Author + information
- Received August 31, 2004
- Revision received March 17, 2005
- Accepted April 19, 2005
- Published online September 6, 2005.
- Rajesh Thaman, MD, MRCP⁎,†,⁎ (, )
- Perry M. Elliott, MD, MRCP, FACC⁎,†,
- Jaymin S. Shah, MD, MRCP⁎,†,
- Bryan Mist, PhD⁎,†,
- Lynne Williams, MRCP‡,
- Ross T. Murphy, MD, MRCP⁎,†,
- William J. McKenna, MD, FRCP, FACC⁎,† and
- Michael P. Frenneaux, MD, FRCP, FACC‡
- ↵⁎Reprint requests and correspondence:
Dr. Rajesh Thaman, The Heart Hospital, Cardiology, 16-18 Westmoreland Street, London, W1G 8PH, United Kingdom.
Objectives We assessed the frequency of abnormal forearm vasodilator responses during lower body negative pressure (LBNP) in 21 non-obstructive hypertrophic cardiomyopathy (HCM) patients (31 ± 8 [20 to 43] years) with abnormal blood pressure response (ABPR) to exercise and the effects of three drugs used to treat vasovagal syncope (propranolol, clonidine, and paroxetine) in a double-blind crossover study.
Background Some HCM patients have an ABPR to exercise, which may be due to paradoxical peripheral vasodilatation. A similar proportion has paradoxical forearm vasodilatation during central volume unloading using LBNP. These abnormal reflexes may be caused by left ventricular mechanoreceptor activation. Similar mechanisms may also contribute to some cases of vasovagal syncope.
Methods Blood pressure changes were assessed during exercise, and forearm vascular responses and baroreceptor sensitivity were assessed during LBNP using plethysmography.
Results Nine (43%) patients (group A) had paradoxical vasodilator responses (forearm vascular resistance [FVR] fell by 7.5 ± 4.6 U), and 12 (57%) patients (group B) had normal vasoconstrictor responses during LBNP (FVR increased by 7.7 ± 4.9 U). Paroxetine augmented systolic blood pressure (SBP) during exercise in group A (21 ± 6 mm Hg vs. 14 ± 11 mm Hg at baseline, p = 0.02); no effect was detected in group B. Paroxetine reversed paradoxical vascular responses during LBNP in seven (78%) patients from group A. Propranolol and clonidine had no significant effect on SBP during exercise but reversed paradoxical vascular responses in some patients from group A (n = 5 and n = 3).
Conclusions Paradoxical vasodilatation during LBNP occurs in 40% of patients with ABPR during exercise and is reversed by propranolol, clonidine, and paroxetine. Paroxetine also improved SBP response to exercise.
Hypertrophic cardiomyopathy (HCM) is an inherited heart muscle disease characterized by unexplained left ventricular (LV) hypertrophy (1). Approximately one-third of patients with HCM exhibit an abnormal blood pressure response (ABPR) during erect exercise (either a blunted increase in systolic blood pressure [SBP] or, less commonly, a fall in blood pressure) (2–4). This is associated with an increased risk of sudden cardiac death, particularly if other risk factors are present (3–8); ABPR may therefore be a potential therapeutic target for interventions aimed at reducing the risk of sudden cardiac death. We reported that ABPR was not primarily due to an impaired cardiac output response in the majority of patients, but was due to an exaggerated fall in systemic vascular resistance (SVR) (2,3). In health, SVR falls between two- to three-fold during maximal erect treadmill exercise, a balance between vasodilatation in exercising vascular beds and vasoconstriction in non-exercising vascular beds. In patients with ABPR, the overall fall in SVR was more marked, and there was paradoxical vasodilatation in non-exercising vascular beds. Furthermore, approximately one-third of patients with HCM manifest a paradoxical forearm vasodilator response during central blood volume unloading (achieved by applying lower body negative pressure [LBNP]) (9,11–13). We have previously proposed that the abnormal vascular responses during exercise and during LBNP in patients with HCM might both be due to activation of stretch-sensitive LV mechanoreceptors, perhaps due to abnormal local wall strains (9). These receptors relay to the brainstem via non-myelinated vagal afferents, and their firing tends to reduce sympathetic efferent and increase vagal efferent activity from the brain stem (13,14–16).
