Marked respiratory-related fluctuations in left ventricular outflow tract gradients in hypertrophic obstructive cardiomyopathy: an observational study

Marked respiratory-related fluctuations in left ventricular outflow tract gradients in... Abstract Aims Left ventricular outflow (LVOT) obstruction in patients with hypertrophic cardiomyopathy (HCM) is dynamic and sensitive to many variables that affect left ventricular preload, afterload, and contractility. The haemodynamic effect of normal respiration on LVOT obstruction has not been described. Methods and results We examined 20 patients with HCM who were noted to have phasic respiratory variation of LVOT obstruction on initial transthoracic 2D echocardiogram and Doppler examination. LVOT gradients were re-examined with simultaneous recording of a respirometer. LVOT gradients varied widely during the respiratory cycle; peak gradients were uniformly lowest during inspiration (50.8 mmHg + 25.6) and highest during expiration (90.1 mmHg + 41.8). On average, there was 82.4% ± 39.1 (P ≤ 0.0001) incremental change from inspiration to expiration, in the severity of LVOT obstruction. In 11 patients with mitral annulus inflow, LV inflow (preload) was decreased during inspiration. In 16 patients with isovolumic relaxation time and ejection time measurements, decreased left atrial filling pressure was noted during inspiration, consistent with decreased LVOT obstruction. When compared with a control group of 20 HCM patients who did not have respiratory variation, the study group patients were more overweight (mean body mass index cases 35.1 ± 7.3 vs. control group 29.1 ± 5.1, P = 0.0045) and more likely to have sleep-disordered breathing (n = 15 study group, n = 5 control group). Conclusions Counterintuitive respiratory-related fluctuations in LVOT gradients were observed in this case series of 20 HCM patients. These findings challenge traditional haemodynamic teaching and demonstrate the contribution of LV transmural pressure to LVOT obstruction in certain HCM patients. hypertrophic cardiomyopathy, echocardiography, obstructive sleep apnoea Introduction Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac condition, and left ventricular (LV) outflow obstruction, present at rest or induced (by Valsalva maneuver, exercise amyl nitrite inhalation) in the majority of patients with HCM, is recognized as an important cause of morbidity and mortality.1–3 Management of symptomatic obstructive HCM ranges from medications and lifestyle modifications to more invasive treatment options including alcohol septal ablation and surgical septal myectomy forming a key part of management of patients with HCM.4 For this reason, the accurate assessment of left ventricular outflow tract (LVOT) obstruction is clinically important. In daily clinical practice, this assessment is performed by transthoracic 2D echocardiogram (TTE) and Doppler examination. The dynamic nature of LVOT obstruction has been documented for more than 50 years. It is also well known that changes in preload, afterload, and contractility can produce profound effects in the magnitude of LVOT obstruction. This phenomenon is well illustrated at the bedside with dynamic auscultation. The murmur of LVOT obstruction increases in intensity during Valsalva strain and on assuming upright/standing position (proposed mechanism—reduced preload). Conversely, the LVOT obstruction decreases, and the murmur gets softer on passive leg raising and on prompt squatting (proposed mechanism—increased preload). However, the effect of normal respiration and respiratory-related changes in gradient is not described in any standard cardiology textbooks.5–7 We, therefore, describe LVOT obstruction in HCM patients related to the phases of respiration. Methods We evaluated patients with obstructive HCM seen at the Hypertrophic Cardiomyopathy Outpatient Clinic at Aurora Health Care, St. Luke’s Medical Center, Milwaukee, WI, USA. Comprehensive TTE was performed by dedicated sonographers as part of the HCM clinic evaluation immediately prior to cardiac consultation. All patients were awake and breathing normally during the examination. Echocardiograms were acquired using GE Vivid E9 and E95 platforms (GE Vingmed Ultrasound Medical Systems, Milwaukee, WI, USA). Assessment of LVOT obstruction was performed from the apical window (apical long-axis or apical five-chamber views) using continuous-wave spectral Doppler; peak gradient was calculated from peak velocity using the modified Bernoulli equation. Resting gradients as well as gradients during the Valsalva manoeuvre were obtained. TTE images were routinely reviewed prior to the patient leaving the echocardiography suite. Significant variations in LVOT velocities were observed in the continuous-wave Doppler tracings of some patients. This variation was noted to be significant and not beat-to-beat dependent but rather appeared cyclical over several heart beats—the pattern and timing suggested that the variation was related to respiratory cycles. This prompted the use of a respirometer, which revealed counterintuitive findings of lower gradients during inspiration and higher gradients during expiration. These observations were noted in 20 patients described in this report (Group 1). LVOT gradients were reassessed in relationship to respiratory stages (inspiration and expiration) and these dedicated images were acquired. Furthermore, during acquisition of these Doppler signals, particular attention was also directed to avoid any mixing of the LVOT obstruction Doppler signals with mitral regurgitation signals. We also ensured that the strength of the signals of mitral inflow and LV outflow were similar, minimizing any minor change in angle of insonation with respiration. In this study, LV end-diastolic volume assessment was not performed; instead, in 11 patients, mitral annulus flow was interrogated to evaluate changes in LV inflow (preload) with respiration. Pulsed-wave Doppler sample volume was placed at mitral annulus, and time velocity integral (TVI) was measured during inspiration and expiration. Additionally, in 16 patients, isovolumic relaxation time (IVRT) and ejection time (ET) were also measured during inspiration and expiration. Invasive cardiac haemodynamics in six patients were evaluated in the cardiac catheterization laboratory with simultaneous recordings of pressure in the aorta and the left ventricle. Clinical variables were queried from the Aurora Health Care electronic health record (EPIC Systems, Verona, WI, USA). Clinical information on an additional 20 cases of HCM seen in the Hypertrophic Cardiomyopathy Clinic was collected and formed the control group (Group 2)—these patients were selected if they demonstrated septal hypertrophy with resting LVOT obstruction, and no respiratory variation was noted on their Doppler tracings. Approval for this study was granted by the Aurora Health Care Institutional Review Board. Data were analysed using STATA 12.0 and reported as means with standard deviations when applicable. Statistical significance was defined as P-value <0.05. Results Twenty patients are included in this case series (Group 1)—a summary of patient characteristics are presented in Table 1. Mean age of patients was 62.1 ± 13.1 years, and 12 patients (60%) were female. All patients had significant septal hypertrophy, with the average septal thickness of 2.18 cm ± 0.29 cm. Eleven patients underwent genetic testing, and four patients were found to have pathogenic mutations. Of the 11 patients who underwent cardiac MRI, 9 patients were noted to have delayed enhancement with gadolinium. All patients were taking beta-blockers at the time of TTE—11 patients were additionally prescribed calcium channel blocker and 4 patients were also taking disopyramide. Implantable cardiac defibrillators were in place in four patients. Six patients subsequently underwent alcohol septal ablation. Table 1 Characteristics of patient population Case  Gender  Age (years)  Max wall thickness (cm)  BMI (kg/m2)  Medications  Obstructive sleep apnoea  Resting LVOT gradient (mmHg)  LVOT gradient during valsalva manoeuvre (mmHg)  1  Female  53  1.8  31  Metoprolol  Probable  Inspiration = 45 mmHg Expiration = 74 mmHg  80  2  Male  55  2.5  43  Metoprolol, verapamil  Yes  Inspiration = 37 mmHg Expiration = 61 mmHg  80  3  Male  56  2.2  25  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 16 mmHg Expiration = 46 mmHg  48  4  Male  67  2.2  27  Metoprolol  Yes  Inspiration = 58 mmHg Expiration = 133 mmHg  140  5  Male  78  2.0  25.3  Metoprolol  No  Inspiration = 31 mmHg Expiration = 64 mmHg  97  6  Male  73  2.0  31  Metoprolol, diltiazem  Probable  Inspiration = 36 mmHg Expiration = 71 mmHg  150  7  Female  59  2.4  44  Metoprolol  Yes  Inspiration = 71 mmHg Expiration = 110 mmHg  115  8  Female  56  2.0  42  Metoprolol  Yes  Inspiration = 18 mmHg Expiration = 34 mmHg  80  9  Male  40  2.9  39  Metoprolol  Yes  Inspiration = 47 mmHg Expiration = 71 mmHg  76  10  Male  56  2.5  42  Metoprolol, diltiazem  No  Inspiration = 25 mmHg Expiration = 48 mmHg  80  11  Female  28  2.0  43  Metoprolol, diltiazem, disopyramide  No  Inspiration = 34 mmHg Expiration = 63 mmHg  71  12  Female  70  2.2  28  Metoprolol, verapamil  Probable  Inspiration = 125 mmHg Expiration = 190 mmHg  190  13  Female  61  2.0  44.8  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 72 mmHg Expiration = 170 mmHg  160  14  Female  73  3.3  35  Atenolol  Yes  Inspiration = 60 mmHg Expiration = 130 mmHg  200  15  Female  74  1.8  25  Metoprolol, diltiazem  unknown  Inspiration = 61 mmHg Expiration = 91 mmHg  100  16  Female  69  2.1  29.1  Metoprolol, diltiazem, disopyramide  unknown  Inspiration = 60 mmHg Expiration = 100 mmHg  110  17  Female  83  2.0  37.8  Metoprolol, verapamil  Probable  Inspiration = 80 mmHg Expiration = 130 mmHg  100  18  Female  63  2.1  34.4  Nevibolol, verapamil  Yes  Inspiration = 29 mmHg Expiration = 60 mmHg  120  19  Female  72  2.7  32.1  Metoprolol, verapamil  Yes  Inspiration = 67 mmHg Expiration = 82 mmHg  Not performed  20  Male  55  2.1  45  Metoprolol  Yes  Inspiration = 44 mmHg Expiration = 73 mmHg  150  Case  Gender  Age (years)  Max wall thickness (cm)  BMI (kg/m2)  Medications  Obstructive sleep apnoea  Resting LVOT gradient (mmHg)  LVOT gradient during valsalva manoeuvre (mmHg)  1  Female  53  1.8  31  Metoprolol  Probable  Inspiration = 45 mmHg Expiration = 74 mmHg  80  2  Male  55  2.5  43  Metoprolol, verapamil  Yes  Inspiration = 37 mmHg Expiration = 61 mmHg  80  3  Male  56  2.2  25  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 16 mmHg Expiration = 46 mmHg  48  4  Male  67  2.2  27  Metoprolol  Yes  Inspiration = 58 mmHg Expiration = 133 mmHg  140  5  Male  78  2.0  25.3  Metoprolol  No  Inspiration = 31 mmHg Expiration = 64 mmHg  97  6  Male  73  2.0  31  Metoprolol, diltiazem  Probable  Inspiration = 36 mmHg Expiration = 71 mmHg  150  7  Female  59  2.4  44  Metoprolol  Yes  Inspiration = 71 mmHg Expiration = 110 mmHg  115  8  Female  56  2.0  42  Metoprolol  Yes  Inspiration = 18 mmHg Expiration = 34 mmHg  80  9  Male  40  2.9  39  Metoprolol  Yes  Inspiration = 47 mmHg Expiration = 71 mmHg  76  10  Male  56  2.5  42  Metoprolol, diltiazem  No  Inspiration = 25 mmHg Expiration = 48 mmHg  80  11  Female  28  2.0  43  Metoprolol, diltiazem, disopyramide  No  Inspiration = 34 mmHg Expiration = 63 mmHg  71  12  Female  70  2.2  28  Metoprolol, verapamil  Probable  Inspiration = 125 mmHg