiawas provoked. These findings suggest that DPI 201–106has novel differential electrophysiological effects on atriaand ventricles.     

Factors of importance to Doppler indices of left ventricular filling in 50-year-old healthy subjects

Age is an important determinant of Doppler indices of left ventriculardiastolic filling in normal subjects. To define reference valuesand factors of importance to Doppler indices of left ventricularfilling in subjects of similar age, 58 men and 76 women aged50 years underwent Doppler echocardiography. All those takingpart in the study were healthy. When gender was analysed ina multivariate model it showed a significant independent correlationwith the peak velocity of early diastolic filling (E wave) (P<0·00l)and the early to atrial peak velocity (E/A) ratio (P<0·0l).The peak E wave velocity was 0·75±0·11m . s^–1 vs 0·66±0·10 m . s^–1(P<0·0O1) and the E/A ratio was 1·24±0·25vs 1·14±0·20 (P<0·05) in womenand men, respectively. In multivariate analyses, heart rate,diastolic blood pressure and body mass index correlated independentlywith the E/A ratio in women (P<0·00l for all), whereasin men, heart rate, diastolic blood pressure, body mass indexand left ventricular diameter correlated independently withthe E/A ratio (P<0·00l for all). Doppler measurementsof left ventricular filling in 50-year-old healthy subjectsshowed a wide variation and were significantly associated withheart rate, diastolic blood pressure, body mass index and gender.     

Effective pulmonary capillary pressure in experimental myocardial ischaemia

Effective pulmonary capillary pressure and extravascular lungwater were investigated in dogs (n=9) with normal heart functionand after development of acute myocardial ischaemia. Duringcontrol, no impairment of cardiopulmonary performance was observed.Extravascular lung water was in the normal range (8.1±2.8ml. kg^–1) and the effective pulmonary capillary pressureaccounted for 1.36 ± 0.53 kPa (10.2±4 mmHg). Nocorrelation between extravascular lung water and effective pulmonarycapillary pressure was observed (r²=0.347, P=0.06). Arterial(R_PA) and venous pulmonary resistance (R_PV) were 70±15% and 30±6%, respectively. Acute myocardial ischaemiawas induced by one stage occlusion of the left anterior descending(LAD) coronary artery; measurements during the ischaemia phasewere performed 60 min following LAD occlusion. Myocardial ischaemiaresulted in moderate changes of cardiac output, heart rate andleft ventricular end-diastolic pressure. Oxygenation deteriorated,but no hypoxaemia occurred in any animal and CO₂ eliminationremained unchanged. Extravascular lung water was elevated (16.5±7.9ml.kg^–1,P0.01), and effective pulmonary capillary pressure was higherwhen compared with the control state (2.32±1.05 kPa (17.4±7.9mmHg),P0.01). There was a significant correlation between both parameters(r²=0.528, P<0.05). Longitudinal distribution of pulmonaryvascular resistance was altered, and RPA decreased to 60±13%(P<0.05), while R_PV increased to 40±8% (P0.05). Itis concluded that development of lung oedema is related to elevatedeffective pulmonary capillary pressure in dogs with acute myocardialischaemia. This is partially a consequence of higher pulmonaryartery pressure, but also due to a vasoconstriction of the pulmonaryvenous compartment leading to a shift of the longitudinal distributionof pulmonary vascular resistance. In addition, release of vasoactivesubstances may induce leakage of the alveolocapillary membrane,favouring accumulation of extravascular lung water. The non-invasiveestimation of P_ceffcan be used for differentiation of factorspromoting lung oedema development in acute myocardial ischaemia.     

Alteration of peripheral vasodilatory reserve capacity after cardioversion of atrial fibrillation

In atrial fibrillation, exercise capacity is often reduced.This is usually ascribed to a decreased cardiac output as comparedwith sinus rhythm. Very few studies, however, have focused onchanges in the peripheral blood flow during atrial fibrillationas a potential mechanism for exercise limitation. The aim ofthe present study was to determine the effect of conversionof atrial fibrillation to sinus rhythm on peripheral blood flow. Calf blood flow, using an electrocardiogram-triggered venousocclusion plethysmograph, and peak oxygen consumption (peakVO₂), using treadmill exercise testing, were studied in 28 patientswith chronic atrial fibrillation eligible for electrical cardioversion.Measurements were performed before cardioversion, and repeated1 day and 1 month thereafter. Calf blood flow at rest, maximalcalf blood flow, and minimal calf vascular resistance duringthe hyperaemic response immediately following 700 J of calfexercise were determined plethysmographically. One day and 1 month after cardioversion, 23 and 14 patientswere still in sinus rhythm, respectively. In patients who stillhad sinus rhythm after 1 month, maximal calf blood flow increasedfrom 33·7±12 to 40·0±13 ml. 100ml ^{–1 min –1} (P<0.01) and minimal calf vascularresistance fell from 3·2±0·9 to 2·7±0·7mmHg.ml^–1. 100 ml^–1. min^–1 (P<0·01);peak VO₂ increased from 21·3±4 to 24·2±5ml. min^–1. kg^–1 (P<0·001). Calf bloodflow at rest did not improve. In contrast, no significant changesin maximal calf blood flow, minimal calf vascular resistanceand peak VO₂ occurred in patients who had atrial fibrillation1 month after cardioversion. A significant correlation was foundbetween changes in maximal calf blood flow and peak VO₂ 1 monthafter cardioversion (r=0·53, P<0·01). One dayafter cardioversion, no changes in calf blood flow or peak VO₂,were found, either in patients with sinus rhythm or atrial fibrillation. In conclusion, transition from chronic atrial fibrillation tosinus rhythm is associated with a (delayed) improvement in maximalcalf blood flow, minimal calf vascular resistance, and peakVO₂. Our findings suggest that increase in vasodilatory reserve capacitymay contribute to the improvement of exercise capacity aftercardioversion of atrial fibrillation.     

