MYBPC3 hypertrophic cardiomyopathy can be detected by using advanced ECG in children and young adults.

INTRODUCTION: The conventional ECG is commonly used to screen for hypertrophic cardiomyopathy (HCM), but up to 25% of adults and possibly larger percentages of children with HCM have no distinctive abnormalities on the conventional ECG, whereas 5 to 15% of healthy young athletes do. Recently, a 5-min resting advanced 12-lead ECG test ("A-ECG score") showed superiority to pooled criteria from the strictly conventional ECG in correctly identifying adult HCM. The purpose of this study was to evaluate whether in children and young adults, A-ECG scoring could detect echocardiographic HCM associated with the MYBPC3 genetic mutation with greater sensitivity than conventional ECG criteria and distinguish healthy young controls and athletes from persons with MYBPC3 HCM with greater specificity. METHODS: Five-minute 12-lead ECGs were obtained from 15 young patients (mean age 13.2years, range 0-30years) with MYBPC3 mutation and phenotypic HCM. The conventional and A-ECG results of these patients were compared to those of 198 healthy children and young adults (mean age 13.2, range 1month-30years) with unremarkable echocardiograms, and to those of 36 young endurance-trained athletes, 20 of whom had athletic (physiologic) left ventricular hypertrophy. RESULTS: Compared with commonly used, age-specific pooled criteria from the conventional ECG, a retrospectively generated A-ECG score incorporating results from just 2 derived vectorcardiographic parameters (spatial QRS-T angle and the change in the vectorcardiographic QRS azimuth angle from the second to the third eighth of the QRS interval) increased the sensitivity of ECG for identifying MYBPC3 HCM from 46% to 87% (p<0.05). Use of the same score also demonstrated superior specificity in a set of 198 healthy controls (94% vs. 87% for conventional ECG criteria; p<0.01) including in a subset of 36 healthy, young endurance-trained athletes (100% vs. 69% for conventional ECG criteria, p<0.001). CONCLUSIONS: In children and young adults, a 2-parameter 12-lead A-ECG score is retrospectively significantly more sensitive and specific than pooled, age-specific conventional ECG criteria for detecting MYBPC3-HCM and in distinguishing such patients from healthy controls, including endurance-trained athletes.

The value of ventricular gradient for predicting pulmonary hypertension and mortality in hemodialysis patients.

Pulmonary hypertension (PHT) is associated with increased mortality in hemodialysis (HD) patients. The ventricular gradient optimized for right ventricular pressure overload (VG-RVPO) is sensitive to early changes in right ventricular overload. The study aimed to assess the ability of the VG-RVPO to detect PHT and predict all-cause and cardiac mortality in HD patients. 265 selected HD patients were enrolled. Clinical, biochemical, electrocardiographic, and echocardiographic parameters were evaluated. Patients were divided into normal and abnormal VG-RVPO groups, and were followed-up for 3 years. Abnormal VG-RVPO patients were more likely to be at high or intermediate risk for PHT, were older, had longer HD vintage, higher prevalence of myocardial infarction, higher parathormone levels, shorter pulmonary flow acceleration time, lower left ventricular ejection fraction, higher values of left atrial volume index, left ventricular mass index, and peak tricuspid regurgitant velocity. Both all-cause and CV mortality were higher in abnormal VG-RVPO group. In multivariate Cox analysis, VG-RVPO remained an independent and strong predictor of all-cause and CV mortality. In HD patients, abnormal VG-RVPO not only predicts PHT, but also all-cause and CV mortality.

Acute manipulations of plasma volume alter arterial pressure responses during Valsalva maneuvers.