Vasovagal syncope is a common syndrome characterized by hypotension with or without bradycardia after certain provocations including orthostatic stress. In patients with vasovagal syncope, abnormal (vasodilator) responses to LBNP and exercise are also commonly observed. Rarely patients with vasovagal syncope may also develop hypotension during exercise (17–20). It is proposed that activation of LV mechanoreceptors (stretch receptors) may be one of the underlying triggers (although not necessarily the sole one) for vasovagal syncope (17,18,21). Recent trials have shown that pharmacological treatment with beta-blockers, clonidine, or paroxetine may be effective in reducing syncope frequency in patients with vasovagal syncope (22–28).
Based on the potential similarity of pathophysiological mechanisms between abnormal vascular control in vasovagal syncope and in HCM, we hypothesized that the same pharmacological agents used to treat vasovagal syncope (beta-blockers, clonidine, paroxetine) might attenuate ABPR and correct abnormal vascular responses during application of LBNP in patients with HCM. We undertook a placebo-controlled double-blind rotational study of these agents on HCM patients with documented ABPR, examining the effects on exercise blood pressure response and on the forearm vascular response to application of LBNP.
The final study population comprised 21 (age 31 ± 8 years, range 20 to 43 years, 9 men, 12 women) consecutive HCM patients seen at the St. Georges Hospital Cardiomyopathy Clinic. These patients were entered into a double-blind crossover study design protocol. All patients demonstrated ABPR during a standard erect cycle exercise test and met the entry criteria. All fulfilled World Health Organization criteria for HCM (1). Patients with hypertension, other cardiac or systemic diseases that could produce hypertrophy, primary valvular heart disease, atrial fibrillation, history of hepatic or renal disease, significant LV outflow tract gradient (≥30 mm Hg), or contraindications to drug therapy used in this study were excluded. All patients with significant chest pain or exertional dyspnea underwent coronary arteriography, and four patients who were found to have obstructive coronary artery disease defined as 50% stenosis in one or more coronary arteries were excluded. All cardioactive medications were withdrawn for at least five half-lives before evaluation and for the duration of the study.
Initial clinical evaluation included history, examination, 12-lead electrocardiogram, two-dimensional and M-mode echocardiography, 48-h Holter, and symptom-limited cardiopulmonary exercise testing on an erect cycle with measurement of blood pressure response; ABPR was defined as either a failure of SBP to rise by at least 25 mm Hg or a fall in SBP from the peak value during exercise of at least 10 mm Hg (7,29).
After baseline evaluation, patients entered a rotational drug study during which they were given in random order: propanolol, paroxetine, clonidine, or placebo for three weeks, each with a washout period of three weeks in between each phase during which time patients received placebo. All trial medication and placebo were placed in capsules, and one capsule was taken three times a day (Table 1).Both investigator and patient were blinded to the type of therapy.
At the end of each three-week period, the effect of treatment was assessed by cardiopulmonary exercise testing with measurement of blood pressure response. Forearm vascular resistance (FVR), forearm blood flow (FBF), and baroreceptor sensitivity (BRS) were assessed before and during application of LBNP.
The study protocol was approved by the hospital local research ethics committee, and all patients gave written informed consent before participating.
Cardiopulmonary exercise testing
All 21 patients underwent maximal cardiopulmonary exercise testing on a bicycle ergometer (Sensormedics Ergometrics 800S) using an incremental ramp protocol of 10 to 15 W/min with respiratory gas sampling (V Max 29 Console, Sensormedics), 12-lead electrocardiogram, and measurement of blood pressure during exercise. Patients cycled at a rate of 60 to 70 revolutions per min to the point of symptom limitation; blood pressure was recorded at 2-min intervals during exercise and for 10 min into recovery by a cuff sphygmomanometer. Peak oxygen consumption (peak Vo2) was defined as the highest Vo2achieved during exercise. Results were expressed as a percentage of the predicted maximal Vo2(%Vo2max) to allow for age, gender, and body size.