Physical responses to different modes of interval exercise in patients with chronic heart failure--application to exercise training

METHOD: In exercise training with chronic heart failure patients, workingmuscles should be stressed with high intensity stimuli withoutcausing cardiac overstraining. This is possible using intervalmethod exercise. In this study, three interval exercise modeswith different ratios of work/recovery phases (30/60 s, 15/60s and 10/60 s) and different work rates were compared duringcycle ergometer exercise in heart failure patients. Work ratefor the three interval modes was 50% (30/60 s), 70% (15/60 s)and 80% (10/60 s) of the maximum achieved during a steep ramptest (increments of 25 w/l0s) corresponding to 71, 98 and 111watts on average. Metabolic and cardiac responses to the threeinterval exercises were then examined including catecholaminelevels and perceived exertion. Parameters measured during intervalexercise were compared with an intensity level of 75% peak VO₂,determined during an ordinary ramp exercise test (incrementsof l2·5 W. min^–1). RESULTS: () (1) In all three interval modes, VO₂, ventilation and lactate did not increase significantlyduring the course of exercise. Mean values during the last workphase were between 754 ± 30 and 803 ± 46 ml. min^–1for VO₂, between 26 ± 3 and 28 ± 11. min^–1for ventilation and between 1·24 ±0·14and l·29 ± 0·10 mmol.1^–1 for lactate.(2) In mode 10/60 s, heart rate and systolic blood pressureincreased significantly (82 ± 485 ± 4 beats. min^–1;124 ± 5134 ± 5 mmHg; P<0·05 each), whilein mode 15/60 s catecholamines increased significantly (norepinephrine0·804 ± 0·0891·135 ± 0·094nmol. 1^–1; P<0·008; epinephrine 0·136± 0·012 0 193 ± 0·019 nmol. 1^–1;P<0·005). (3) In all three modes, rating of leg fatigueand dyspnoea increased significantly during exercise but remainedwithin the range of values considered ‘very light to fairlylight’ on the Borg scale. (4) Compared to an intensitylevel of 75% peak VO₂, work rate durrng interval work phaseswas between 143 and 221%, while cardiac stress (rate-pressureproduct) was significantly lower (83–88%). CONCLUSION: All three interval modes resulted in physical response in anacceptable range of values, and thus can be recommended.     

Effects of positive inotropic stimulation (post-extrasystolic potentiation) on non-uniformity of left ventricular contraction in patients with coronary artery disease

In patients with chronic coronary artery disease, post-extrasystolicpotentiation (PESP) slightly worsens relaxation, increasingthe constant of ventricular pressure decay. However, it doesnot negatively influence left ventricular (LV) diastolic filling.To our knowledge, no data are available on the effects of PESPon segmental relaxation in chronic coronary artery disease. The effects of PESP on the LV pressure–volume (P/V) relationshipand on segmental pressure–length loops (P/L) were studiedin eight patients with coronary artery disease submitted toLV angiography. P/V loops were constructed by means of frame-to-frame analysisof ventriculograms and simultaneous high-fidelity LV pressuretracings; P/L loops were calculated by the endocardial movementof 45 chords intersecting the LV outline (centreline method).PESP was produced by programmed stimulation during ventriculography.P/V and P/L loops were studied in basal conditions and afterPESP. Results showed enhanced LV pump function (ejection fractionfrom 0.45 ± 0.14 to 0.54 ± 0.13, P<0.01; LVstroke work index from 62±29 to 79±28 g. m^–1.m^–2,P<0.01; the LV end-systolic pressure–volume relationfrom 2.9±1 to 3.2±2 mmHg.ml^–1, P<0.05)associated with impaired relaxation (time constant _w, from 40±9to 48±8 ms, P<0.01; time constant _m from 53±11to 61±10 ms, P<0.05;peak filling rate from 3.7 ±1 to 2.3 ± 1 EDV.s^–1, P<0.01; minimal diastolicpressure from 6±6 to 7.5±6 mmHg, P<0.05) andwith increased preload (EDVI from 97±27 to 106±27ml.m^–2, P<0.01; LVEDP from 16 ± 9 to 19 ±7 mmHg, P<0.01). P/L loops showed increased non-unformityof LV relaxation after PESP. The effects were more evident inthe segments showing P/L loops inclined to the left, where PESPincreased or caused the appearance of post-systolic shortening.PESP showed only slight or no effect in the segments showingP/L loops inclined towards the right. PESP slightly impaired early left ventricular filling by decreasingthe rate of fall of intraventricular pressure and increasingthe non-unformity of contraction and relaxation. However, itdid not change the isovolumic phases of pressure–lengthloops of normal segments, while worsened relaxation of hypokinetic(probably ischaemic) segments with the appearance of post-systolicshortening in the loops inclined to the left.     