The effects of changes in blood volume on arterial pressure patterns during the Valsalva maneuver are incompletely understood. In the present study we measured beat-to-beat arterial pressure and heart rate responses to supine Valsalva maneuvers during normovolemia, hypovolemia induced with intravenous furosemide, and hypervolemia induced with ingestion of isotonic saline. Valsalva responses were analyzed according to the four phases as previously described (W. F. Hamilton, R. A. Woodbury, and H. T. Harper, Jr. JAMA 107: 853-856, 1936; W. F. Hamilton, R. A. Woodbury, and H. T. Harper, Jr. Am. J. Physiol. 141: 42-50, 1944). Phase I is the initial onset of straining, which elicits a rise in arterial pressure; phase II is the period of straining, during which venous return is impeded and pressure falls (early) and then partially recovers (late); phase III is the initial release of straining; and phase IV consists of a rapid "overshoot" of arterial pressure after the release. During hypervolemia, early phase II arterial pressure decreases were significantly less than those during hypovolemia, thus making the response more "square." Systolic pressure hypervolemic vs. hypovolemic falls were -7.4 +/- 2.1 vs. -30.7 +/- 7 mmHg (P = 0.005). Diastolic pressure hypervolemic vs. hypovolemic falls were -2.4 +/- 1.6 vs. -15.2 +/- 2.6 mmHg (P = 0.05). A significant direct correlation was found between plasma volume and phase II systolic pressure falls, and a significant inverse correlation was found between plasma volume and phase III-IV systolic pressure overshoots. Heart rate responses to systolic pressure falls during phase II were significantly less during hypovolemia than during hypervolemia (0.7 +/- 0.2 vs. 2.82 +/- 0.2 beats. min-1. mmHg-1; P = 0.05) but were not different during phase III-IV overshoots. We conclude that acute changes in intravascular volume from hypovolemia to hypervolemia affect cardiovascular responses, particularly arterial pressure changes, to the Valsalva maneuver and should be considered in both clinical and research applications of this maneuver.

Effect of acute exposure to hypergravity (GX vs. GZ) on dynamic cerebral autoregulation.

We examined the effects of 30 min of exposure to either +3GX (front-to-back) or +GZ (head-to-foot) centrifugation on cerebrovascular responses to 80 degrees head-up tilt (HUT) in 14 healthy individuals. Both before and after +3 GX or +3 GZ centrifugation, eye-level blood pressure (BP(eye)), end tidal PCO2 (PET(CO2)), mean cerebral flow velocity (CFV) in the middle cerebral artery (transcranial Doppler ultrasound), cerebral vascular resistance (CVR), and dynamic cerebral autoregulatory gain (GAIN) were measured with subjects in the supine position and during subsequent 80 degrees HUT for 30 min. Mean BP(eye) decreased with HUT in both the GX (n = 7) and GZ (n = 7) groups (P < 0.001), with the decrease being greater after centrifugation only in the GZ group (P < 0.05). PET(CO2) also decreased with HUT in both groups (P < 0.01), but the absolute level of decrease was unaffected by centrifugation. CFV decreased during HUT more significantly after centrifugation than before centrifugation in both groups (P < 0.02). However, these greater decreases were not associated with greater increases in CVR. In the supine position after centrifugation compared with before centrifugation, GAIN increased in both groups (P < 0.05, suggesting an autoregulatory deficit), with the change being correlated to a measure of otolith function (the linear vestibulo-ocular reflex) in the GX group (r = 0.76, P < 0.05) but not in the GZ group (r = 0.24, P = 0.60). However, GAIN was subsequently restored to precentrifugation levels during postcentrifugation HUT (i.e., as BP(eye) decreased), suggesting that both types of centrifugation resulted in a leftward shift of the cerebral autoregulation curve. We speculate that this leftward shift may have been due to vestibular activation (especially during +GX) or potentially to an adaptation to reduced cerebral perfusion pressure during +GZ.

Cardiovascular and Valsalva responses during parabolic flight.

We investigated the integrated cardiovascular responses of 15 human subjects to the acute gravitational changes (micro- and hypergravity portions) of parabolic flight. Measurements were made with subjects quietly seated and while subjects performed controlled Valsalva maneuvers. During quiet, seated, parabolic flight, mean arterial pressure increased during the transition into microgravity but decreased as microgravity was sustained. The decrease in mean arterial pressure was accompanied by immediate reflexive increases in heart rate but by absent (or later-than-expected) reflexive increases in total vascular resistance. Mean arterial pressure responses in Valsalva phases IIl, III, and IV were accentuated in hypergravity relative to microgravity (P < 0.01, P < 0.01, and P < 0. 05, respectively), but accentuations differed qualitatively and quantitatively from those induced by a supine-to-seated postural change in 1 G. This study is the first systematic evaluation of temporal and Valsalva-related changes in cardiovascular parameters during parabolic flight. Results suggest that arterial baroreflex control of vascular resistance may be modified by alterations of cardiopulmonary, vestibular, and/or other receptor activity.

