Using pulsatility responses to breath-hold maneuvers to predict readmission rates in continuous-flow left ventricular assist device patients.

BACKGROUND: Dynamic respiratory maneuvers induce heterogenous changes to flow-pulsatility in continuous-flow left ventricular assist device patients. We evaluated the association of these pulsatility responses with patient hemodynamics and outcomes. METHODS: Responses obtained from HVAD (Medtronic) outpatients during successive weekly clinics were categorized into three ordinal groups according to the percentage reduction in flow-waveform pulsatility (peak-trough flow) upon inspiratory-breath-hold, (%∆P): (1) minimal change (%∆P ≤ 50), (2) reduced pulsatility (%∆P > 50 but <100), (3) flatline (%∆P = 100). Same-day echocardiography and right-heart-catheterization were performed. Readmissions were compared between patients with ≥1 flatline response (F-group) and those without (NF-group). RESULTS: Overall, 712 responses were obtained from 55 patients (82% male, age 56.4 ± 11.5). When compared to minimal change, reduced pulsatility and flatline responses were associated with lower central venous pressure (14.2 vs. 11.4 vs. 9.0 mm Hg, p = 0.08) and pulmonary capillary wedge pressure (19.8 vs. 14.3 vs. 13.0 mm Hg, p = 0.03), lower rates of ≥moderate mitral regurgitation (48% vs. 13% vs. 10%, p = 0.01), lower rates of ≥moderate right ventricular impairment (62% vs. 25% vs. 27%, p = 0.03), and increased rates of aortic valve opening (32% vs. 50% vs. 75%, p = 0.03). The F-group (n = 28) experienced numerically lower all-cause readmissions (1.51 vs. 2.79 events-per-patient-year [EPPY], hazard-ratio [HR] = 0.67, p = 0.12), reduced heart failure readmissions (0.07 vs. 0.57 EPPY, HR = 0.15, p = 0.008), and superior readmission-free survival (HR = 0.47, log-rank p = 0.04). Syncopal readmissions occurred exclusively in the F-group (0.20 vs. 0 EPPY, p = 0.01). CONCLUSION: Responses to inspiratory-breath-hold predicted hemodynamics and readmission risk. The impact of inspiratory-breath-hold on pulsatility can non-invasively guide hemodynamic management decisions, patient optimization, and readmission risk stratification.

Longitudinal analysis left ventricular chamber responses under durable LVAD support.

BACKGROUND: Left ventricular assist device (LVAD) support offers remodeling potential in some patients. Our goal was to use noninvasively derived pressure-volume (PV) loops to understand the effect of demographic and device variables on serial changes in cardiac function under pump support. METHODS: Thirty-two consecutive Medtronic HeartWare Ventricular Assist Device (HVAD) patients (mean 55.9 ± 12.3 years, 81.3% male) were prospectively recruited. Single-cycle ventricular pressure and volume were estimated using a validated algorithm. PV loops (n = 77) and corresponding cardiac chamber dynamics were derived at predefined postimplant timepoints (1, 3, 6 months). Changes in PV loop parameters sustained across the 6-month period were characterized using mixed-effects modeling. The influence of demographic and device variables on the observed changes was assessed. RESULTS: Across a 6-month period, the mean ventricular function parameters remained stable. Significant predictors of monthly improvement of stroke work include: lower pump speeds (2400 rpm vs 2500-2800 rpm) [0.0.051 mm Hg/liter/month (p = 0.001)], high pulsatility index (>1.0 vs <1.0) [0.052 mm Hg/liter/month (p = 0.012)], and ischemic cardiomyopathy indication for LVAD implantation (vs nonischemic) [0.0387 mm Hg/liter/month (p = 0.007)]. Various other cardiac chamber function parameters including cardiac power, peak systolic pressure, and LV elastance also showed improvements in these cohorts. CONCLUSIONS: Factors associated with improvement in ventricular energetics and hemodynamics under LVAD support can be determined with noninvasive PV loops. Understanding the basis of increasing ventricular load to optimize myocardial remodeling may prove valuable in selecting eligible recovery candidates.

Safety and tolerability of sodium-glucose cotransporter-2 inhibitors in bridge-to-transplant patients supported with centrifugal-flow left ventricular assist devices.