Expiration = 190 mmHg  190  13  Female  61  2.0  44.8  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 72 mmHg Expiration = 170 mmHg  160  14  Female  73  3.3  35  Atenolol  Yes  Inspiration = 60 mmHg Expiration = 130 mmHg  200  15  Female  74  1.8  25  Metoprolol, diltiazem  unknown  Inspiration = 61 mmHg Expiration = 91 mmHg  100  16  Female  69  2.1  29.1  Metoprolol, diltiazem, disopyramide  unknown  Inspiration = 60 mmHg Expiration = 100 mmHg  110  17  Female  83  2.0  37.8  Metoprolol, verapamil  Probable  Inspiration = 80 mmHg Expiration = 130 mmHg  100  18  Female  63  2.1  34.4  Nevibolol, verapamil  Yes  Inspiration = 29 mmHg Expiration = 60 mmHg  120  19  Female  72  2.7  32.1  Metoprolol, verapamil  Yes  Inspiration = 67 mmHg Expiration = 82 mmHg  Not performed  20  Male  55  2.1  45  Metoprolol  Yes  Inspiration = 44 mmHg Expiration = 73 mmHg  150  BMI, body mass index; LVOT, left ventricular outflow tract. Table 1 Characteristics of patient population Case  Gender  Age (years)  Max wall thickness (cm)  BMI (kg/m2)  Medications  Obstructive sleep apnoea  Resting LVOT gradient (mmHg)  LVOT gradient during valsalva manoeuvre (mmHg)  1  Female  53  1.8  31  Metoprolol  Probable  Inspiration = 45 mmHg Expiration = 74 mmHg  80  2  Male  55  2.5  43  Metoprolol, verapamil  Yes  Inspiration = 37 mmHg Expiration = 61 mmHg  80  3  Male  56  2.2  25  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 16 mmHg Expiration = 46 mmHg  48  4  Male  67  2.2  27  Metoprolol  Yes  Inspiration = 58 mmHg Expiration = 133 mmHg  140  5  Male  78  2.0  25.3  Metoprolol  No  Inspiration = 31 mmHg Expiration = 64 mmHg  97  6  Male  73  2.0  31  Metoprolol, diltiazem  Probable  Inspiration = 36 mmHg Expiration = 71 mmHg  150  7  Female  59  2.4  44  Metoprolol  Yes  Inspiration = 71 mmHg Expiration = 110 mmHg  115  8  Female  56  2.0  42  Metoprolol  Yes  Inspiration = 18 mmHg Expiration = 34 mmHg  80  9  Male  40  2.9  39  Metoprolol  Yes  Inspiration = 47 mmHg Expiration = 71 mmHg  76  10  Male  56  2.5  42  Metoprolol, diltiazem  No  Inspiration = 25 mmHg Expiration = 48 mmHg  80  11  Female  28  2.0  43  Metoprolol, diltiazem, disopyramide  No  Inspiration = 34 mmHg Expiration = 63 mmHg  71  12  Female  70  2.2  28  Metoprolol, verapamil  Probable  Inspiration = 125 mmHg Expiration = 190 mmHg  190  13  Female  61  2.0  44.8  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 72 mmHg Expiration = 170 mmHg  160  14  Female  73  3.3  35  Atenolol  Yes  Inspiration = 60 mmHg Expiration = 130 mmHg  200  15  Female  74  1.8  25  Metoprolol, diltiazem  unknown  Inspiration = 61 mmHg Expiration = 91 mmHg  100  16  Female  69  2.1  29.1  Metoprolol, diltiazem, disopyramide  unknown  Inspiration = 60 mmHg Expiration = 100 mmHg  110  17  Female  83  2.0  37.8  Metoprolol, verapamil  Probable  Inspiration = 80 mmHg Expiration = 130 mmHg  100  18  Female  63  2.1  34.4  Nevibolol, verapamil  Yes  Inspiration = 29 mmHg Expiration = 60 mmHg  120  19  Female  72  2.7  32.1  Metoprolol, verapamil  Yes  Inspiration = 67 mmHg Expiration = 82 mmHg  Not performed  20  Male  55  2.1  45  Metoprolol  Yes  Inspiration = 44 mmHg Expiration = 73 mmHg  150  Case  Gender  Age (years)  Max wall thickness (cm)  BMI (kg/m2)  Medications  Obstructive sleep apnoea  Resting LVOT gradient (mmHg)  LVOT gradient during valsalva manoeuvre (mmHg)  1  Female  53  1.8  31  Metoprolol  Probable  Inspiration = 45 mmHg Expiration = 74 mmHg  80  2  Male  55  2.5  43  Metoprolol, verapamil  Yes  Inspiration = 37 mmHg Expiration = 61 mmHg  80  3  Male  56  2.2  25  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 16 mmHg Expiration = 46 mmHg  48  4  Male  67  2.2  27  Metoprolol  Yes  Inspiration = 58 mmHg Expiration = 133 mmHg  140  5  Male  78  2.0  25.3  Metoprolol  No  Inspiration = 31 mmHg Expiration = 64 mmHg  97  6  Male  73  2.0  31  Metoprolol, diltiazem  Probable  Inspiration = 36 mmHg Expiration = 71 mmHg  150  7  Female  59  2.4  44  Metoprolol  Yes  Inspiration = 71 mmHg Expiration = 110 mmHg  115  8  Female  56  2.0  42  Metoprolol  Yes  Inspiration = 18 mmHg Expiration = 34 mmHg  80  9  Male  40  2.9  39  Metoprolol  Yes  Inspiration = 47 mmHg Expiration = 71 mmHg  76  10  Male  56  2.5  42  Metoprolol, diltiazem  No  Inspiration = 25 mmHg Expiration = 48 mmHg  80  11  Female  28  2.0  43  Metoprolol, diltiazem, disopyramide  No  Inspiration = 34 mmHg Expiration = 63 mmHg  71  12  Female  70  2.2  28  Metoprolol, verapamil  Probable  Inspiration = 125 mmHg Expiration = 190 mmHg  190  13  Female  61  2.0  44.8  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 72 mmHg Expiration = 170 mmHg  160  14  Female  73  3.3  35  Atenolol  Yes  Inspiration = 60 mmHg Expiration = 130 mmHg  200  15  Female  74  1.8  25  Metoprolol, diltiazem  unknown  Inspiration = 61 mmHg Expiration = 91 mmHg  100  16  Female  69  2.1  29.1  Metoprolol, diltiazem, disopyramide  unknown  Inspiration = 60 mmHg Expiration = 100 mmHg  110  17  Female  83  2.0  37.8  Metoprolol, verapamil  Probable  Inspiration = 80 mmHg Expiration = 130 mmHg  100  18  Female  63  2.1  34.4  Nevibolol, verapamil  Yes  Inspiration = 29 mmHg Expiration = 60 mmHg  120  19  Female  72  2.7  32.1  Metoprolol, verapamil  Yes  Inspiration = 67 mmHg Expiration = 82 mmHg  Not performed  20  Male  55  2.1  45  Metoprolol  Yes  Inspiration = 44 mmHg Expiration = 73 mmHg  150  BMI, body mass index; LVOT, left ventricular outflow tract. Group 1 patients were all overweight [body mass index (BMI) greater than 25 kg/m2], and 15 (75%) patients were obese (BMI >30 kg/m2). In Group 1, mean BMI was 35.1 kg/m2 + 7.3. Of the 20 patients, 15 (75%) patients were noted to have sleep-disordered breathing [11 had obstructive sleep apnoea (OSA) and 4 patients with probable OSA on the basis of abnormal overnight pulse oximetry]. One patient was noted to have chronic obstructive pulmonary disease—no other respiratory disorders were noted in clinical history. Group 1 patients were all in sinus rhythm throughout the study, and no meaningful changes in R–R interval were noted during spectral Doppler recording [inspiration mean R–R interval 945.86 ms, expiration mean R–R interval 947.11 ms, and mean difference was −1.25 ms (−17.35 to 44.0)]. All Group 1 patients had LVOT obstruction at rest (65.9 ± 32.6 mmHg), which increased during Valsalva manoeuvre (113 ± 41.8 mmHg). LVOT gradients varied widely during the respiratory cycle in all 20 patients in this study group (3 case examples—Figures 1–3). Peak gradients were uniformly lowest during inspiration (50.8 mmHg ± 25.6) and highest during expiration (90.1 mmHg ± 41.8) (P < 0.05) (Figure 4). On average, there was 82.4% ± 39.1 (P < 0.0001) increase in gradient from inspiration to expiration. This change in gradient could not be accounted for by changes in heart rate, as R–R intervals were similar throughout the recordings and no ectopy was noted on EKG tracings. Figure 1 View largeDownload slide Transthoracic echocardiogram images with respirometer. This patient is a 73-year-old man (Case 6) with hypertrophic obstructive cardiomyopathy with basal septal hypertrophy, measuring 2.0 cm and systolic anterior motion of mitral valve leaflets (Panel A). He was obese (BMI 31 kg/m2) and was also noted to have moderate pulmonary hypertension (PASP 51 mmHg). Panel B demonstrates initial spectral Doppler performed on patient to quantify the left ventricular outflow (LVOT) obstruction. Note the variation in velocities is beat to beat, but there is cyclical grouping of beats suggestive of respiratory-related variation. Without a respirometer, it could be surmised that the third beat (highest velocity) occurred during inspiration when LVOT obstruction would be expected to increase as preload decreased. However, in Panel C, when a respirometer was placed, a paradox was observed (upward deflection represents inspiration, downward deflection represents expiration). During inspiration, the LVOT obstruction decreased (the second and fifth beats) and increased during expiration (third, fourth, and sixth beats). Figure 1 View largeDownload slide Transthoracic echocardiogram images with respirometer. This patient is a 73-year-old man (Case 6) with hypertrophic obstructive cardiomyopathy with basal septal hypertrophy, measuring 2.0 cm and systolic anterior motion of mitral valve leaflets (Panel A). He was obese (BMI 31 kg/m2) and was also noted to have moderate pulmonary hypertension (PASP 51 mmHg). Panel B demonstrates initial spectral Doppler performed on patient to quantify the left ventricular outflow (LVOT) obstruction. Note the variation in velocities is beat to beat, but there is cyclical grouping of beats suggestive of respiratory-related variation. Without a respirometer, it could be surmised that the third beat (highest velocity) occurred during inspiration when LVOT obstruction would be expected to increase as preload decreased. However, in Panel C, when a respirometer was placed, a paradox was observed (upward deflection represents inspiration, downward deflection represents expiration). During inspiration, the LVOT obstruction decreased (the second and fifth beats) and increased during expiration (third, fourth, and sixth beats). Figure 2 View largeDownload slide Respiratory variation in multiple breathing cycles. This 67-year-old man (Case 4) with hypertrophic obstructive cardiomyopathy was noted to have asymmetric septal hypertrophy (both mid- and basal hypertrophy), maximum wall thickness 2.2 cm (Panel A). His symptoms had been controlled with beta-blockers only. This patient was mildly overweight (BMI 27 kg/m2) and was diagnosed to have obstructive sleep apnoea. As seen in Panel B, he initially also was noted to have phasic variation in left ventricular outflow (LVOT) obstruction during normal inspiration in the awake state. In Panels C and D, with simultaneously recorded respirometer and with adjustment of sweep speed, one can see multiple respiratory cycles with decreased LVOT obstruction evident during inspiration and maximal LVOT obstruction noted during expiration. Figure 2 View largeDownload slide Respiratory variation in multiple breathing cycles. This 67-year-old man (Case 4) with hypertrophic obstructive cardiomyopathy was noted to have asymmetric septal hypertrophy (both mid- and basal hypertrophy), maximum wall thickness 2.2 cm (Panel A). His symptoms had been controlled with beta-blockers only. This patient was mildly overweight (BMI 27 kg/m2) and was diagnosed to have obstructive sleep apnoea. As seen in Panel B, he initially also was noted to have phasic variation in left ventricular outflow (LVOT) obstruction during normal inspiration in the awake state. In Panels C and D, with simultaneously recorded respirometer and with adjustment of sweep speed, one can see multiple respiratory cycles with decreased LVOT obstruction evident during inspiration and maximal LVOT obstruction noted during expiration. Figure 3 View largeDownload slide Respiratory variation of great magnitude. This 73-year-old woman (Case 14) with HCM had basal septal hypertrophy and severe left ventricular outflow obstruction. She was diagnosed with obstructive sleep apnoea. She was also obese (BMI of 35 kg/m2). Note the marked variation with respiration with marked decrease in LV outflow gradient with inspiration (inspiration = 60 mmHg, expiration = 130 mmHg). Figure 3 View largeDownload slide Respiratory variation of great magnitude. This 73-year-old woman (Case 14) with HCM had basal