Assessment of forearm vascular responses during application of LBNP
Patients were studied in a quiet environment at a constant room temperature of between 22°C and 24°C. Patients were asked to lie supine in a specially constructed lower body suction bed encased from below the iliac crests in an airtight seal. A small transducer measured the pressure within the device. Heart rate and blood pressure changes were recorded using the Finapres (Ohmeda 2300, Anglewood) apparatus. This consists of a front-end box worn on the wrist with two finger cuffs and a waist belt. The cuffs were placed on the ring and middle fingers and inflated alternately in order to avoid prolonged cuff inflation in a single finger. The waist belt houses a battery and microcomputer, which stores beat-to-beat pressure data including systolic, diastolic, and mean arterial pressures and pulse rate. The software identifies height of systolic upstroke, time of upstroke, mean arterial pressure, and arterial end-diastolic pressure for each heart beat. Data from the Finapress were used to calculate BRS using the validated sequence analysis of beat-to-beat interaction of SBP with R-R interval as described by Blaber et al. (30). Baroreceptor sensitivity was calculated before application of LBNP and 2 min after commencing application of LBNP.
Forearm blood flow was assessed before and during application of 20 mm Hg LBNP using mercury in silastic strain gauge plethysmography (Hokanson). A strain gauge was placed around the left forearm approximately 5 cm below the antecubital crease. A cuff was placed around the upper forearm. Circulation to the hand was occluded by inflating another small cuff placed around the wrist to suprasystolic pressures. Measurements of FBF were obtained by inflating the forearm cuff to 40 mm Hg to prevent venous return. The rate of increase of forearm girth is then proportional to FBF. The cuff was inflated to 40 mm Hg for 10 s and deflated for 10 s. This was repeated three times, and the forearm flow was calculated from the mean of three slopes. Forearm vascular resistance was calculated as the quotient of the mean arterial pressure (mm Hg) and FBF (ml/min/per 100 ml) and expressed in resistance units. Patients were divided into those in whom FVR fell during LBNP (group A) versus those in whom it increased (group B). According to the prespecified study design, analysis of the effects of therapy was performed separately in these two groups of patients. All physiological variables recorded were acquired and stored using Powerlab, Chart for Windows software, on a Dell Inspiron 5000e computer and measurements were analyzed off-line.
Statistical analysis was performed using SPSS (version 10.0) statistical software (SPSS Inc., Chicago, Illinois). All data are presented as mean ± SD unless otherwise stated. A paired sample ttest was used to assess treatment effects for each individual treatment arm, as a difference from baseline values (31). The chi-square test was used to compare frequencies of dichotomous variables. Analysis of covariance (ANCOVA) was used to examine the influence of baseline changes in FVR and FBF on drug effect. All analyses were performed on a per-protocol basis. A p value of <0.05 was regarded as significant.
The baseline demographic, clinical, and echocardiographic characteristics of the 21 patients studied are summarized in Table 2.No patients had a history of previous cardiac arrest or ventricular fibrillation. Three patients had an implantable cardioverter-defibrillator for prevention of sudden cardiac death, but no discharges had been recorded. Eight of the patients entered into the study had undergone coronary angiography and were found to have no significant epicardial coronary artery stenosis.
All patients performed an adequate exercise test (respiratory exchange ratio >1.0), the mean exercise duration being 8.03 ± 1.45 min. Exercise was terminated because of fatigue in 67%, breathlessness in 29%, and chest discomfort in 5%. The mean %Vo2max achieved was 78% ± 19%. A reduction in SBP of 10 mm Hg from baseline at the start of exercise was seen in 5% of patients, and the other 95% had a flat blood pressure response (i.e., <25 mm Hg increase). No patients became syncopal or had a significant arrhythmia during exercise.