Coronary vasodilation without myocardial erection: Simultaneous haemodynamic, echocardiographic and arteriographic findings during adenosine and dipyridamole infusion

AIM: The aim of this study was to evaluate simultaneously echocardiographic,haemodynamic and angiographic changes that occur during adenosineand dipyridamole infusion, in patients with one-vessel coronaryartery stenosis. This would assess whether deterioration inleft ventricular haemodynamics during vasodilator agent infusionis influenced by vasodilation per se, or the development ofmyocardial ischaemia. METHODS AND RESULTS: We performed adenosine (140 µg.kg^–1.min^–1over 4 min) and dipyridamole (up to 0·84 mg.kg^–1over 10 min) stress echocardiography tests, together with angiographicand haemodynamic assessment, in 26 patients undergoing electivecoronary angioplasty. In 12 of 26 patients, adenosine and dipyridamoletests were repeated 24 h after angioplasty. The criterion forechocardiography test positivity was the appearance of a newtransient regional wall motion abnormality. Coronary angiogramswere analysed with quantitative coronary arteriography. Adenosineand dipyridamole induced regional dysfunction in 18/26 (69%)and 14/26 (54%) patients before angioplasty, respectively (P=ns).In the echocardiography-positive patients, the percent diameterstenosis was significantly (P<0·05) tighter stenosisthan in the echocardiography-negative patients (adenosine, 66·6±8·3%vs 58·0±8·9%; dipyridamole, 69·2±7·1%vs 57·±7·6%). During both tests, left ventricularend-diastolic pressure significantly increased (P<0·05)in echocardiography-positive patients (adenosine, 9·8±2·7mmHg to 13·5±4·1 mmHg; dipyridamole, 10·1±2·8mmHg to 14·1±4·3 mmHg), but not in echocardiography-negativepatients. In the patients who had undergone successful angioplasty(reduction to <50% diameter stenosis), both adenosine anddipyridamole confirmed the arteriographic success of the procedure(echocardiography negative in all patients). In this group ofpatients, no significant change was observed in left ventricularend-diastolic pressure during adenosine or dipyridamole infusion. CONCLUSIONS: Intravenous infusion of either adenosine or dipyridamole wasaccompanied by an obvious increase in left ventricular end-diastolicpressure only in patients with induced wall motion abnormalities.Coronary vasodilation per se has no significant effect on leftventricular end-diastolic pressure when no ischaemia is induced,disproving any clinically significant ‘erectile’and adverse effects of coronary vasodilation per se.     

Skeletal muscle lactate accumulation and creatine phosphate depletion during heavy exercise in congestive heart failure: Cause of limited exercise capacity?

OBJECTIVE: To study the mechanisms of limited exercise capacity and skeletalmuscle energy production in male patients with congestive heartfailure. DESIGN: Muscle biopsy study. PATIENTS: Skeletal muscle metabolic response to maximal bicycle exercisewas studied in 10 patients with chronic congestive heart failure(ejection fraction 0·22±0·05; peak oxygenconsumption, Vo₂ 15·1±4·9 ml. min^–1.kg^–1) and in nine healthy subjects (peak Vo₂ 33·5±6·7ml. min^–1. kg^–1). Activities of skeletal muscleenzymes were measured from the vastus lateralis muscle of 48patients (ejection fraction 0·24±0·06,peak Vo₂ 17·4±5·4 ml. min^–1. kg^–1)and 36 healthy subjects (peak Vo₂ 38·3±8·4ml. min^–1. kg^–1). RESULTS: Although blood lactate levels were lower in patients than inhealthy subjects (2·2±0·3 vs 5·2±0·6mmol. 1^–1; P<0·001) at peak exercise (96±11W for patients and 273±14 W for controls), skeletal musclelactate was similarly elevated (25·6±3·2vs 22·7±2·7 mmol.kg^–1) and creatinephosphate was equally depressed (P<0·02) to low levels(7·0±1·9 vs 6·7±0·9mmol.kg^–1). The muscle ATP decreased by 21% (P<0·05)and 8% (P<0·01) in the patients and controls, respectively.Activities of rate limiting enzymes of the citric acid cycle(alpha-ketoglutarate dehydrogenase) and oxidation of free fattyacids (carnitine palmitoyltransferase II) were 48% and 21% lowerthan in controls, but the mean phosphofructokinase activitywas unchanged in congestive heart failure. CONCLUSIONS: It seems that the main limiting factor of exercise performanceduring heavy exercise is the same in congestive heart failureand healthy subjects, a high rate of skeletal muscle lactateaccumulation and high-energy phosphate depletion. In congestiveheart failure, the low activity of aerobic enzymes is likelyto impair energy production and lead to lactate acidosis atlow workloads.     