septal hypertrophy and severe left ventricular outflow obstruction. She was diagnosed with obstructive sleep apnoea. She was also obese (BMI of 35 kg/m2). Note the marked variation with respiration with marked decrease in LV outflow gradient with inspiration (inspiration = 60 mmHg, expiration = 130 mmHg). Figure 4 View largeDownload slide This graph demonstrates each case’s inspiratory and expiratory maximum gradient. Figure 4 View largeDownload slide This graph demonstrates each case’s inspiratory and expiratory maximum gradient. Mitral annulus flow was performed and TVI was measured in 11 patients at inspiration and at expiration. In these patients, average inspiration TVI was significantly smaller than average expiration TVI (inspiration 14.3 cm ± 3.8 vs. expiration TVI 17.0 ± 4.3, P = 0.0007). During inspiration, there was a 15.9% decline in preload compared with expiration. IVRT was recorded in 16 patients, and mean IVRT at inspiration was longer than at expiration [inspiration 110.9 ms ± 28.5 vs. expiration 83.0 ms ± 23.7 (P < 0.0001)]. Correspondingly, ET was shorter during inspiration [inspiration 314.6 ms ± 24.6 vs. expiration 339.9 ms ± 27.3 (P < 0.0001)]. Six patients underwent cardiac catheterization. Pressure recordings were obtained in the cardiac catheterization laboratory along with a respirometer to mark inspiration and expiration. As can be seen in these two examples from patients (Figure 5A and B), respiratory variation was noted in the cardiac catheterization laboratory as well. Figure 5 View largeDownload slide Tracings from cardiac catheterization laboratory. (Panel A) This 56-year-old man (Case 3) was referred for alcohol septal ablation after having persistent symptoms on maximal medical therapy. Simultaneous left ventricle and aortic pressure tracings showed the effect of respiration on left ventricular (LV) outflow gradients. In Beat 1 (expiration), LVOT obstruction was severe, gradient = 60 mmHg. With inspiration, it decreased significantly and, in Beat 4, LVOT obstruction = 25 mmHg; in Beat 5, LVOT obstruction was abolished. With expiration, it recurred; in Beats 6–10, LVOT obstruction was again 60 mmHg. The red arrow demonstrates the negative intrathoracic pressure (−20 mmHg) generated by inspiration. (Panel B) This patient is a 61-year-old woman (Case 13) also referred for alcohol septal ablation. In Beats 1–3, during inspiration, LVOT gradient = 30 mmHg and note the contour of the aortic pressure tracing (red line) is normal. During expiration, LV pressure markedly increased to 210 mmHg and aortic pressure decreased to 100 mmHg; LVOT gradient = 110 mmHg. Note the aortic pressure tracing contour developed the classic ‘spike-and-dome’ appearance during expiration. This tracing demonstrates ‘pulsus paradoxus reverses’ in that contrary to the expected drop in blood pressure of greater than 10 mmHg during inspiration in pulsus paradoxus, and our patient demonstrated reversed haemodynamic teachings of an inspiratory increase in aortic pressure. Figure 5 View largeDownload slide Tracings from cardiac catheterization laboratory. (Panel A) This 56-year-old man (Case 3) was referred for alcohol septal ablation after having persistent symptoms on maximal medical therapy. Simultaneous left ventricle and aortic pressure tracings showed the effect of respiration on left ventricular (LV) outflow gradients. In Beat 1 (expiration), LVOT obstruction was severe, gradient = 60 mmHg. With inspiration, it decreased significantly and, in Beat 4, LVOT obstruction = 25 mmHg; in Beat 5, LVOT obstruction was abolished. With expiration, it recurred; in Beats 6–10, LVOT obstruction was again 60 mmHg. The red arrow demonstrates the negative intrathoracic pressure (−20 mmHg) generated by inspiration. (Panel B) This patient is a 61-year-old woman (Case 13) also referred for alcohol septal ablation. In Beats 1–3, during inspiration, LVOT gradient = 30 mmHg and note the contour of the aortic pressure tracing (red line) is normal. During expiration, LV pressure markedly increased to 210 mmHg and aortic pressure decreased to 100 mmHg; LVOT gradient = 110 mmHg. Note the aortic pressure tracing contour developed the classic ‘spike-and-dome’ appearance during expiration. This tracing demonstrates ‘pulsus paradoxus reverses’ in that contrary to the expected drop in blood pressure of greater than 10 mmHg during inspiration in pulsus paradoxus, and our patient demonstrated reversed haemodynamic teachings of an inspiratory increase in aortic pressure. The 20 patients in Group 2 had a mean age of 56.7 years ± 17.0, and mean septal wall thickness was 2.24 cm ± 0.5. In six of these patients, genotype testing identified pathogenic mutations. In these patients, there were no significant differences in maximal wall thickness or resting LVOT obstruction between the study and the control groups. However, mean BMI was significantly smaller in the control group (study group 35.1 ± 7.3 vs. control group 28.4 ± 4.8, P = 0.0013). Only five patients in Group 2 were noted to have OSA (n = 4 definite OSA, n = 1 probable OSA on the basis of nightly pulse oximetry testing) compared with 15 patients with sleep-disordered breathing in Group 1. Discussion This case series demonstrates the profound effect of quiet and spontaneous respiration on LVOT obstruction in select obese and awake patients with HCM. Inspiration was uniformly noted to have the lowest gradients, whereas the highest gradients were noted during expiration. These observations in our patients are unexpected and counterintuitive, contradicting the traditional teaching of the haemodynamic effects of respiration on the heart, which have focused on volume changes in the left and right hearts with breathing.8,9 During normal respiration, negative intrathoracic pressure during inspiration leads to increased systemic venous return to the right side, leading to increase in right atrial and right ventricle filling. As the lungs expand, the pulmonary vascular bed increases its capacitance and blood pools in these vessels, leading to decreased filling of the left atrium and left ventricle (decreased preload). These variations are small in healthy individuals and of little significant haemodynamic consequence as evidenced by minor variations in mitral and tricuspid valve inflow in healthy individuals and a small decrease in systemic stroke volume and in blood pressure as a consequence. This volume-based theory also forms the basis of our understanding of cardiac murmur intensity in valvular diseases—left-sided murmurs decrease in intensity due to decreased preload during inspiration, whereas the intensity of right-sided murmurs increases.5 If one extends the volume-based model to HCM patients with LVOT obstruction, then decreased LV preload with inspiration intuitively should lead to an increase in LVOT obstruction. We noted that, in 11 patients with data available, LV inflow was, indeed, reduced during inspiration by 15.9%. Instead, we observed a counterintuitive decrease in LVOT obstruction with inspiration. We were able to measure ET and IVRT in relation with the phases of respiration in 16 of 20 patients. LV ET increased during expiration (inspiration mean 314.6 ms vs. expiration mean 339.9 ms, P < 0.0001), consistent with the observed increased LVOT obstruction during expiration. Mean IVRT was 110.9 ms during inspiration and 83.0 ms during expiration (P < 0.0001). IVRT shortened during expiration on account of two mechanisms: first, due to prolongation of ET from increased LVOT obstruction; secondly, as a result of increased LA pressure from increased MR when the LV outflow gradient was maximum, which is expected to result in worsening mitral regurgitation, in turn, increasing the left atrial pressure in conjunction with increased left atrial filling from pulmonary veins during expiration. IVRT was significantly longer during inspiration, reflecting a shorter ET as well as reduced left atrial pressure from, inferred to be from, less LVOT obstruction and decreased pulmonary venous flow into the left atrium. Hence, the observed changes are real changes in haemodynamics with respiration and do not represent spurious findings due to changes in the angle of insonation during respiration. If preload changes were the predominant effect of respiration on the heart, an inspiratory reduction in LV preload would reduce the separation of the anterior mitral leaflets from the ventricular septum, thus increasing LV outflow obstruction. Therefore, deductive reasoning would lead to the conclusion that inspiration should lead to increased LV outflow obstruction in HCM. Instead, we observed a counterintuitive decrease in LV outflow obstruction with inspiration. Looking for an explanation for our observations, we searched the literature and discovered that these observations were first recorded in a case series over 50 years ago in 1965.10 Shah et al.10 studied nine patients in the cardiac catheterization laboratory. They instructed their sedated patients to take deep inspirations during their pressure recordings (exaggerated respiration). They noted a decrease in LVOT obstruction with deep inspiration; they concluded that LV volume increased with inspiration, contrary to traditional teaching, and used that explanation for their observations. In 1973, Massumi published a case report of two patients with HCM, who were also obese.11 They also noted a decrease in LVOT obstruction with inspiration; however, they concluded that the reason LVOT obstruction increased with expiration was that exaggerated expiration equalled a mild Valsalva manoeuvre. They termed this observation ‘reversed pulsus paradoxus.’ Buda et al.12 reported, in 1981, a series of nine patients with muscular subaortic stenosis who underwent cardiac catheterization. These sedated patients were instructed to take deep breaths during the haemodynamic study, and a decrease in LVOT gradients were observed with deep inspiration (60 + 11 mmHg vs. 34 + 6 mmHg). These authors postulated that deep inspiration increased the LV transmural pressure (LVTMP), effectively increasing LV afterload, and decreasing LVOT obstruction. These observations of respiratory-induced changes in LVOT obstruction remained buried in the literature for three decades, until two case reports published in 2004 and 2010, each based upon a single patient from the same institution (Mayo Clinic).13,14 Brilakas et al.13 and Schwartenzberg et al.14 also noted this observation in sedated patients in the cardiac catheterization laboratory. Thus, our study is the only study to date in the literature to document this haemodynamic paradox prospectively in non-sedated and non-fasting patients during normal, quiet spontaneous respiration. This is significant, as it suggests that this observation occurs in the daily life of overweight patients with HCM and sleep-disordered breathing. Thus, this select group of patients with obstructive HCM have marked variations in the severity of their obstruction in a resting state, and this severity is likely compounded when exposed to other haemodynamic factors. The soundest explanation for our findings appears to be an increase in LVTMP with inspiration (Figure 6). In addition to changes in LV preload, LVOT obstruction is well known to be sensitive to afterload changes,15 as seen by response to inhalation of amyl nitrite leading to peripheral arterial vasodilation, which decreases afterload, leading to increased LVOT obstruction. On the