FVR during application of LBNP
Nine patients (43%) had an abnormal vasodilator response to LBNP (group A). In these patients, FVR fell by 7.5 ± 4.6 U associated with an increase in FBF of 0.56 ± 0.37 ml/min−1. The remaining 12 patients (57%) had a normal vasoconstrictor response to LBNP (group B). In these patients FVR increased by 7.7 ± 4.9 U associated by a fall in FBF of 0.8 ± 0.6 ml/min−1.
Baseline characteristics of patients from groups A and B
Table 3shows the baseline clinical characteristics of patients in groups A and B. Patients in group A had a higher prevalence of syncope (66% vs. 25%), a smaller LV end-systole diameter (21.7 mm vs. 27.4 mm), and greater percentage of fractional shortening (46.6% vs. 39.7%) than patients in group B. There were no other significant differences in clinical or echocardiographic characteristics, including severity of outflow tract obstruction. Resting FVR and FBF, resting SBP, and the increment in SBP during exercise were similar in the two groups.
The effect of medications
The effect of medications on exercise variables and forearm vascular reflexes during application of LBNP are shown in Tables 4 and 5⇓⇓and Figures 1 and 2,⇓⇓respectively. There were no carryover effects noted at the end of each washout period.
Compared to baseline, placebo therapy was not associated with any significant changes in exercise duration, percentage of Vo2, resting SBP, or in the increment in SBP during exercise. No patient with an ABPR developed a normal blood pressure response (NBPR) to exercise. There was no significant change in the forearm vascular response to application of LBNP in patients in either group A or B, and no patients from group A changed from a vasodilator to a vasoconstrictor response to LBNP.
All patients achieved target doses without adverse effects. After three weeks of propanolol therapy, four (44%) patients from group A and three (25%) from group B reported less chest pain and reduced breathlessness as shown in Table 4. Propanolol was associated with a significant reduction in resting heart rate, peak exercise heart rate, percentage of predicted heart rate achieved during exercise, and resting SBP; %Vo2max was not significantly different from baseline, and there was no significant change in the increment in SBP during exercise in the entire group, or for group A or B separately (Table 4); however, one patient from group A converted to an NBPR during exercise on propanolol.
Propanolol therapy was associated with significant changes in FVR and FBF during application of LBNP in group A patients: mean FVR increased by 5.5 (95% confidence interval [CI] −7.2 to 18.3) on propranolol compared to a mean reduction of −7.6 (95% CI −4.0 to −11.0) at baseline (p = 0.05), and FBF decreased by −0.1 (95% CI −0.3 to 0.2) on propranolol compared with an increase of 0.7 (95% CI 0.3 to 0.9) at baseline (p = 0.001). This effect was independent of baseline changes in FVR on propranolol as assessed by ANCOVA. Paradoxical vascular responses to LBNP normalized in five (71%) patients in group A and remained vasodilator in the remaining four (29%) patients. Forearm vascular responses remained vasoconstrictor after propanolol in all patients from group B. The results are summarized in Table 5.
Clonidine was poorly tolerated by 11 (52%) patients and was discontinued by 9 (43%) patients (4 patients from group A and 5 from group B) due to severe lethargy, dizziness, or nausea. In patients who were able to tolerate clonidine, an improvement in symptoms (reduced breathlessness) was reported by one patient from group A only. Only 12 patients completed the clonidine phase of the study and underwent repeat studies. Because this study was designed to assess the effect of these drugs on pathophysiological mechanisms, we present the data for the remainder who had paired data, rather than analyzing on intention-to-treat principles. As shown in Table 4, on cardiopulmonary exercise testing compared to baseline, there were no significant changes in resting heart rate, peak heart rate, percent of predicted heart rate achieved during exercise, %Vo2max, or resting SBP. There was no significant difference in the increment in SBP during exercise for the entire group, or for group A or B separately. No patient with an ABPR developed an NBPR on clonidine.