Orthostatic intolerance and motion sickness after parabolic flight.

Because it is not clear that the induction of orthostatic intolerance in returning astronauts always requires prolonged exposure to microgravity, we investigated orthostatic tolerance and autonomic cardiovascular function in 16 healthy subjects before and after the brief micro- and hypergravity of parabolic flight. Concomitantly, we investigated the effect of parabolic flight-induced vomiting on orthostatic tolerance, R-wave-R-wave interval and arterial pressure power spectra, and carotid-cardiac baroreflex and Valsalva responses. After parabolic flight 1) 8 of 16 subjects could not tolerate 30 min of upright tilt (compared to 2 of 16 before flight); 2) 6 of 16 subjects vomited; 3) new intolerance to upright tilt was associated with exaggerated falls in total peripheral resistance, whereas vomiting was associated with increased R-wave-R-wave interval variability and carotid-cardiac baroreflex responsiveness; and 4) the proximate mode of new orthostatic failure differed in subjects who did and did not vomit, with vomiters experiencing comparatively isolated upright hypocapnia and cerebral vasoconstriction and nonvomiters experiencing signs and symptoms reminiscent of the clinical postural tachycardia syndrome. Results suggest, first, that syndromes of orthostatic intolerance resembling those developing after space flight can develop after a brief (i.e., 2-h) parabolic flight and, second, that recent vomiting can influence the results of tests of autonomic cardiovascular function commonly utilized in returning astronauts.

Cerebral vasoconstriction precedes orthostatic intolerance after parabolic flight.

The effects of brief but repeated bouts of micro- and hypergravity on cerebrovascular responses to head-up tilt (HUT) were examined in 13 individuals after (compared to before) parabolic flight. Middle cerebral artery mean flow velocity (MCA MFV; transcranial Doppler ultrasound), eye level blood pressure (BP) and end tidal CO(2) (P(ET)CO(2)) were measured while supine and during 80 degrees HUT for 30 min or until presyncope. In the postflight tests subjects were classified as being orthostatically tolerant (OT) (n = 7) or intolerant (OI) (n = 6). BP was diminished with HUT in the OT group in both tests (p < 0.05) whereas postflight BP was not different from supine in the OI group. Postflight compared to preflight, the reduction in P(ET)CO(2) with HUT (p < 0.05) increased in both groups, although significantly so only in the OI group (p < 0.05). The OI group also had a significant decrease in supine MCA MFV postflight (p < 0.05) that was unaccompanied by a change in supine P(ET)CO(2). The decrease in MCA MFV that occurred during HUT in both groups preflight (p < 0.05) was accentuated only in the OI group postflight, particularly during the final 30 s of HUT (p < 0.05). However, this accentuated decrease in MCA MFV was not correlated to the greater decrease in P(ET)CO(2) during the same period (R = 0.20, p = 0.42). Although cerebral vascular resistance (CVR) also increased in the OI group during the last 30 s of HUT postflight (p < 0.05), the dynamic autoregulatory gain was not simultaneously changed. Therefore, we conclude that in the OI individuals, parabolic flight was associated with cerebral hypoperfusion following a paradoxical augmentation of CVR by a mechanism that was not related to changes in autoregulation nor strictly to changes in P(ET)CO(2).

Non-invasive detection of coronary artery disease by a newly developed high-frequency QRS electrocardiogram.