contrary, handgrip manoeuvre or infusion of phenylephrine leads to peripheral vasoconstriction, which increase afterload, resulting in a decrease in LVOT obstruction. Therefore, we theorize that the transmission of increased negative intrathoracic pressure results in an increase of LV afterload via LVTMP. This effective afterload increase results in reduced LVOT obstruction, analogous to a handgrip manoeuvre. LVTMP is the systolic pressure corrected for intrathoracic pressure (LVTMP = systolic pressure − intrapleural pressure)16 and is considered to be a more accurate representation of cardiac afterload, and studies have also demonstrated that LVTMP is increased in inspiration.16–18 During inspiration, the intrathoracic pressure becomes negative, and, thus, even though systolic arterial pressure may decrease slightly, the net effect is a slight increase in LVTMP. We documented this in six patients who underwent haemodynamic evaluation in the cardiac catheterization laboratory—as the patients deeply inspired, intrathoracic pressure became markedly negative, thus increasing LVTMP (increased afterload) and resulting in a decrease in LVOT obstruction despite decreased preload. As LVOT gradients in HCM are known to be extremely labile based on loading conditions, therefore increased LV afterload (LVTMP) over-rode the effect of decreased preload and results in the reduction of obstructive gradients we observed during inspiration. In the normal healthy heart, preload mediated effects are predominant, whereas in HCM patients, afterload sensitivity can be profound. Figure 6 View largeDownload slide Schematic of LVTMP. This schematic of the left ventricular transmural pressure shows the multifactorial effect of inspiration on the left and right ventricle. Figure 6 View largeDownload slide Schematic of LVTMP. This schematic of the left ventricular transmural pressure shows the multifactorial effect of inspiration on the left and right ventricle. In our study, all patients were overweight and a high percentage had sleep-disordered breathing. Both issues could be contributing to generation of greater negative intrathoracic pressure during quiet inspiration, thus leading to increased LV wall stress. OSA is known to decrease lung compliance, thus augmenting negative intrathoracic pressure changes during inspiration. Inspiration against a threshold load has been demonstrated to further decrease the relative LV stroke volume through an increase in end-systolic volume.19 Obese patients also demonstrate reduced lung compliance,20 and this reduction is proportional to BMI—as BMI increases, lung compliance reduces. This relationship is particularly seen in the recumbent position.21,22 Thus, sleep-disordered breathing and obesity decrease lung compliance by virtue of increasing the negative intrathoracic pressure that must be generated for any given tidal volume—these larger swings may offer an explanation for our observation in these 20 cases. Furthermore, we speculate that our observation may offer a link between observed morbidity in patients with HCM and sleep-disordered breathing.23 Mechanistically, clinicians understand the relationship between preload and LVOT obstruction, i.e. an increase in LVOT obstruction during inspiration due to a decrease in LV preload. The concept that afterload is also increased during inspiration and can over-ride the effect of decreased preload, hence decreasing LVOT obstruction, is not one that is widely known to clinicians. Our report doubles the number of cases in which this observation has been reported, thus offering a redux of this paradox initially described over 50 years ago. Study limitations Limitations include the inability to directly measure intrathoracic pressure. In addition, volumetric analysis of the left ventricle was not performed at inspiration and expiration due to limitations of image acquisition. Additionally, it is unknown at what critical negative inspiratory thoracic pressure the LVTMP will overcome the opposing influences of decreased preload during inspiration. It is also important to point out the inherent limitation that may exist in interpreting data across several respiratory and cardiac cycles, as a normal respiratory cycle extends across several cardiac cycles. The heart also exhibits translational motion during respiration, although the order of magnitude of change in LV outflow gradients demonstrated here surpasses the minor changes that can be demonstrated with mild angle variations during respiration; additionally, echocardiograms were performed under direct supervision of the senior author to ensure that translational motion on angle of Doppler recording was minimal; particular attention was also paid to patient breathing, to ensure normal, quiet, spontaneous respiration, and not exaggerated respiration. In addition, changes in preload, afterload, and intrathoracic pressure do not occur in isolation, and an integrative approach is needed to understand the summative effects of these respiratory changes on cardiac haemodynamics. This study provides an assessment of 20 patients observed through clinical practice in a dedicated Hypertrophic Cardiomyopathy Clinic; as not all patients with HCM and LVOT obstruction routinely underwent gradient measurements with respiration, it is possible that many other patients could have been detected. Conclusions We report the largest case series of respiratory variation of LVOT obstruction in HCM in non-sedated patients during normal quiet respiration. We noted these significant and counterintuitive variations based only on conventional preload mechanisms. This study provides evidence of changes in LVOT gradients with spontaneous respiration in HCM patients, challenging traditional haemodynamic concepts. These findings provide a foundation for future studies to help identify the mechanistic considerations and clinical implications of altered respiratory mechanics in HCM patients, particularly in those who are obese and in those with sleep-disordered breathing. These findings also have significant clinical implications on the diagnosis and assessment of severity of obstructive HCM. Conflict of interest: None declared. Acknowledgements The authors thank Zach Singsank, D.O., for his assistance in collecting recordings from the cardiac catheterization laboratory. The authors gratefully acknowledge Susan Nord and Jennifer Pfaff of Aurora Cardiovascular Services for editorial preparation of the manuscript, and Brian Miller and Brian Schurrer of Aurora Research Institute for their help in preparing figures. References 1 Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT et al.   Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation  2006; 114: 2232– 9. Google Scholar CrossRef Search ADS PubMed  2 Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA et al.   Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med  2003; 348: 295– 303. Google Scholar CrossRef Search ADS PubMed  3 Elliott PM, Gimeno JR, Tomé MT, Shah J, Ward D, Thaman R et al.   Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J  2006; 27: 1933– 41. Google Scholar CrossRef Search ADS PubMed  4 Authors/Task Force members, Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS et al.   2011 ACCF/AHA guidelines for the diagnosis and treatment of hypertrophic cardiomyopathy. J Am Coll Cardiol  2011; 58: e212– 60. Google Scholar CrossRef Search ADS PubMed  5 Braunwald E, Zipes DP, Libby P, Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine , 9th ed. Philadelphia, PA: Saunders; 2011. 6 Fuster V, O’rourke RA, Walsh RA, Poole-Wilson P, Hurst’s The Heart , 12th ed. New York, NY: The McGraw-Hill Medical Publishing Division; 2008. 7 Tajik AJ, Jan MF, Hypertrophic cardiomyopathy. In: Chatterjee K, ed. Cardiology: An Illustrated Textbook . New Delhi, India: Jaypee Brothers Medical Publishers; 2013. 8 Shuler RH, Ensor C, Gunning RE, Moss WG, Johnson V. The differential effects of respiration on the left and right ventricles. Am J Physiology  1942; 137: 620– 7. 9 Santamore WP, Lynch PR, Meier G, Heckman J, Bove AA. Myocardial interaction between the ventricles. J Appl Physiol  1976; 41: 362– 8. Google Scholar PubMed  10 Shah PM, Yipintsoi T, Amarasingham R, Oakley CM. Effects of respiration on the hemodynamics of hypertrophic obstructive cardiomyopathy. Am J Cardiol  1965; 15: 793– 800. Google Scholar CrossRef Search ADS PubMed  11 Massumi RA, Mason DT, Vera Z, Zelis R, Otero J, Amsterdam EA et al.   Reversed pulsus paradoxus. N Engl J Med  1973; 289: 1272– 5. Google Scholar CrossRef Search ADS PubMed  12 Buda AJ, MacKenzie GW, Wigle ED. Effect of negative intrathoracic pressure on left ventricular outflow tract obstruction in muscular subaortic stenosis. Circulation  1981; 63: 875– 81. Google Scholar CrossRef Search ADS PubMed  13 Brilakis ES, Nishimura RA. Dynamic respiratory changes in hypertrophic cardiomyopathy. Heart  2004; 90: 296. Google Scholar CrossRef Search ADS PubMed  14 Schwartzenberg S, Sorajja P. Cardiac tamponade or normal respiratory variation? An illustrative case of septal ablation for obstructive hypertrophic cardiomyopathy. Catheter Cardiovasc Interv  2010; 76: 901. Google Scholar CrossRef Search ADS PubMed  15 Wigle ED, David PR, Labroose CJ, McMeekan J. Muscular subaortic stenosis; the interrelation of wall tension, outflow tract “distending pressure” and orifice radius. Am J Cardiol  1965; 15: 761– 72. Google Scholar CrossRef Search ADS PubMed  16 Buda AJ, Pinsky MR, Ingels NBJr, Daughters GT2nd, Stinson EB, Alderman EL. Effect of intrathoracic pressure on left ventricular performance. N Engl J Med  1979; 301: 453. Google Scholar CrossRef Search ADS PubMed  17 Summer WR, Permutt S, Sagawa K, Shoukas AA, Bromberger-Barnea B. Effects of spontaneous respiration on canine left ventricular function. Circ Res  1979; 45: 719– 28. Google Scholar CrossRef Search ADS PubMed  18 Tyson GSJr, Maier GW, Olsen CO, Davis JW, Rankin JS. Pericardial influences on ventricular filling in the conscious dog. An analysis based on pericardial pressure. Circ Res  1984; 54: 173– 84. Google Scholar CrossRef Search ADS PubMed  19 Karam M, Wise RA, Natarajan TK, Permutt S, Wagner HN. Mechanism of decreased left ventricular stroke volume during inspiration in man. Circulation  1984; 69: 866– 73. Google Scholar CrossRef Search ADS PubMed  20 Salome CM, King GG, Berend N. Physiology of obesity and effects on lung function. J Appl Physiol  2010; 108: 206– 11. Google Scholar CrossRef Search ADS PubMed  21 Parameswaran K, Todd DC, Soth M. Altered respiratory physiology in obesity. Can Respir J  2006; 13: 203– 10. Google Scholar CrossRef Search ADS PubMed  22 Pelosi P, Croci M, Ravagnan I, Tredici S, Pedoto A, Lissoni A et al.   The effects of body mass on lung volumes, respiratory mechanics, and gas exchange during general anesthesia. Anesth Analg  1998; 87: 654– 60. Google Scholar PubMed  23 Sengupta PP, Sorajja D, Eleid MF, Somers VK, Ommen SR, Parish JM et al.   Hypertrophic obstructive cardiomyopathy and sleep-disordered breathing: an unfavorable combination. Nat Clin Pract Cardiovasc Med  2009; 6: 14– 5. Google Scholar CrossRef Search ADS PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

Marked respiratory-related fluctuations in left ventricular outflow tract gradients in hypertrophic obstructive cardiomyopathy: an observational study

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Oxford University Press
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.