As shown in Table 5, compared to baseline, clonidine was associated with significant changes in FVR and FBF during application of LBNP in patients from group A: mean FVR increased by 3.2 (95% CI −5.0 to 11.4) on clonidine compared to a mean reduction of −7.6 (95% CI −4.0 to −11.0) at baseline (p = 0.001), and FBF decreased by −0.04 (95% CI 0.3 to −0.3) on clonidine compared with an increase of 0.7 (95% CI 0.3 to 0.9) at baseline (p = 0.01). This effect was independent of baseline changes in FVR on clonidine as assessed by ANCOVA. Paradoxical vascular responses normalized in three (60%) patients in group A and remained vasodilator in two (40%). Forearm vascular responses remained vasoconstrictor in all patients from group B (Table 5).
In four (44%) patients from group A and two (17%) from group B, presyncope and lethargy were reported during the first week of paroxetine, although this did not require discontinuation of therapy. Side effects resolved by the third week of therapy in all patients. Less chest pain and breathlessness were reported by the end of week three in 33% of patients in group A and 8% of group B. As shown in Table 4, on cardiopulmonary exercise testing compared to baseline, there were no significant changes in resting heart rate, peak exercise heart rate, percentage of predicted heart rate achieved during exercise, %Vo2max, or resting SBP. There was a significant augmentation in the SBP response to exercise on paroxetine compared to baseline in group A patients (21 ± 6, 95% CI 16.2 to 27.1 vs. 14 ± 11, 95% CI 6.0 to 21.8 mm Hg increment in SBP, p = 0.02), and five (55%) patients from group A were reclassified as having an NBPR on paroxetine. In these patients, SBP increased by 25 ± 3 mm Hg compared to 15 ± 3 mm Hg at baseline (p = 0.001). In patients from group B, no significant change in SBP response to exercise was recorded compared to baseline, and no patient developed an NBPR.
Paroxetine therapy was also associated with significant changes in FVR and FBF during application of LBNP in group A patients: mean FVR increased by 7.6 (95% CI −2.9 to 18.1) on paroxetine compared to a mean reduction of −7.6 (95% CI −4.0 to −11.0) at baseline (p = 0.01), and FBF decreased by −0.2 (95% CI −0.5 to 0.05) on paroxetine compared with an increase of 0.7 (95% CI 0.3 to 0.9) at baseline (p = 0.001). This effect was independent of baseline changes in FVR on paroxetine as assessed by ANCOVA. Paradoxical vascular responses normalized in seven (78%) of patients in group A. Forearm vascular responses remained vasoconstrictor in all patients from group B (Table 5).
At initial evaluation, BRS was significantly lower in patients from group A than group B before applying LBNP (5.73 ± 0.48 vs. 8.29 ± 2.01, p = 0.01). During LBNP there was a further reduction in BRS in patients from group A (by −5.73 ± 6.76), whereas in group B there was a mean increase in BRS (by 0.93 ± 6.13). Medications had no significant effect on BRS in patients from groups A or B (Table 6).
There are four important findings of this study. First, approximately 40% of patients with ABPR during erect cycle exercise exhibited paradoxical forearm vasodilatation during application of LBNP. Second, both the exercise blood pressure response and the forearm vascular response during application of LBNP are reproducible as shown by the placebo limb of the study. Third, exercise blood pressure responses were improved by paroxetine therapy, and abnormal forearm vascular responses during application of LBNP were attenuated or normalized by propranolol, clonidine, and paroxetine. Finally, BRS was lower in those patients with abnormal vascular responses during LBNP, but was unaffected by any of these therapies.
Mechanism of abnormal vascular responses in HCM
In man, the forearm vasoconstriction response to application of subhypotensive LBNP appears to be predominantly mediated by inactivationof LV mechanoreceptors. The paradoxical forearm vasodilatation in some HCM patients most likely represents abnormal activationof LV mechanoreceptors (9,11). We have previously suggested that ABPR during exercise may also be due to abnormal activation of LV mechanoreceptors (7). The reason for this is unknown, but possible causes include intrinsic abnormalities of ventricular mechanoreceptors or increased LV local wall strains, due either to high intraventricular pressures or to the myocyte disarray and fibrosis, which characterizes the disorder. Whatever the mechanism, excessive or inappropriate afferent input from ventricular mechanoreceptors during exercise could overcome the normal constrictor input from central command and skeletal muscle afferents resulting in a withdrawal of sympathetic efferent outflow from the brainstem and consequently inappropriate peripheral vasodilatation and hypotension. However, this is speculative, and there is as yet no direct proof that these abnormal vascular responses are triggered by LV mechanoreceptor activation.