Pattern of left ventricular filling in hypertrophic cardiomyopathy: Assessment by Doppler echocardiography and radionuclide angiography

Aims The left ventricle in hypertrophic cardiomyopathy is anatomicallyand functionally non-uniform. This study was undertaken to verifywhether a heterogeneity in the pattern of diastolic fillingcan be detected along the left ventricular inflow tract in hypertrophiccardiomyopathy. Methods and results Early (E) and late (A) diastolic velocitieswere recorded by Doppler echocardiography at mitral and at mid-ventricularlevel in 16 normal volunteers and 30 patients with hypertrophiccardiomyopathy. Patients with hypertrophic cardiomyopathy alsounderwent radionuclide angiography to assess left ventricularfunction. E wave decreased significantly in normal volunteers(80±15 to 60±14cm.s^–1;P<0·001),but it increased in hypertrophic cardiomyopathy (76±22to 87±28cm.s^–1;P=0·04), whereas the A wavedecreased similarly in both. By multivariate analysis, systolicasynchrony and the ejection fraction of left ventricular lateralwall were directly related to the pattern of early filling progression(r=0·656; F=9·467;P<0·002). Moreover,systolic asynchrony showed a univariate direct correlation withchanges in E velocity (r=0·42;P=0·02). Conclusion Many patients with hypertrophic cardio-myopathy havean acceleration of filling within the left ventricular inflowtract; this phenomenon is directly related to systolic asynchronyand ejection fraction of the left ventricular lateral wall,suggesting increased suction.     

Determinants of heart rate variability in heart transplanted subjects during physical exercise

Respiratory sinus arrhythmia has been described in heart transplantedsubjects. In order to investigate the mecha nisms involved inthe generation of this condition in the transplanted heart andits evolution after surgery, graded exercise was performed (0–75W in 25 W steps) on a cycle ergometer by 41 subjects (mean age44 years) who had undergone heart transplantation 28 months(range 3–60) earlier and by six age matched-control subjects.R-R interval, respiratory signal, O₂ consumption (VO₂ and CO₂production (VCO were measured. Respiratory sinus arrhythmiawas assessed by the autoregressive power spectrum of the R-Rinterval and respiration. All subjects reached the anaerobicthreshold (heart transplants: 60% at 50 W, 40% at 75W Controls:150 W). In control subjects, the respiratory sinus arrhythmiawas higher than in heart transplanted subjects (5·80± 0·30 vs 1·45 ± 0·16 lnms²) and it decreased significantly (4·66 ± 0·30In ms² P<0·05) during exercise, despite the increasein breathing rate and depth. When the group of heart transplantedsubjects was considered as a whole, respiratory sinus arrhythmiawas found to be present in all conditions. It significantlyincreased at 25 W (from 1·45 ± 0·16 to2·00 ± 0·17 In ms² P<0·01), thensignificantly fell below baseline during recovery (to 0·97± 0·23 In ms P<0·01). Multiple regressionanalysis showed that a linear combination of heart rate (inversecorrelation) and VO² (direct correlation) together with monthshaving passed since transplantation surgery, could explain theobserved changes in heart rate during exercise (multiple regression:r=0·658, P<0·0001). In five long-term transplantedsubjects, non respiratory-related low frequency (0·1Hz) waves were present on the R-R spectrum, but respiratorysinus arrhythmia is also present in the recently transplantedheart and depends on the opposing effects of ventilation andheart rate. In a few cases, sympathetic modulation (re-innervation)could not be excluded. (Eur Heart J 1996; 17: 462–471)     

Does dobutamine prevent the rise in left ventricular filling pressures observed during exercise after heart transplantation?