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2047-2404
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10.1093/ehjci/jex215
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Abstract

Abstract Aims Left ventricular outflow (LVOT) obstruction in patients with hypertrophic cardiomyopathy (HCM) is dynamic and sensitive to many variables that affect left ventricular preload, afterload, and contractility. The haemodynamic effect of normal respiration on LVOT obstruction has not been described. Methods and results We examined 20 patients with HCM who were noted to have phasic respiratory variation of LVOT obstruction on initial transthoracic 2D echocardiogram and Doppler examination. LVOT gradients were re-examined with simultaneous recording of a respirometer. LVOT gradients varied widely during the respiratory cycle; peak gradients were uniformly lowest during inspiration (50.8 mmHg + 25.6) and highest during expiration (90.1 mmHg + 41.8). On average, there was 82.4% ± 39.1 (P ≤ 0.0001) incremental change from inspiration to expiration, in the severity of LVOT obstruction. In 11 patients with mitral annulus inflow, LV inflow (preload) was decreased during inspiration. In 16 patients with isovolumic relaxation time and ejection time measurements, decreased left atrial filling pressure was noted during inspiration, consistent with decreased LVOT obstruction. When compared with a control group of 20 HCM patients who did not have respiratory variation, the study group patients were more overweight (mean body mass index cases 35.1 ± 7.3 vs. control group 29.1 ± 5.1, P = 0.0045) and more likely to have sleep-disordered breathing (n = 15 study group, n = 5 control group). Conclusions Counterintuitive respiratory-related fluctuations in LVOT gradients were observed in this case series of 20 HCM patients. These findings challenge traditional haemodynamic teaching and demonstrate the contribution of LV transmural pressure to LVOT obstruction in certain HCM patients. hypertrophic cardiomyopathy, echocardiography, obstructive sleep apnoea Introduction Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac condition, and left ventricular (LV) outflow obstruction, present at rest or induced (by Valsalva maneuver, exercise amyl nitrite inhalation) in the majority of patients with HCM, is recognized as an important cause of morbidity and mortality.1–3 Management of symptomatic obstructive HCM ranges from medications and lifestyle modifications to more invasive treatment options including alcohol septal ablation and surgical septal myectomy forming a key part of management of patients with HCM.4 For this reason, the accurate assessment of left ventricular outflow tract (LVOT) obstruction is clinically important. In daily clinical practice, this assessment is performed by transthoracic 2D echocardiogram (TTE) and Doppler examination. The dynamic nature of LVOT obstruction has been documented for more than 50 years. It is also well known that changes in preload, afterload, and contractility can produce profound effects in the magnitude of LVOT obstruction. This phenomenon is well illustrated at the bedside with dynamic auscultation. The murmur of LVOT obstruction increases in intensity during Valsalva strain and on assuming upright/standing position (proposed mechanism—reduced preload). Conversely, the LVOT obstruction decreases, and the murmur gets softer on passive leg raising and on prompt squatting (proposed mechanism—increased preload). However, the effect of normal respiration and respiratory-related changes in gradient is not described in any standard cardiology textbooks.5–7 We, therefore, describe LVOT obstruction in HCM patients related to the phases of respiration. Methods We evaluated patients with obstructive HCM seen at the Hypertrophic Cardiomyopathy Outpatient Clinic at Aurora Health Care, St. Luke’s Medical Center, Milwaukee, WI, USA. Comprehensive TTE was performed by dedicated sonographers as part of the HCM clinic evaluation immediately prior to cardiac consultation. All patients were awake and breathing normally during the examination. Echocardiograms were acquired using GE Vivid E9 and E95 platforms (GE Vingmed Ultrasound Medical Systems, Milwaukee, WI, USA). Assessment of LVOT obstruction was performed from the apical window (apical long-axis or apical five-chamber views) using continuous-wave spectral Doppler; peak gradient was calculated from peak velocity using the modified Bernoulli equation. Resting gradients as well as gradients during the Valsalva manoeuvre were obtained. TTE images were routinely reviewed prior to the patient leaving the echocardiography suite. Significant variations in LVOT velocities were observed in the continuous-wave Doppler tracings of some patients. This variation was noted to be significant and not beat-to-beat dependent but rather appeared cyclical over several heart beats—the pattern and timing suggested that the variation was related to respiratory cycles. This prompted the use of a respirometer, which revealed counterintuitive findings of lower gradients during inspiration and higher gradients during expiration. These observations were noted in 20 patients described in this report (Group 1). LVOT gradients were reassessed in relationship to respiratory stages (inspiration and expiration) and these dedicated images were acquired. Furthermore, during acquisition of these Doppler signals, particular attention was also directed to avoid any mixing of the LVOT obstruction Doppler signals with mitral regurgitation signals. We also ensured that the strength of the signals of mitral inflow and LV outflow were similar, minimizing any minor change in angle of insonation with respiration. In this study, LV end-diastolic volume assessment was not performed; instead, in 11 patients, mitral annulus flow was interrogated to evaluate changes in LV inflow (preload) with respiration. Pulsed-wave Doppler sample volume was placed at mitral annulus, and time velocity integral (TVI) was measured during inspiration and expiration. Additionally, in 16 patients, isovolumic relaxation time (IVRT) and ejection time (ET) were also measured during inspiration and expiration. Invasive cardiac haemodynamics in six patients were evaluated in the cardiac catheterization laboratory with simultaneous recordings of pressure in the aorta and the left ventricle. Clinical variables were queried from the Aurora Health Care electronic health record (EPIC Systems, Verona, WI, USA). Clinical information on an additional 20 cases of HCM seen in the Hypertrophic Cardiomyopathy Clinic was collected and formed the control group (Group 2)—these patients were selected if they demonstrated septal hypertrophy with resting LVOT obstruction, and no respiratory variation was noted on their Doppler tracings. Approval for this study was granted by the Aurora Health Care Institutional Review Board. Data were analysed using STATA 12.0 and reported as means with standard deviations when applicable. Statistical significance was defined as P-value <0.05. Results Twenty patients are included in this case series (Group 1)—a summary of patient characteristics are presented in Table 1. Mean age of patients was 62.1 ± 13.1 years, and 12 patients (60%) were female. All patients had significant septal hypertrophy, with the average septal thickness of 2.18 cm ± 0.29 cm. Eleven patients underwent genetic testing, and four patients were found to have pathogenic mutations. Of the 11 patients who underwent cardiac MRI, 9 patients were noted to have delayed enhancement with gadolinium. All patients were taking beta-blockers at the time of TTE—11 patients were additionally prescribed calcium channel blocker and 4 patients were also taking disopyramide. Implantable cardiac defibrillators were in place in four patients. Six patients subsequently underwent alcohol septal ablation. Table 1 Characteristics of patient population Case  Gender  Age (years)  Max wall thickness (cm)  BMI (kg/m2)  Medications  Obstructive sleep apnoea  Resting LVOT gradient (mmHg)  LVOT gradient during valsalva manoeuvre (mmHg)  1  Female  53  1.8  31  Metoprolol  Probable  Inspiration = 45 mmHg Expiration = 74 mmHg  80  2  Male  55  2.5  43  Metoprolol, verapamil  Yes  Inspiration = 37 mmHg Expiration = 61 mmHg  80  3  Male  56  2.2  25  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 16 mmHg Expiration = 46 mmHg  48  4  Male  67  2.2  27  Metoprolol  Yes  Inspiration = 58 mmHg Expiration = 133 mmHg  140  5  Male  78  2.0  25.3  Metoprolol  No  Inspiration = 31 mmHg Expiration = 64 mmHg  97  6  Male  73  2.0  31  Metoprolol, diltiazem  Probable  Inspiration = 36 mmHg Expiration = 71 mmHg  150  7  Female  59  2.4  44  Metoprolol  Yes  Inspiration = 71 mmHg Expiration = 110 mmHg  115  8  Female  56  2.0  42  Metoprolol  Yes  Inspiration = 18 mmHg Expiration = 34 mmHg  80  9  Male  40  2.9  39  Metoprolol  Yes  Inspiration = 47 mmHg Expiration = 71 mmHg  76  10  Male  56  2.5  42  Metoprolol, diltiazem  No  Inspiration = 25 mmHg Expiration = 48 mmHg  80  11  Female  28  2.0  43  Metoprolol, diltiazem, disopyramide  No  Inspiration = 34 mmHg Expiration = 63 mmHg  71  12  Female  70  2.2  28  Metoprolol, verapamil  Probable  Inspiration = 125 mmHg Expiration = 190 mmHg  190  13  Female  61  2.0  44.8  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 72 mmHg Expiration = 170 mmHg  160  14  Female  73  3.3  35  Atenolol  Yes  Inspiration = 60 mmHg Expiration = 130 mmHg  200  15  Female  74  1.8  25  Metoprolol, diltiazem  unknown  Inspiration = 61 mmHg Expiration = 91 mmHg  100  16  Female  69  2.1  29.1  Metoprolol, diltiazem, disopyramide  unknown  Inspiration = 60 mmHg Expiration = 100 mmHg  110  17  Female  83  2.0  37.8  Metoprolol, verapamil  Probable  Inspiration = 80 mmHg Expiration = 130 mmHg  100  18  Female  63  2.1  34.4  Nevibolol, verapamil  Yes  Inspiration = 29 mmHg Expiration = 60 mmHg  120  19  Female  72  2.7  32.1  Metoprolol, verapamil  Yes  Inspiration = 67 mmHg Expiration = 82 mmHg  Not performed  20  Male  55  2.1  45  Metoprolol  Yes  Inspiration = 44 mmHg Expiration = 73 mmHg  150  Case  Gender  Age (years)  Max wall thickness (cm)  BMI (kg/m2)  Medications  Obstructive sleep apnoea  Resting LVOT gradient (mmHg)  LVOT gradient during valsalva