Mechanism of action of pharmacologic interventions
All three drugs studied normalized or attenuated the abnormal forearm vasodilatation associated with application of LBNP; however, only paroxetine therapy was associated with an improvement in blood pressure response to exercise. It should be noted that the effects of clonidine in this study were more difficult to ascertain due to the high withdrawal rate, which might also be expected to limit any possible therapeutic potential. It is also important to note that, although no patient reported adverse effects on withdrawal of any of the medications used in this study, all three may be associated with rebound symptoms on sudden withdrawal, and therefore caution should be exercised before discontinuing any of these medications, particularly when used over a long period of time.
The three drugs are thought to act at different points along the baroreflex arc (32,33). Beta-blocking agents are thought to act through their negatively inotropic actions, opposing the stretch stimulation of the LV mechanoreceptors, although they have also been shown to have central actions that tend to reduce sympathetic efferent activity and promote cardiac vagal outflow. Clonidine is an alpha-adrenoceptor agonist, the pathophysiological basis for the action of clonidine is based on its partial selective alpha 2 agonist activity. Clonidine acts peripherally on alpha 2 receptors in large capacitance vessels significantly reducing venous capcitance, thus decreasing the likelihood of triggering the vasovagal reflex after gravitational stress (33). Clonidine also acts centrally on vasomotor areas within the brain stem leading to a reduction in tonic sympathetic efferent activity within the brain stem and noripherherine release (hence its use as an antihypertensive); clonidine may also stimulate tonic parasympathetic outflow, and more recently it has been suggested that clonidine may act on imidazole receptors. Clonidine also appears to prevent acute reductions in sympathetic efferent activity in vasovagal syncope and in carotid sinus syndrome (34–37). Paroxetine is a highly selective serotonin (5HT) re-uptake inhibitor and has been shown to provide functional improvement in patients with vasovagal syncope (26–28). The mechanism by which this occurs is unclear, but animal and human evidence support a sudden increase in 5HT levels within the brainstem with activation of 5HT-2 receptors as a key to the mechanism of vasovagal syncope. Paroxetine is thought to act by down-regulating 5HT receptors and thereby increasing the threshold for the vasovagal response (37–42).
Abnormal blood pressure response during exercise defines a subset of patients generally at increased risk of sudden cardiac death (2–6). Although unproven, it has been suggested that episodic hypotension may result in myocardial ischemia and that in patients with an underlying electrical instability due to myocyte disarray and fibrosis, this may provide the trigger for ventricular arrhythmia. The association in the present study between abnormal forearm vascular responses during application of LBNP and a history of syncope suggests that abnormal vascular responses might also be involved in the pathophysiology of syncope in some patients. By reversing or attenuating the ABPR during exercise, and the abnormal vascular response during abrupt reductions in central blood volume, paroxetine may potentially reduce the number or severity of hypotensive episodes and/or syncope in patients with HCM and ABPR, and might conceivably reduce the risk of sudden cardiac death. Longitudinal placebo-controlled studies are required to verify or refute this hypothesis.
Despite the fact that 55% of patients with ABPR were reclassified as having a “NBPR” after paroxetine therapy, the increase in SBP during exercise in these patients was still relatively modest (25 to 30 mm Hg). The definition of ABPR employed in this study (increase in SBP <25 mm Hg) is based on studies examining the impact on prognosis (7,29). Previous data from a series of untrained normal individuals of similar age and gender in our own department showed an average increase in SBP of 58 ± 18 mm Hg (40 to 90 mm Hg). Therefore, although there was an improvement in SBP after paroxetine, the BPR response in these patients remains abnormal compared to unaffected individuals.