The purpose of the study was to evaluate whether infusion ofa beta-adrenergic agonist, prior to and during exercise, couldcompensate for reduced sympathetic stimulation and correct deficientacceleration of left ventricular relaxation, so preventing arise in left ventricular filling pressures during exercise aftercardiac transplantation. Abnormal left ventricular relaxationkinetics can contribute to exercise-induced diastolic dysfunctionof the cardiac allograft. This was demonstrated in transplantrecipients whose acceleration of left ventricular relaxationduring exercise was almost negligible recently and whose elevationof left ventricular end-diastolic pressure was high. Decreasedadrenergic tone due to denervation could be involved in deficientleft ventricular lusitropic response to exercise, because accelerationof left ventricular relaxation during exercise depends on adequatesympathetic stimulation. Serial supine bicycle exercise was performed at an identicalworkload in eight transplant recipients while in the controlstate and during continuous infusion of dobutamine, titratedbefore exercise to achieve a heart rate matching the heart rateat peak exercise in the control state. During control exercise,heart rate rose from 87 ± 8 to 104 ± 12 beats.min^–1 (P<0.05), left ventricular end-diastolic pressurefrom 14 ± 5 to 20 ± 4 mmHg (P<0.05), left ventriculardP/dt_max from 1374 ± 172 to 1854 ± 278 mmHg. s^–1(P<0.05), and cardiac output from 5.8 ± 0.9 to 8.5± 1.11. min^–1 P<0.05). There was a small butsignificant decrease of the time constant of left ventricularpressure decay (T) from 42 ± 6 to 38 ± 6 ms (P<0.05).During dobutamine infusion, exercise resulted in a further increasein heart rate from 108± 11 to 122 ± 17 mmHg (P<0.05),in cardiac output from 7.4 ± 0.9 to 10.3 ± 2.5l. min^–1 (P<0.05), and in left ventricular dP/dt_maxfrom2181 ± 220 to 2620 ± 214 mmHg. s^–1 (P<0.05).These values were higher than the measurements obtained at theend of the control exercise run (P<0.05). T failed to change(29 ± 4 vs 27 ± 5 mmHg, P>0.05) and left ventricularend-diastolic pressure increased from 5 ± 3 to 11 ±5 mmHg (P<0.05) but remained lower than at the end of thecontrol exercise run (11 ± 5 vs 20 ± 4 mmHg, P<0.05). Compensation for reduced sympathetic stimulation by administrationof dobutamine improves exercise haemodynamics in cardiac transplantrecipients, but cannot prevent the exercise-induced rise inleft ventricular end-diastolic pressure and correct deficientacceleration of left ventricular relaxation. Abnormal exercisehaemodynamics after heart transplantation are therefore onlypartly related to deficient sympathetic stimulation.     

Coronary vasodilator reserve in primary and secondary left ventricular hypertrophy: A study with positron emission tomography

Objectives Coronary vasodilator reserve is reduced in hypertrophiccardiomyopathy and secondary left ventricular hypertrophy despiteangiographically normal coronaries. The aim of the present studywas to assess whether quantitative differences exist betweenthese conditions. Methods Using positron emission tomography with H₂¹⁵O, myocardialblood flow was measured at baseline and following intravenousdipyridamole (0·56 mg. kg ^–1) in 12 hypertrophiccardiomyopathy patients (age 34 (11) years, mean (SD), all male),16 secondary left ventricular hypertrophy patients (age 58 (20)years, P<0·01 vs hypertrophic cardiomyopathy; 10 female)and 40 normal controls (age 54 (20), 13 female). In view ofthe known decline of post-dipyridamole myocardial blood flowwith age, myocardial blood flow was compared between the patientgroups and appropriately matched subsets of the total controlgroup. Results Baseline myocardial blood flow in the hypertrophic cardiomyopathypatients was 0·82 (0·23) ml. min^–1 . g^–1vs 0·94 (0·14) ml. min^–1 . g^–1 inits matched control group, P=ns. For the secondary left ventricularhypertrophy patient group, baseline myocardial blood flow was1·17 (0·40) ml . min^–1 . g^–1 vs 1·06(0·28) ml . min^–1 . g^–1 for the secondaryleft ventricular hypertrophy matched control group, P=ns. Followingdipyridamole, myocardial blood flow was 1·64 (0·44)ml . min^–1 . g^–1 in hypertrophic cardiomyopathypatients vs 3·50 (0·95) ml . min^–1 . g^–1forthe hypertrophic cardiomyopathy matched control group, P=0·0001.For the left ventricular hypertrophy patients, post-dipyridamolemyocardial blood flow was 2·27 (0·60)ml . min^–1. g^–1 vs 2·94(1·29) ml . min^–1 . g^–1for the left ventricular hypertrophy controls, P 0·06.Coronary vasodilator reserve (dipyridamole-myocardial bloodflow/baseline-myocardial blood flow) was 2·05 (0·61)for hypertrophic cardiomyopathy patients vs 3·81 (0·98)for the hypertrophic cardiomyopathy controls (P=0 0001, patientsvs controls) and 2·06 (0·62) for left ventricularhypertrophy patients vs 2·90 (1·38) for the leftventricular hypertrophy controls, P<0·03 patientsvs controls. After correction of baseline myocardial blood flowfor baseline heart rate x systolic pressure product, coronaryvasodilator reserve for the hypertrophic cardiomyopathy patientswas 2·06 (1·06) vs 4·34 (1·54) forthe hypertrophic cardiomyopathy controls, P=0·0002 andin the secondary left ventricular hypertrophy patients, thevalues were 2·13 (0·64) vs 2·89 (1·42)in the secondary left ventricular hypertrophy controls, P<0·05. Conclusions In both hypertrophic cardiomyopathy and secondaryleft ventricular hypertrophy, the computed coronary vasodilatorreserve is impaired, even after correction for baseline cardiacwork. However, the extent of the reduction is greater in thehypertrophic cardiomyopathy patients. In the blunting of vasodilatorreserve of secondary left ventricular hypertrophy, the patients'greater hyperaemic response is partly offset by the higher baselinemyocardial blood flow.     