manoeuvre (mmHg)  1  Female  53  1.8  31  Metoprolol  Probable  Inspiration = 45 mmHg Expiration = 74 mmHg  80  2  Male  55  2.5  43  Metoprolol, verapamil  Yes  Inspiration = 37 mmHg Expiration = 61 mmHg  80  3  Male  56  2.2  25  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 16 mmHg Expiration = 46 mmHg  48  4  Male  67  2.2  27  Metoprolol  Yes  Inspiration = 58 mmHg Expiration = 133 mmHg  140  5  Male  78  2.0  25.3  Metoprolol  No  Inspiration = 31 mmHg Expiration = 64 mmHg  97  6  Male  73  2.0  31  Metoprolol, diltiazem  Probable  Inspiration = 36 mmHg Expiration = 71 mmHg  150  7  Female  59  2.4  44  Metoprolol  Yes  Inspiration = 71 mmHg Expiration = 110 mmHg  115  8  Female  56  2.0  42  Metoprolol  Yes  Inspiration = 18 mmHg Expiration = 34 mmHg  80  9  Male  40  2.9  39  Metoprolol  Yes  Inspiration = 47 mmHg Expiration = 71 mmHg  76  10  Male  56  2.5  42  Metoprolol, diltiazem  No  Inspiration = 25 mmHg Expiration = 48 mmHg  80  11  Female  28  2.0  43  Metoprolol, diltiazem, disopyramide  No  Inspiration = 34 mmHg Expiration = 63 mmHg  71  12  Female  70  2.2  28  Metoprolol, verapamil  Probable  Inspiration = 125 mmHg Expiration = 190 mmHg  190  13  Female  61  2.0  44.8  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 72 mmHg Expiration = 170 mmHg  160  14  Female  73  3.3  35  Atenolol  Yes  Inspiration = 60 mmHg Expiration = 130 mmHg  200  15  Female  74  1.8  25  Metoprolol, diltiazem  unknown  Inspiration = 61 mmHg Expiration = 91 mmHg  100  16  Female  69  2.1  29.1  Metoprolol, diltiazem, disopyramide  unknown  Inspiration = 60 mmHg Expiration = 100 mmHg  110  17  Female  83  2.0  37.8  Metoprolol, verapamil  Probable  Inspiration = 80 mmHg Expiration = 130 mmHg  100  18  Female  63  2.1  34.4  Nevibolol, verapamil  Yes  Inspiration = 29 mmHg Expiration = 60 mmHg  120  19  Female  72  2.7  32.1  Metoprolol, verapamil  Yes  Inspiration = 67 mmHg Expiration = 82 mmHg  Not performed  20  Male  55  2.1  45  Metoprolol  Yes  Inspiration = 44 mmHg Expiration = 73 mmHg  150  BMI, body mass index; LVOT, left ventricular outflow tract. Table 1 Characteristics of patient population Case  Gender  Age (years)  Max wall thickness (cm)  BMI (kg/m2)  Medications  Obstructive sleep apnoea  Resting LVOT gradient (mmHg)  LVOT gradient during valsalva manoeuvre (mmHg)  1  Female  53  1.8  31  Metoprolol  Probable  Inspiration = 45 mmHg Expiration = 74 mmHg  80  2  Male  55  2.5  43  Metoprolol, verapamil  Yes  Inspiration = 37 mmHg Expiration = 61 mmHg  80  3  Male  56  2.2  25  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 16 mmHg Expiration = 46 mmHg  48  4  Male  67  2.2  27  Metoprolol  Yes  Inspiration = 58 mmHg Expiration = 133 mmHg  140  5  Male  78  2.0  25.3  Metoprolol  No  Inspiration = 31 mmHg Expiration = 64 mmHg  97  6  Male  73  2.0  31  Metoprolol, diltiazem  Probable  Inspiration = 36 mmHg Expiration = 71 mmHg  150  7  Female  59  2.4  44  Metoprolol  Yes  Inspiration = 71 mmHg Expiration = 110 mmHg  115  8  Female  56  2.0  42  Metoprolol  Yes  Inspiration = 18 mmHg Expiration = 34 mmHg  80  9  Male  40  2.9  39  Metoprolol  Yes  Inspiration = 47 mmHg Expiration = 71 mmHg  76  10  Male  56  2.5  42  Metoprolol, diltiazem  No  Inspiration = 25 mmHg Expiration = 48 mmHg  80  11  Female  28  2.0  43  Metoprolol, diltiazem, disopyramide  No  Inspiration = 34 mmHg Expiration = 63 mmHg  71  12  Female  70  2.2  28  Metoprolol, verapamil  Probable  Inspiration = 125 mmHg Expiration = 190 mmHg  190  13  Female  61  2.0  44.8  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 72 mmHg Expiration = 170 mmHg  160  14  Female  73  3.3  35  Atenolol  Yes  Inspiration = 60 mmHg Expiration = 130 mmHg  200  15  Female  74  1.8  25  Metoprolol, diltiazem  unknown  Inspiration = 61 mmHg Expiration = 91 mmHg  100  16  Female  69  2.1  29.1  Metoprolol, diltiazem, disopyramide  unknown  Inspiration = 60 mmHg Expiration = 100 mmHg  110  17  Female  83  2.0  37.8  Metoprolol, verapamil  Probable  Inspiration = 80 mmHg Expiration = 130 mmHg  100  18  Female  63  2.1  34.4  Nevibolol, verapamil  Yes  Inspiration = 29 mmHg Expiration = 60 mmHg  120  19  Female  72  2.7  32.1  Metoprolol, verapamil  Yes  Inspiration = 67 mmHg Expiration = 82 mmHg  Not performed  20  Male  55  2.1  45  Metoprolol  Yes  Inspiration = 44 mmHg Expiration = 73 mmHg  150  Case  Gender  Age (years)  Max wall thickness (cm)  BMI (kg/m2)  Medications  Obstructive sleep apnoea  Resting LVOT gradient (mmHg)  LVOT gradient during valsalva manoeuvre (mmHg)  1  Female  53  1.8  31  Metoprolol  Probable  Inspiration = 45 mmHg Expiration = 74 mmHg  80  2  Male  55  2.5  43  Metoprolol, verapamil  Yes  Inspiration = 37 mmHg Expiration = 61 mmHg  80  3  Male  56  2.2  25  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 16 mmHg Expiration = 46 mmHg  48  4  Male  67  2.2  27  Metoprolol  Yes  Inspiration = 58 mmHg Expiration = 133 mmHg  140  5  Male  78  2.0  25.3  Metoprolol  No  Inspiration = 31 mmHg Expiration = 64 mmHg  97  6  Male  73  2.0  31  Metoprolol, diltiazem  Probable  Inspiration = 36 mmHg Expiration = 71 mmHg  150  7  Female  59  2.4  44  Metoprolol  Yes  Inspiration = 71 mmHg Expiration = 110 mmHg  115  8  Female  56  2.0  42  Metoprolol  Yes  Inspiration = 18 mmHg Expiration = 34 mmHg  80  9  Male  40  2.9  39  Metoprolol  Yes  Inspiration = 47 mmHg Expiration = 71 mmHg  76  10  Male  56  2.5  42  Metoprolol, diltiazem  No  Inspiration = 25 mmHg Expiration = 48 mmHg  80  11  Female  28  2.0  43  Metoprolol, diltiazem, disopyramide  No  Inspiration = 34 mmHg Expiration = 63 mmHg  71  12  Female  70  2.2  28  Metoprolol, verapamil  Probable  Inspiration = 125 mmHg Expiration = 190 mmHg  190  13  Female  61  2.0  44.8  Metoprolol, verapamil, disopyramide  Yes  Inspiration = 72 mmHg Expiration = 170 mmHg  160  14  Female  73  3.3  35  Atenolol  Yes  Inspiration = 60 mmHg Expiration = 130 mmHg  200  15  Female  74  1.8  25  Metoprolol, diltiazem  unknown  Inspiration = 61 mmHg Expiration = 91 mmHg  100  16  Female  69  2.1  29.1  Metoprolol, diltiazem, disopyramide  unknown  Inspiration = 60 mmHg Expiration = 100 mmHg  110  17  Female  83  2.0  37.8  Metoprolol, verapamil  Probable  Inspiration = 80 mmHg Expiration = 130 mmHg  100  18  Female  63  2.1  34.4  Nevibolol, verapamil  Yes  Inspiration = 29 mmHg Expiration = 60 mmHg  120  19  Female  72  2.7  32.1  Metoprolol, verapamil  Yes  Inspiration = 67 mmHg Expiration = 82 mmHg  Not performed  20  Male  55  2.1  45  Metoprolol  Yes  Inspiration = 44 mmHg Expiration = 73 mmHg  150  BMI, body mass index; LVOT, left ventricular outflow tract. Group 1 patients were all overweight [body mass index (BMI) greater than 25 kg/m2], and 15 (75%) patients were obese (BMI >30 kg/m2). In Group 1, mean BMI was 35.1 kg/m2 + 7.3. Of the 20 patients, 15 (75%) patients were noted to have sleep-disordered breathing [11 had obstructive sleep apnoea (OSA) and 4 patients with probable OSA on the basis of abnormal overnight pulse oximetry]. One patient was noted to have chronic obstructive pulmonary disease—no other respiratory disorders were noted in clinical history. Group 1 patients were all in sinus rhythm throughout the study, and no meaningful changes in R–R interval were noted during spectral Doppler recording [inspiration mean R–R interval 945.86 ms, expiration mean R–R interval 947.11 ms, and mean difference was −1.25 ms (−17.35 to 44.0)]. All Group 1 patients had LVOT obstruction at rest (65.9 ± 32.6 mmHg), which increased during Valsalva manoeuvre (113 ± 41.8 mmHg). LVOT gradients varied widely during the respiratory cycle in all 20 patients in this study group (3 case examples—Figures 1–3). Peak gradients were uniformly lowest during inspiration (50.8 mmHg ± 25.6) and highest during expiration (90.1 mmHg ± 41.8) (P < 0.05) (Figure 4). On average, there was 82.4% ± 39.1 (P < 0.0001) increase in gradient from inspiration to expiration. This change in gradient could not be accounted for by changes in heart rate, as R–R intervals were similar throughout the recordings and no ectopy was noted on EKG tracings. Figure 1 View largeDownload slide Transthoracic echocardiogram images with respirometer. This patient is a 73-year-old man (Case 6) with hypertrophic obstructive cardiomyopathy with basal septal hypertrophy, measuring 2.0 cm and systolic anterior motion of mitral valve leaflets (Panel A). He was obese (BMI 31 kg/m2) and was also noted to have moderate pulmonary hypertension (PASP 51 mmHg). Panel B demonstrates initial spectral Doppler performed on patient to quantify the left ventricular outflow (LVOT) obstruction. Note the variation in velocities is beat to beat, but there is cyclical grouping of beats suggestive of respiratory-related variation. Without a respirometer, it could be surmised that the third beat (highest velocity) occurred during inspiration when LVOT obstruction would be expected to increase as preload decreased. However, in Panel C, when a respirometer was placed, a paradox was observed (upward deflection represents inspiration, downward deflection represents expiration). During inspiration, the LVOT obstruction decreased (the second and fifth beats) and increased during expiration (third, fourth, and sixth beats). Figure 1 View largeDownload slide Transthoracic echocardiogram images with respirometer. This patient is a 73-year-old man (Case 6) with hypertrophic obstructive cardiomyopathy with basal septal hypertrophy, measuring 2.0 cm and systolic anterior motion of mitral valve leaflets (Panel A). He was obese (BMI 31 kg/m2) and was also noted to have moderate pulmonary hypertension (PASP 51 mmHg). Panel B demonstrates initial spectral Doppler performed on patient to quantify the left ventricular outflow (LVOT) obstruction. Note the variation in velocities is beat to beat, but there is cyclical grouping of beats suggestive of respiratory-related variation. Without a respirometer, it could be surmised that the third beat (highest velocity) occurred during inspiration when LVOT obstruction would be expected to increase as preload decreased. However, in Panel C, when a respirometer was placed, a paradox was observed (upward deflection represents inspiration, downward deflection represents expiration). During inspiration, the LVOT obstruction decreased (the second and fifth