The main limitation of this study is that forearm vascular responses were not recorded during erect exercise. This is because of the inherent limitations in performing plethysmogaphy during exercise due to movement artefact. Therefore, we cannot exclude the possibility that the beneficial effect of paroxetine on exercise blood pressure response was due to a higher cardiac output rather than a normalization of the vascular response. However, paroxetine has no known effects on cardiac performance, and in the present study had no effect on oxygen pulse (Table 4), which argues strongly against this. Secondly, no invasive hemodynamic measurements were performed, so we cannot be certain that central venous pressure decreased equally during application of LBNP in patients with and without vasodilatory forearm vascular responses. However, in a previous study using the same methodology, we showed that the fall in central venous pressure was similar in the two groups (9).
Finally, in this study we have inferred that ABPRs during exercise and abnormal vascular responses during central volume unloading using LBNP in patients with HCM are probably linked mechanistically. Although little direct evidence for this exists, studies have shown that both responses occur in a similar proportion of HCM patients, both are due to peripheral vasodilatation in certain vascular beds including forearm vasculature, and it is probable that both are triggered by LV mechanoreceptor activation.
Our data suggest that abnormal vascular responses in HCM may be favorably modified by pharmacological therapy. Propranolol, clonidine, and paroxetine were each effective in reversing or attenuating abnormal forearm vasodilator responses during application of LBNP, and paroxetine also improved blood pressure response to exercise.(10)
Drs. Thaman, McKenna, and Frenneaux were supported by the British Heart Foundation, and Dr. Murphy was supported by a scholarship from Trinity College, Dublin.
- Abbreviations and Acronyms
- abnormal blood pressure response
- baroreceptor sensitivity
- forearm blood flow
- forearm vascular resistance
- hypertrophic cardiomyopathy
- lower body negative pressure
- left ventricle/ventricular
- normal blood pressure response
- systolic blood pressure
- systemic vascular resistance
- oxygen consumption
- percentage of the predicted maximal Vo2
- Received August 31, 2004.
- Revision received March 17, 2005.
- Accepted April 19, 2005.
- American College of Cardiology Foundation
- 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies
- Frenneaux M.P.,
- Counihan P.J.,
- Chikamori T.,
- Caforio A.L.P.,
- McKenna W.J.
- Counihan P.J.,
- Frenneaux M.P.,
- Webb D.J.,
- McKenna W.J.
- Spirito P.,
- Seidman C.E.,
- McKenna W.J.,
- Maron B.J.
- Sadoul N.,
- Prasad K.,
- Elliott P.M.,
- Bannerjee S.,
- Frenneaux M.P.,
- McKenna W.J.
- Olivotto I.,
- Maron B.J.,
- Montereggi A.,
- Mazzuoli F.,
- Dolara A.,
- Cecchi F.
- Thomson H.L.,
- Morris-Thurgood J.,
- Atherton J.,
- Frenneaux M.
- Chevalier P.A.,
- Weber K.C.,
- Lyons G.W.,
- Nicoloff D.M.,
- Fox D.
- Bishop V.S.,
- Malliani A.,
- Thoren P.
- Thomson H.L.,
- Wright K.,
- Frenneaux M.
- Ludbrook J.,
- Graham W.F.
- Flevari P.,
- Livanis E.G.,
- Theodorakis G.N.,
- Zarvalis E.,
- Mesiskli T.,
- Kremastinos D.T.
- Biffi M.,
- Boriani G.,
- Sabbatani P.,
- et al.
- Di Girolamo E.,
- Di Iorio C.,
- Sabatini P.,
- Leonzio L.,
- Barbone C.,
- Barsotti A.
- Elliott P.M.,
- Poloniecki J.,
- Dickie S.,
- et al.
- Blaber A.P.,
- Yamamoto Y.,
- Hughson R.L.
- Biffi M.,
- Boriani G.,
- Sabbatani P.,
- et al.
- Halper J.P.,
- Mann J.J.
- Ramage A.G.
- Dan D.,
- Grubb B.P.,
- Mouhaffel A.H.,
- et al.