Effects of percutaneous balloon mitral valvuloplasty and exercise training on the kinetics of recovery oxygen consumption after exercise in patients with mitral stenosis

Aims Kinetics of recovery oxygen consumption after exercise playsan important role in determining exer-cise capacity. This studywas performed to assess the kinetics of recovery oxygen consumptionin mitral stenosis and evaluate the effects of percutaneousballoon mitral valvuloplasty and exercise training on the kinetics. Methods and Results Thirty patients with mitral stenosis (valve area 1·0cm²)and same sized age- and size-matched healthy volunteers wereincluded for this study. All subjects performed maximal uprightgraded bicycle exercise. Thirty consecutive patients who underwentsuccessful percutaneous balloon mitral valvuloplasty (valvearea 1·5cm²and mitral regurgitation grade 2), were randomizedto an exercise training group or non-training group. The exercisegroup performed daily exercise training for 3 months. Half-recoverytime of peak oxygen consumption was significantly delayed inmitral stenosis as compared to normal subjects (120±42svs 59±5,P<0·01). Peak oxygen consumption (ml.min^–1.kg^–1)was significantly increased in both the training (16·8±4·9to 25·3±6·9) and non-training groups (16·3±5·1to 19·6±6·0) 3 months after percutaneousballoon mitral valvuloplasty. Half-recovery time of peak oxygenconsumption was significantly shortened in the training group(124±39 to 76±13,P<0·01), but not inthe non-training group (114±46 to 109±44s,P=0·12)at 3 months follow-up. The degrees of symptomatic improvementafter percutaneous balloon mitral valvuloplasty were more closelycorrelated with the changes of the half-recovery time of peakoxygen consumption than those of peak oxygen consumption. Conclusion Kinetics of recovery oxygen consumption was markedly delayedin mitral stenosis, which was improved after exercise trainingbut not after percutaneous balloon mitral valvuloplasty alone.These results suggest that adjunctive exercise training maybe useful for improvement of recovery kinetics and subjectivesymptoms after percutaneous balloon mitral valvuloplasty.     

Impact of dietary sodium intake on left ventricular diastolic filling in early essential hypertension

Aims Dietary sodium intake modulates left ventricular hypertrophyin established essential hypertension independent of blood pressurelevel. We conducted this study to elucidate the relationshipbetween sodium intake and left ventricular structural or functionalchanges in early essential hypertension. Methods Forty-four young male patients (age 25·9±2·6years) with mild essential hypertension that had never beentreated and 45 normotensive male control subjects of similarage were examined. Dietary sodium intake was measured from 24hurinary sodium excretion, blood pressure from 24h ambulatorymonitoring (SpaceLabs 90207), left ventricular structure from2-D guided M-mode echocardiography, and diastolic filling ofthe left ventricle (as the main compound of diastolic functionin a young population) by pulse-wave Doppler sonography. Results In hypertensive patients, daily sodium excretion correlatedwith the ratio of late (A) to early (E) maximum velocity (VmaxA/E; r=+0·27,P=0·07), velocity time integrals(A/E; r=+0·54,P<0·001) as well as atrial contribution,as a percent of left ventricular filling (VH ATCO; r=+0·52,P<0·001)independent of heart rate, whereas the opposite correlationswere observed in normotensives (allP<0·001). Stepwisemultiple regression analysis confirmed these results. Sodiumexcretion emerged as the strongest independent determinant ofimpaired diastolic filling in hypertensive patients (velocitytime integrals A/E: R²=0·49, ß=+0·57,P=0·0001;VH ATCO: R²=0·48, ß=+0·56,P<0·0001;Vmax A/E: ns). In normotensive subjects, sodium excretion wasa similar strong, but inverse deter-minant of diastolic filling(velocity time integrals A/E: R²=0·40, ß=–0·43,P=0·0028).Heart rate was a strong determinant of diastolic filling inhypertensive patients (ß=+0·55,P=0·0002)and in normotensive subjects (ß=+0·34,P=0·011).Left ventricular mass and end-diastolic volume index were notrelated to diastolic filling in either group. Conclusion In early essential hypertension, sodium excretion is correlatedwith impaired left ventricular diastolic filling independentof left ventricular mass. The renin-angiotensin-aldosteronesystem might be a mediator of the observed correlation.     