beats) and increased during expiration (third, fourth, and sixth beats). Figure 2 View largeDownload slide Respiratory variation in multiple breathing cycles. This 67-year-old man (Case 4) with hypertrophic obstructive cardiomyopathy was noted to have asymmetric septal hypertrophy (both mid- and basal hypertrophy), maximum wall thickness 2.2 cm (Panel A). His symptoms had been controlled with beta-blockers only. This patient was mildly overweight (BMI 27 kg/m2) and was diagnosed to have obstructive sleep apnoea. As seen in Panel B, he initially also was noted to have phasic variation in left ventricular outflow (LVOT) obstruction during normal inspiration in the awake state. In Panels C and D, with simultaneously recorded respirometer and with adjustment of sweep speed, one can see multiple respiratory cycles with decreased LVOT obstruction evident during inspiration and maximal LVOT obstruction noted during expiration. Figure 2 View largeDownload slide Respiratory variation in multiple breathing cycles. This 67-year-old man (Case 4) with hypertrophic obstructive cardiomyopathy was noted to have asymmetric septal hypertrophy (both mid- and basal hypertrophy), maximum wall thickness 2.2 cm (Panel A). His symptoms had been controlled with beta-blockers only. This patient was mildly overweight (BMI 27 kg/m2) and was diagnosed to have obstructive sleep apnoea. As seen in Panel B, he initially also was noted to have phasic variation in left ventricular outflow (LVOT) obstruction during normal inspiration in the awake state. In Panels C and D, with simultaneously recorded respirometer and with adjustment of sweep speed, one can see multiple respiratory cycles with decreased LVOT obstruction evident during inspiration and maximal LVOT obstruction noted during expiration. Figure 3 View largeDownload slide Respiratory variation of great magnitude. This 73-year-old woman (Case 14) with HCM had basal septal hypertrophy and severe left ventricular outflow obstruction. She was diagnosed with obstructive sleep apnoea. She was also obese (BMI of 35 kg/m2). Note the marked variation with respiration with marked decrease in LV outflow gradient with inspiration (inspiration = 60 mmHg, expiration = 130 mmHg). Figure 3 View largeDownload slide Respiratory variation of great magnitude. This 73-year-old woman (Case 14) with HCM had basal septal hypertrophy and severe left ventricular outflow obstruction. She was diagnosed with obstructive sleep apnoea. She was also obese (BMI of 35 kg/m2). Note the marked variation with respiration with marked decrease in LV outflow gradient with inspiration (inspiration = 60 mmHg, expiration = 130 mmHg). Figure 4 View largeDownload slide This graph demonstrates each case’s inspiratory and expiratory maximum gradient. Figure 4 View largeDownload slide This graph demonstrates each case’s inspiratory and expiratory maximum gradient. Mitral annulus flow was performed and TVI was measured in 11 patients at inspiration and at expiration. In these patients, average inspiration TVI was significantly smaller than average expiration TVI (inspiration 14.3 cm ± 3.8 vs. expiration TVI 17.0 ± 4.3, P = 0.0007). During inspiration, there was a 15.9% decline in preload compared with expiration. IVRT was recorded in 16 patients, and mean IVRT at inspiration was longer than at expiration [inspiration 110.9 ms ± 28.5 vs. expiration 83.0 ms ± 23.7 (P < 0.0001)]. Correspondingly, ET was shorter during inspiration [inspiration 314.6 ms ± 24.6 vs. expiration 339.9 ms ± 27.3 (P < 0.0001)]. Six patients underwent cardiac catheterization. Pressure recordings were obtained in the cardiac catheterization laboratory along with a respirometer to mark inspiration and expiration. As can be seen in these two examples from patients (Figure 5A and B), respiratory variation was noted in the cardiac catheterization laboratory as well. Figure 5 View largeDownload slide Tracings from cardiac catheterization laboratory. (Panel A) This 56-year-old man (Case 3) was referred for alcohol septal ablation after having persistent symptoms on maximal medical therapy. Simultaneous left ventricle and aortic pressure tracings showed the effect of respiration on left ventricular (LV) outflow gradients. In Beat 1 (expiration), LVOT obstruction was severe, gradient = 60 mmHg. With inspiration, it decreased significantly and, in Beat 4, LVOT obstruction = 25 mmHg; in Beat 5, LVOT obstruction was abolished. With expiration, it recurred; in Beats 6–10, LVOT obstruction was again 60 mmHg. The red arrow demonstrates the negative intrathoracic pressure (−20 mmHg) generated by inspiration. (Panel B) This patient is a 61-year-old woman (Case 13) also referred for alcohol septal ablation. In Beats 1–3, during inspiration, LVOT gradient = 30 mmHg and note the contour of the aortic pressure tracing (red line) is normal. During expiration, LV pressure markedly increased to 210 mmHg and aortic pressure decreased to 100 mmHg; LVOT gradient = 110 mmHg. Note the aortic pressure tracing contour developed the classic ‘spike-and-dome’ appearance during expiration. This tracing demonstrates ‘pulsus paradoxus reverses’ in that contrary to the expected drop in blood pressure of greater than 10 mmHg during inspiration in pulsus paradoxus, and our patient demonstrated reversed haemodynamic teachings of an inspiratory increase in aortic pressure. Figure 5 View largeDownload slide Tracings from cardiac catheterization laboratory. (Panel A) This 56-year-old man (Case 3) was referred for alcohol septal ablation after having persistent symptoms on maximal medical therapy. Simultaneous left ventricle and aortic pressure tracings showed the effect of respiration on left ventricular (LV) outflow gradients. In Beat 1 (expiration), LVOT obstruction was severe, gradient = 60 mmHg. With inspiration, it decreased significantly and, in Beat 4, LVOT obstruction = 25 mmHg; in Beat 5, LVOT obstruction was abolished. With expiration, it recurred; in Beats 6–10, LVOT obstruction was again 60 mmHg. The red arrow demonstrates the negative intrathoracic pressure (−20 mmHg) generated by inspiration. (Panel B) This patient is a 61-year-old woman (Case 13) also referred for alcohol septal ablation. In Beats 1–3, during inspiration, LVOT gradient = 30 mmHg and note the contour of the aortic pressure tracing (red line) is normal. During expiration, LV pressure markedly increased to 210 mmHg and aortic pressure decreased to 100 mmHg; LVOT gradient = 110 mmHg. Note the aortic pressure tracing contour developed the classic ‘spike-and-dome’ appearance during expiration. This tracing demonstrates ‘pulsus paradoxus reverses’ in that contrary to the expected drop in blood pressure of greater than 10 mmHg during inspiration in pulsus paradoxus, and our patient demonstrated reversed haemodynamic teachings of an inspiratory increase in aortic pressure. The 20 patients in Group 2 had a mean age of 56.7 years ± 17.0, and mean septal wall thickness was 2.24 cm ± 0.5. In six of these patients, genotype testing identified pathogenic mutations. In these patients, there were no significant differences in maximal wall thickness or resting LVOT obstruction between the study and the control groups. However, mean BMI was significantly smaller in the control group (study group 35.1 ± 7.3 vs. control group 28.4 ± 4.8, P = 0.0013). Only five patients in Group 2 were noted to have OSA (n = 4 definite OSA, n = 1 probable OSA on the basis of nightly pulse oximetry testing) compared with 15 patients with sleep-disordered breathing in Group 1. Discussion This case series demonstrates the profound effect of quiet and spontaneous respiration on LVOT obstruction in select obese and awake patients with HCM. Inspiration was uniformly noted to have the lowest gradients, whereas the highest gradients were noted during expiration. These observations in our patients are unexpected and counterintuitive, contradicting the traditional teaching of the haemodynamic effects of respiration on the heart, which have focused on volume changes in the left and right hearts with breathing.8,9 During normal respiration, negative intrathoracic pressure during inspiration leads to increased systemic venous return to the right side, leading to increase in right atrial and right ventricle filling. As the lungs expand, the pulmonary vascular bed increases its capacitance and blood pools in these vessels, leading to decreased filling of the left atrium and left ventricle (decreased preload). These variations are small in healthy individuals and of little significant haemodynamic consequence as evidenced by minor variations in mitral and tricuspid valve inflow in healthy individuals and a small decrease in systemic stroke volume and in blood pressure as a consequence. This volume-based theory also forms the basis of our understanding of cardiac murmur intensity in valvular diseases—left-sided murmurs decrease in intensity due to decreased preload during inspiration, whereas the intensity of right-sided murmurs increases.5 If one extends the volume-based model to HCM patients with LVOT obstruction, then decreased LV preload with inspiration intuitively should lead to an increase in LVOT obstruction. We noted that, in 11 patients with data available, LV inflow was, indeed, reduced during inspiration by 15.9%. Instead, we observed a counterintuitive decrease in LVOT obstruction with inspiration. We were able to measure ET and IVRT in relation with the phases of respiration in 16 of 20 patients. LV ET increased during expiration (inspiration mean 314.6 ms vs. expiration mean 339.9 ms, P < 0.0001), consistent with the observed increased LVOT obstruction during expiration. Mean IVRT was 110.9 ms during inspiration and 83.0 ms during expiration (P < 0.0001). IVRT shortened during expiration on account of two mechanisms: first, due to prolongation of ET from increased LVOT obstruction; secondly, as a result of increased LA pressure from increased MR when the LV outflow gradient was maximum, which is expected to result in worsening mitral regurgitation, in turn, increasing the left atrial pressure in conjunction with increased left atrial filling from pulmonary veins during expiration. IVRT was significantly longer during inspiration, reflecting a shorter ET as well as reduced left atrial