BACKGROUND: The safety and tolerability of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with end-stage heart failure supported with left-ventricular-assist-devices (LVADs), irrespective of diabetes mellitus, is not known. METHODS: A retrospective analysis of 31 outpatients implanted with LVADs as bridge-to-transplant (BTT) was conducted. Patients with biventricular support, aged under 18 years, who were discharged from the index hospitalisation, or were prescribed SGLT2i prior to their first outpatient clinic were excluded. Patient demographics, laboratory studies, pump haemodynamic and adverse event data was collected. RESULTS: Sixteen (51.6%) of 31 patients were prescribed SGLT2i over median 101.5 days (37.5-190.8). No patients discontinued SGLT2i use or reported attributable adverse symptoms. No significant differences between patients prescribed SGLT2i compared to those SGLT2i-naïve were seen in: [1] renal function; [2] weight; [3] mean arterial pressure. There were numerically lower infection-related (n = 4 vs 7, HR 0.32 (0.08-1.28), p = 0.11) and haemocompatibility-related (n = 3 vs 4, HR 0.52 (0.09-2.83), p = 0.45) adverse events in the SGLT2i group, albeit non-significant. CONCLUSIONS: We found SGLT2i to be safe and well-tolerated in the BTT LVAD cohort with no significant difference in rates of infection or haemocompatibility-related adverse events with SGLT2i use. Larger studies will inform further beneficial effects of SGLT2i prescription in this cohort.

Characteristic changes to pulsatile and steady-state load according to pulmonary hypertension classification.

It is of increasing importance to understand and predict changes to the systemic and pulmonary circulations in pulmonary hypertension (PH). To do so, it is necessary to describe the circulation in complete quantitative terms. Characteristic impedance (Zc) expresses opposition of the circulation to pulsatile blood flow. Evaluation of systemic and pulmonary Zc relationships according to PH classification has not previously been described. Prospective study of 40 clinically indicated patients referred for CMR and RHC (56 ± 18 years; 70% females, eight mPAP ≤ 25 mmHg, 16 pre-capillary [Pre-cPH], eight combined pre- and post-capillary [Cpc-PH] and eight isolated left-heart disease [Ipc-PH]). CMR provided assessment of ascending aortic (Ao) and pulmonary arterial (PA) flow, and RHC, central Ao and PA pressure. Systemic and pulmonary Zc were expressed as the relationship of pressure to flow in the frequency domain. Baseline demographic characteristics were well-matched across PH subclasses. In those with a mPAP ≤25mHg, systemic Zc and SVR were >2 times higher than pulmonary Zc and PVR. Only Pre-cPH was associated with inverse pulsatile (systemic Zc 58 [45-69] vs pulmonary Zc 70 [58-85]), but not steady-state (SVR 1101 [986-1752] vs. PVR 483 [409-557]) relationships. Patients with CpcPH and IpcPH had concordant pulsatile and steady-state relationships (Graphical Abstract). Measurement of, and the relationship between, systemic and pulmonary Zc in patients according to PH sub-classification has not previously been described. Systemic Zc was routinely higher than pulmonary Zc, except in patients with newly diagnosed Pre-cPH, where inverse pulsatile but not steady-state relationships were observed.

Prognostic role of pulmonary impedance estimation to predict right ventricular dysfunction in pulmonary hypertension.

BACKGROUND: The effect of pulmonary hypertension (PH) on right ventricular (RV) afterload is commonly defined by elevation of pulmonary artery (PA) pressure or pulmonary vascular resistance (PVR). In humans however, one-third to half of the hydraulic power in the PA is contained in pulsatile components of flow. Pulmonary impedance (Zc) expresses opposition of the PA to pulsatile blood flow. We evaluate pulmonary Zc relationships according to PH classification using a cardiac magnetic resonance (CMR)/right heart catheterization (RHC) method. METHODS: Prospective study of 70 clinically indicated patients referred for same-day CMR and RHC [60 ± 16 years; 77% females, 16 mPAP <25 mmHg (PVR <240 dynes.s.cm-5 /mPCWP <15 mmHg), 24 pre-capillary (PrecPH), 15 isolated post-capillary (IpcPH), 15 combined pre-capillary/post-capillary (CpcPH)]. CMR provided assessment of PA flow, and RHC, central PA pressure. Pulmonary Zc was expressed as the relationship of PA pressure to flow in the frequency domain (dynes.s.cm-5 ). RESULTS: Baseline demographic characteristics were well matched. There was a significant difference in mPAP (P < 0.001), PVR (P = 0.001), and pulmonary Zc between mPAP<25 mmHg patients and those with PH (mPAP <25 mmHg: 47 ± 19 dynes.s.cm-5 ; PrecPH 86 ± 20 dynes.s.cm-5 ; IpcPH 66 ± 30 dynes.s.cm-5 ; CpcPH 86 ± 39 dynes.s.cm-5 ; P = 0.05). For all patients with PH, elevated mPAP was found to be associated with raised PVR (P < 0.001) but not with pulmonary Zc (P = 0.87), except for those with PrecPH (P < 0.001). Elevated pulmonary Zc was associated with reduced RVSWI, RVEF, and CO (all P < 0.05), whereas PVR and mPAP were not. CONCLUSIONS: Raised pulmonary Zc was independent of elevated mPAP in patients with PH and more strongly predictive of maladaptive RV remodelling than PVR and mPAP. Use of this straightforward method to determine pulmonary Zc may help to better characterize pulsatile components of RV afterload in patients with PH than mPAP or PVR alone.