Age-related transmural peak mean velocities and peak velocity gradients by Doppler myocardial imaging in normal subjects

Doppler myocardial imaging is a new cardiac ultrasound techniquebased on the principles of colour Doppler imaging which candetermine myocardial velocities by detecting the changes ofphase-shift of the ultrasound signal returning directly fromthe myocardium. To determine the normal range of transmuralvelocities in healthy hearts a prospective study was carriedout involving 42 normal subjects (age from 21 to 78, mean 47±16years). Using M-mode Doppler myocardial imaging the peak valuesof the mean velocity and velocity gradient across the left ventricularposterior wall were measured during standardized phases of thecardiac cycle. Peak mean velocities had the following valuesduring the cardiac cycle: isovolumic contraction –1·3±1·2cm.s^–1, early ventricular ejection 4·2±1·2cm.s^–1, late ventricular ejection 1·8±1·1cm.s^–1, isovolumic relaxation –2·0±0·8cm.s^–1, rapid ventricular filling –6·6±2·2cm.s^–1, atrial contraction –2·8±1·8cm.s^–1, atrial relaxation 1·2±1·1cm.s^–1. Peak velocity gradients were: isovolumic contraction1·3±1·9 s^–1, early ventricular contraction4·7±1·9s^–1, late ventricular contraction1·1 ±1·0 s^–1, isovolumic relaxation–0·6±0·5 s^–1, rapid ventricularfilling 6·1±3·4 s^–1, atrial contraction2·6±1·7 s^–1, atrial relaxation 0·0±0·3s^–1. Linear regression analysis showed that with the increaseof age, peak velocity gradient decreases during rapid ventricularfilling (r=0·83; P<0·0001) and increases duringatrial contraction (r=0·86; P<0·0001) whilepeak mean velocity increases only during atrial contraction(r=0·80, P<0·0001). Thus, there was no correlationbetween increasing age and systolic peak mean velocity and peakvelocity gradient but both diastolic filling phases rapid ventricularfilling and atrial contraction demonstrated age-related changes. In summary, this study has determined the age-related rangeof normal transmural myocardial velocities within the left ventricularposterior wall in healthy hearts during the cardiac cycle. Weconclude that these measurements of peak mean velocities andpeak velocity gradients, should form the baseline for subsequentDoppler myocardial imaging clinical studies on myocardial diseasesprocesses.     

Beneficial effect of enalapril on left ventricular remodelling in patients with a severe residual stenosis after acute anterior wall infarction

OBJECTIVE: The present study was designed to evaluate the effects of earlyangiotensin converting enzyme (ACE) inhibition on left ventricularenlargement in patients with anterior wall infarction followingreperfusion therapy. METHODS: Seventy-one consecutive patients with an anterior wall myocardialinfarction were randomly allocated to enalapril (n=36) or placebo(n=35). All patients received either thrombolytic therapy (n=46)or underwent primary coronary angioplasty (n=25). Medicationwas started within 48 h admission to hospital and continuedfor 48 weeks. The process of left ventricular remodelling wasassessed with two-dimensional echocardiography at 3 weeks and1 year after the acute onset, and was related to the severityof the residual stenosis of the infarct-related artery. RESULTS: Baseline left ventricular ejection fraction was 39·2±8·7%.During the study period, left ventricular end-diastolic volumeindex increased from 48·2±9·9 ml. m^–2to 54·6±12·2 ml. m^–2 at 3 weeks,and to 59·4±170 ml. m^–2 after 1 year incontrol patients (P<0·001). In the enalapril-treatedpatients, left ventricular end-diastolic volume index increasedfrom 50·0±16·1 to 57·7±19·3ml. m^–2 at 3 weeks, and to 61·9±22·7ml. m^–2 after 1 year (P<0·001). Both at 3 weeksand after 1 year, no overall differences in left ventricularvolumes were observed between the enalapril and the placebogroup (both ns). However, patients with a residual stenosisseverity of 70% in the infarct-related artery (n=43) showedsignificant attenuation of remodelling by enalapril (n=22) whencompared to placebo (n=21). In patients on enalapril, left ventricularend-diastolic volume index increased from 470±130 to53·7±17·7 ml. m^–2 compared to 48·0±9·6to 60·3±16·3 ml . m^–2 in controlpatients (P<0·03). Also diastolic filling parameterswere significantly improved in patients with 70% residual stenosis. CONCLUSION: In patients with an anterior wall infarction and a severe residualinfarct-related coronary artery stenosis following reperfusion,treatment with enalapril prevents the process of left ventricularremodelling. As left ventricular dilatation is an early processwe suggest that treatment with ACE inhibition should be startedas soon as possible in this group of patients.     