pressure from, inferred to be from, less LVOT obstruction and decreased pulmonary venous flow into the left atrium. Hence, the observed changes are real changes in haemodynamics with respiration and do not represent spurious findings due to changes in the angle of insonation during respiration. If preload changes were the predominant effect of respiration on the heart, an inspiratory reduction in LV preload would reduce the separation of the anterior mitral leaflets from the ventricular septum, thus increasing LV outflow obstruction. Therefore, deductive reasoning would lead to the conclusion that inspiration should lead to increased LV outflow obstruction in HCM. Instead, we observed a counterintuitive decrease in LV outflow obstruction with inspiration. Looking for an explanation for our observations, we searched the literature and discovered that these observations were first recorded in a case series over 50 years ago in 1965.10 Shah et al.10 studied nine patients in the cardiac catheterization laboratory. They instructed their sedated patients to take deep inspirations during their pressure recordings (exaggerated respiration). They noted a decrease in LVOT obstruction with deep inspiration; they concluded that LV volume increased with inspiration, contrary to traditional teaching, and used that explanation for their observations. In 1973, Massumi published a case report of two patients with HCM, who were also obese.11 They also noted a decrease in LVOT obstruction with inspiration; however, they concluded that the reason LVOT obstruction increased with expiration was that exaggerated expiration equalled a mild Valsalva manoeuvre. They termed this observation ‘reversed pulsus paradoxus.’ Buda et al.12 reported, in 1981, a series of nine patients with muscular subaortic stenosis who underwent cardiac catheterization. These sedated patients were instructed to take deep breaths during the haemodynamic study, and a decrease in LVOT gradients were observed with deep inspiration (60 + 11 mmHg vs. 34 + 6 mmHg). These authors postulated that deep inspiration increased the LV transmural pressure (LVTMP), effectively increasing LV afterload, and decreasing LVOT obstruction. These observations of respiratory-induced changes in LVOT obstruction remained buried in the literature for three decades, until two case reports published in 2004 and 2010, each based upon a single patient from the same institution (Mayo Clinic).13,14 Brilakas et al.13 and Schwartenzberg et al.14 also noted this observation in sedated patients in the cardiac catheterization laboratory. Thus, our study is the only study to date in the literature to document this haemodynamic paradox prospectively in non-sedated and non-fasting patients during normal, quiet spontaneous respiration. This is significant, as it suggests that this observation occurs in the daily life of overweight patients with HCM and sleep-disordered breathing. Thus, this select group of patients with obstructive HCM have marked variations in the severity of their obstruction in a resting state, and this severity is likely compounded when exposed to other haemodynamic factors. The soundest explanation for our findings appears to be an increase in LVTMP with inspiration (Figure 6). In addition to changes in LV preload, LVOT obstruction is well known to be sensitive to afterload changes,15 as seen by response to inhalation of amyl nitrite leading to peripheral arterial vasodilation, which decreases afterload, leading to increased LVOT obstruction. On the contrary, handgrip manoeuvre or infusion of phenylephrine leads to peripheral vasoconstriction, which increase afterload, resulting in a decrease in LVOT obstruction. Therefore, we theorize that the transmission of increased negative intrathoracic pressure results in an increase of LV afterload via LVTMP. This effective afterload increase results in reduced LVOT obstruction, analogous to a handgrip manoeuvre. LVTMP is the systolic pressure corrected for intrathoracic pressure (LVTMP = systolic pressure − intrapleural pressure)16 and is considered to be a more accurate representation of cardiac afterload, and studies have also demonstrated that LVTMP is increased in inspiration.16–18 During inspiration, the intrathoracic pressure becomes negative, and, thus, even though systolic arterial pressure may decrease slightly, the net effect is a slight increase in LVTMP. We documented this in six patients who underwent haemodynamic evaluation in the cardiac catheterization laboratory—as the patients deeply inspired, intrathoracic pressure became markedly negative, thus increasing LVTMP (increased afterload) and resulting in a decrease in LVOT obstruction despite decreased preload. As LVOT gradients in HCM are known to be extremely labile based on loading conditions, therefore increased LV afterload (LVTMP) over-rode the effect of decreased preload and results in the reduction of obstructive gradients we observed during inspiration. In the normal healthy heart, preload mediated effects are predominant, whereas in HCM patients, afterload sensitivity can be profound. Figure 6 View largeDownload slide Schematic of LVTMP. This schematic of the left ventricular transmural pressure shows the multifactorial effect of inspiration on the left and right ventricle. Figure 6 View largeDownload slide Schematic of LVTMP. This schematic of the left ventricular transmural pressure shows the multifactorial effect of inspiration on the left and right ventricle. In our study, all patients were overweight and a high percentage had sleep-disordered breathing. Both issues could be contributing to generation of greater negative intrathoracic pressure during quiet inspiration, thus leading to increased LV wall stress. OSA is known to decrease lung compliance, thus augmenting negative intrathoracic pressure changes during inspiration. Inspiration against a threshold load has been demonstrated to further decrease the relative LV stroke volume through an increase in end-systolic volume.19 Obese patients also demonstrate reduced lung compliance,20 and this reduction is proportional to BMI—as BMI increases, lung compliance reduces. This relationship is particularly seen in the recumbent position.21,22 Thus, sleep-disordered breathing and obesity decrease lung compliance by virtue of increasing the negative intrathoracic pressure that must be generated for any given tidal volume—these larger swings may offer an explanation for our observation in these 20 cases. Furthermore, we speculate that our observation may offer a link between observed morbidity in patients with HCM and sleep-disordered breathing.23 Mechanistically, clinicians understand the relationship between preload and LVOT obstruction, i.e. an increase in LVOT obstruction during inspiration due to a decrease in LV preload. The concept that afterload is also increased during inspiration and can over-ride the effect of decreased preload, hence decreasing LVOT obstruction, is not one that is widely known to clinicians. Our report doubles the number of cases in which this observation has been reported, thus offering a redux of this paradox initially described over 50 years ago. Study limitations Limitations include the inability to directly measure intrathoracic pressure. In addition, volumetric analysis of the left ventricle was not performed at inspiration and expiration due to limitations of image acquisition. Additionally, it is unknown at what critical negative inspiratory thoracic pressure the LVTMP will overcome the opposing influences of decreased preload during inspiration. It is also important to point out the inherent limitation that may exist in interpreting data across several respiratory and cardiac cycles, as a normal respiratory cycle extends across several cardiac cycles. The heart also exhibits translational motion during respiration, although the order of magnitude of change in LV outflow gradients demonstrated here surpasses the minor changes that can be demonstrated with mild angle variations during respiration; additionally, echocardiograms were performed under direct supervision of the senior author to ensure that translational motion on angle of Doppler recording was minimal; particular attention was also paid to patient breathing, to ensure normal, quiet, spontaneous respiration, and not exaggerated respiration. In addition, changes in preload, afterload, and intrathoracic pressure do not occur in isolation, and an integrative approach is needed to understand the summative effects of these respiratory changes on cardiac haemodynamics. This study provides an assessment of 20 patients observed through clinical practice in a dedicated Hypertrophic Cardiomyopathy Clinic; as not all patients with HCM and LVOT obstruction routinely underwent gradient measurements with respiration, it is possible that many other patients could have been detected. Conclusions We report the largest case series of respiratory variation of LVOT obstruction in HCM in non-sedated patients during normal quiet respiration. We noted these significant and counterintuitive variations based only on conventional preload mechanisms. This study provides evidence of changes in LVOT gradients with spontaneous respiration in HCM patients, challenging traditional haemodynamic concepts. These findings provide a foundation for future studies to help identify the mechanistic considerations and clinical implications of altered respiratory mechanics in HCM patients, particularly in those who are obese and in those with sleep-disordered breathing. These findings also have significant clinical implications on the diagnosis and assessment of severity of obstructive HCM. Conflict of interest: None declared. Acknowledgements The authors thank Zach Singsank, D.O., for his assistance in collecting recordings from the cardiac catheterization laboratory. The authors gratefully acknowledge Susan Nord and Jennifer Pfaff of Aurora Cardiovascular Services for editorial preparation of the manuscript, and Brian Miller and Brian Schurrer of Aurora Research Institute for their help in preparing figures. 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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Sep 7, 2017

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