Compared to other non-invasive methods, the conventional 12-lead electrocardiogram (ECG) has low sensitivity and specificity for identifying coronary artery disease (CAD). We compared the newly developed high-frequency QRS electrocardiogram (HFQRS ECG, 150-250 Hz) with adenosine sestamibi myocardial perfusion study (MPI)-the most sensitive non-invasive study in cardiology practice. Using advanced 12-lead computer-based ECG software recently developed at NASA, criteria for a positive 12-lead HFQRS-ECG test for obstructive CAD were developed using 300 signal-averaged beats from patients undergoing elective coronary angiograms for evaluation of chest pain. These criteria, which rely strictly upon the presence or the absence of morphologic 'reduced amplitude zones' (RAZs) and not upon the 'root mean squared' (RMS) voltage amplitudes of the HFQRS complexes, were then applied prospectively to 18 patients undergoing MPI. Active CAD was considered present when reversible ischemic defects were present on MPI. Of the 18 patients, 9 had reversible defects on MPI (positive scan), whereas the other 9 had no reversible perfusion defects (negative scan). Patients with a positive nuclear study went on to coronary angiography confirming CAD, except in one patient who had nonobstructive coronary disease (<50% stenosis). Eight of the 18 subjects therefore had active CAD, whereas 10 were judged not to have active CAD. The 12-lead HFQRS-ECG result was consistent with nuclear scan results in 14 of 18 patients. The HFQRS-ECG and nuclear results differed in: (1) one patient who had a low score positive MPI, negative HFQRS-ECG and normal coronary angiogram; (2) one patient who had a small reversible anterior wall perfusion defect, 60% LAD lesion on angiogram but a negative HF-QRS result; and (3) two individuals who had positive HFQRS-ECG results in the face of negative nuclear scans but who did not undergo angiography. 12-lead HFQRS ECG had excellent sensitivity (87.5% based on 7/8 true positives correctly identified) and specificity (no worse than 80%, >8/10 true negatives correctly identified) for identifying CAD. 12-lead HFQRS ECG is an easily performed, inexpensive and potentially widely available technique that utilizes the same leads and electrodes as the conventional 12-lead ECG. It had accuracy comparable to MPI in this study. Resting 12-lead HFQRS ECG appears to be a very promising non-invasive technique for identifying CAD and may represent a viable alternative to many of the more expensive and time-consuming techniques presently utilized for non-invasively identifying CAD.

Advanced electrocardiographic parameters change with severity of mitral regurgitation in Cavalier King Charles Spaniels in sinus rhythm.

BACKGROUND: Multiple advanced resting ECG (A-ECG) techniques have improved the diagnostic or prognostic value of ECG in detecting human cardiac diseases even before onset of clinical signs or changes in conventional ECG. OBJECTIVE: To determine which A-ECG parameters, derived from 12-lead A-ECG recordings, change with severity of mitral regurgitation (MR) caused by myxomatous mitral valve disease (MMVD) in Cavalier King Charles Spaniels (CKCSs) in sinus rhythm. ANIMALS: Seventy-six privately owned CKCSs. METHODS: Dogs were prospectively divided into 5 groups according to the degree of MR (estimated by color Doppler mapping as the percentage of the left atrial area affected by the MR jet) and presence of clinical signs. High fidelity approximately 5-minute 12-lead ECG recordings were evaluated using custom software to calculate multiple conventional and A-ECG parameters. RESULTS: Nineteen of 76 ECG parameters were significantly different (P < .05) across the 5 dog groups. A 4-parameter model that incorporated results from 1 parameter of heart rate variability, 2 parameters of QT variability, and 1 parameter of QRS amplitude was identified that explained 82.4% of the variance with a correlation coefficient (R) of 0.60 (P < .01). When age or murmur grade was included in the statistical model the prediction value further increased the R to 0.74 and 0.85 (P < .01), respectively. CONCLUSION: In CKCSs with sinus rhythm, 4 selected A-ECG parameters further improve prediction of MR jet severity beyond age and murmur grade, although the predictive increment in this study probably is not sufficient to warrant utilization in clinical veterinary practice.

Advanced electrocardiographic predictors of mortality in familial dysautonomia.

OBJECTIVE: To identify electrocardiographic predictors of mortality in patients with familial dysautonomia (FD). METHODS: Ten-minute resting high-fidelity 12-lead electrocardiograms (ECGs) were obtained from 14 FD patients and 14 age/gender-matched healthy subjects. Multiple conventional and advanced ECG parameters were studied for their ability to predict mortality over a subsequent 4.5-year period, including representative parameters of heart rate variability (HRV), QT variability (QTV), T-wave complexity, signal averaged ECG, and 3-dimensional ECG. RESULTS: Four of the 14 FD patients died during the follow-up period, three with concomitant pulmonary disorder. Of the ECG parameters studied, increased non-HRV-correlated QTV and decreased HRV were the most predictive of death. Compared to controls as a group, FD patients also had significantly increased ECG voltages, JTc intervals and waveform complexity, suggestive of structural heart disease. CONCLUSION: Increased QTV and decreased HRV are markers for increased risk of death in FD patients. When present, both markers may reflect concurrent pathological processes, especially hypoxia due to pulmonary disorders and sleep apnea.