The electrophysiological effects of flosequinan

We have evaluated the acute electrophysiological effects offlosequinan in 18 patients with normal ventricular function.Following intravenous infusion of flosequinan 100 mg over 1h, mean (SD) systolic blood pressure fell from 131 ±19 to 120±22mmHg (P<0·02) and there was significantshortening of sinus cycle length (732±151 to 575±93ms, P<0·001), AH interval (110±45 to 71±19ms, P<0·01) QRS duration (98±28 to 91±26ms, P<0·02) and QT interval (373±47 to 337±35ms, P<0·001 but no change in sinus node recovery time,intra-atrial conduction time, HV interval or the corrected QT_cinterval. There was a reduction in both anterograde atrioventricularWenckebach cycle length (299±53 to 259 ±52 ms,P<0·01) and retrograde ventriculoatrial Wenckebachcycle length (375 ± 77 to 300 ± 56 ms, P<0·01).There was no change in atrial or ventricular effective refractoryperiod (ERP) but atrial functional refractory period (FRP) shortened(233 ± 31 to 212 ± 24 ms, P=007) as did ventricularFRP (249 ± 24 to 234 ± 21 ms, P<0·01).Patients received an oral dose of flosequinan 50 mg 12 h later.By 24 h, sinus cycle length, QRS duration and the QT intervalhad all returned towards baseline values, but ventricular ERPhad lengthened (199±22 to 215±26 ms, P<0·06).Programmed ventricular stimulation did not result in any sustainedarrhythmias before or after flosequinan. The observed electrophysiologicaleffects of flosequinan infusion are consistent with reflex sympatheticactivation. There was no conclusive evidence for any directelectrophysiological effect or for contraction-excitation feedback.No proarrhythmic effects were observed.     

The electrophysiological effects of flosequinan

We have evaluated the acute electrophysiological effects offlosequinan in 18 patients with normal ventricular function.Following intravenous infusion of flosequinan 100 mg over 1h, mean (SD) systolic blood pressure fell from 131 ±19 to 120±22mmHg (P<0·02) and there was significantshortening of sinus cycle length (732±151 to 575±93ms, P<0·001), AH interval (110±45 to 71±19ms, P<0·01) QRS duration (98±28 to 91±26ms, P<0·02) and QT interval (373±47 to 337±35ms, P<0·001 but no change in sinus node recovery time,intra-atrial conduction time, HV interval or the corrected QT_cinterval. There was a reduction in both anterograde atrioventricularWenckebach cycle length (299±53 to 259 ±52 ms,P<0·01) and retrograde ventriculoatrial Wenckebachcycle length (375 ± 77 to 300 ± 56 ms, P<0·01).There was no change in atrial or ventricular effective refractoryperiod (ERP) but atrial functional refractory period (FRP) shortened(233 ± 31 to 212 ± 24 ms, P=007) as did ventricularFRP (249 ± 24 to 234 ± 21 ms, P<0·01).Patients received an oral dose of flosequinan 50 mg 12 h later.By 24 h, sinus cycle length, QRS duration and the QT intervalhad all returned towards baseline values, but ventricular ERPhad lengthened (199±22 to 215±26 ms, P<0·06).Programmed ventricular stimulation did not result in any sustainedarrhythmias before or after flosequinan. The observed electrophysiologicaleffects of flosequinan infusion are consistent with reflex sympatheticactivation. There was no conclusive evidence for any directelectrophysiological effect or for contraction-excitation feedback.No proarrhythmic effects were observed.     

Influence of haemodynamics and myocardial ischaemia on Doppler transmitral flow in patients undergoing dobutamine echocardiography

To examine whether pulsed Doppler left ventricular filling indicescan reliably detect myocardial ischaemia in patients with coronaryartery disease undergoing dobutamine stress echocardiographywe studied three groups matched for age and global indices ofleft ventricular function. Group 1 patients (n=10) had normalcoronary arteries whereas those in Groups 2 (n=12) and 3 (n=15)had significant coronary disease (70% diameter stenosis) atangiography. After stopping cardiouctive treatment, patientsunderwent incremental dobutamine stress (5, 10, 15 and 20 µg.kg^–1. min^–1) during pulsed Doppler interrogationof diastolic filling with simultaneous heart rate and bloodpressure measurements. Only Group 3 patients developed myocardialischaemia using electrocardiographic and cross sectional echocardiographiccriteria, subset 3A (n=4) comprised those with inducible mitralregurgitation on colour Doppler. Electrocardiographic R-R intervaldecreased (–311 ± 123 ms, P<0·001) andmean blood pressure altered (5±17 mmHg, P=ns) uniformlyacross groups. The respective changes in peak early velocity,peak atrial velocity and their ratio for Groups 1 (0·08± 0·09 m. s^–1, 0·26 ± 0·18m.s^–1 and – 0·32 ± 0·36), 2(0·07 ± 0·07 m.s^–1 0·18±0·15m.s^–1 and –0·13±0·21) and 3(0·09±0·12 m.s^–1, 0·20±0·13m.s^–1 and –0·17±0·21) weresimilar (all P=ns between groups). Corresponding data for subset3A (0·23 ± 0·04 m.s^–1 0·20± 0·10 m.s^–1and 0·00 ± 0·16)revealed a significantly greater increase in peak early velocityand normalized velocity ratio in these patients. Overall, changesin peak early (r= –0·47, P<0·01) andatrial velocity (r–0·65, P<0·001) andtheir ratio (r=0·35, P<0·05) correlated withreduction in R-R interval but not alterations in blood pressure.In conclusion, tachycardia during dobutamine stress masks theeffects of myocardial ischaemia on Doppler diastolic indicesalthough a minority of patients with inducible mitral regurgitationmanifest a relatively distinct filling profile.