Interpretation of the central aortic pressure waveform in elderly patients with aortic stenosis.

The central aortic pressure waveform, while simple in form, is complex in its physiological interpretation. Although general agreement has been reached on the contour and mechanisms responsible for pressure waveforms in the ascending aorta of healthy humans, in recent years there has been increasing interest in the contour of the pressure wave in elderly patients with aortic valve stenosis (AS). As aortic valve leaflets succumb to fibrosis and calcification, they increase opposition to forward flow. This results in a protracted pressure rise and manifests as the classical finding of pulsus parvus et tardus. Equally, changes to arterial properties (including elasticity and geometry) and pulse wave velocity (PWV) with age, heart failure, or hypertension can cause profound changes to the contour. Increased accessibility of methods to measure the central aortic pressure waveform, as well as the rapid uptake of transcatheter aortic valve implantation technologies, has created a renewed focus on better understanding of characteristic perturbations to the waveform in elderly patients with AS. In this review, we investigate the evolution of our understanding of the central aortic pressure waveform in varying AS disease states to highlight the importance of the physiological and biological basis for alterations in this waveform.

Pulsatile energy consumption as a surrogate marker for vascular afterload improves with time post transcatheter aortic valve replacement in patients with aortic stenosis.

The effect of arterial stiffening on elevated pulsatile left ventricular afterload patients with aortic stenosis (AS) is pronounced beyond systemic hypertension. Circulatory afterload pulsatile efficiency (CAPE) is a marker of vascular function, defined as the ratio of steady state energy consumption (SEC) to maintain systemic circulation and pulsatile energy consumption (PEC). Twenty patients aged 80 ± 7 years were assessed at baseline and a median of 60 days post transcatheter aortic valve replacement (TAVR), with pulsatile vascular load calculated using simultaneous radial applanation tonometry derived aortic pressure and cardiac magnetic resonance phase-contrast imaging derived ascending aortic flow. Eight out of 20 patients had a reduction in PEC post TAVR, and the reduction of PEC correlated strongly with the number of days post TAVR (R = 0.62, P < 0.01). Patients assessed within the 100 days of TAVR had a rise in their PEC when compared to baseline (0.19 ± 0.09 vs 0.14 ± 0.08 W, P = 0.04). Baseline PEC correlated moderately with baseline SEC (R = 0.49, P = 0.03), and a high baseline PEC was predictive of post TAVR PEC reduction (R = 0.54, P =0.01). Overall, no significant differences were found between baseline and post TAVR for systolic aortic pressure (131 ± 20 vs 131 ± 20 mmHg), systemic vascular resistance (1894 ± 493 vs 2015 ± 519 dynes.s/cm5), aortic valve ejection time (337 ± 22 vs 324 ± 34 ms) or aortic characteristic impedance (120 ± 48 vs 107 ± 41 dynes.s/cm5). Improved flow profiles after TAVR likely unmask the true vascular properties by altering ventriculo-valvulo-arterial coupling, leading to downstream vascular remodelling secondary to flow conditioning, and results in eventual improvement of pulsatile afterload as reflected by our proposed index of CAPE.

Arterial Compliance and Continuous-Flow Left Ventricular Assist Device Pump Function.

Durable continuous-flow left ventricular assist devices (cfLVADs) demonstrate superior survival, cardiac functional status, and overall quality of life compared to medical therapy alone in advanced heart failure. Previous studies have not considered the impact arterial compliance may have on pump performance or developed arterial pressure. This study assessed the impact of alterations in arterial compliance, preload, and afterload on continuous-flow pump function and measured hemodynamics using an in-vitro pulsatile mock circulatory loop. Decreased arterial compliance was associated with a significant increase in arterial pressure pulsatility which was not evident in the flow pulsatility, as displayed in pump flow waveforms. There were marked changes in the pump flow waveforms due to the significant alteration in the aortoventricular gradient during diastole according to the changes in compliance. This study demonstrates that changes in systemic blood pressure, afterload, and left ventricular contractility each significantly affects the flow waveform. The association of hypertension with lower aortic compliance results in markedly decreased diastolic flow rates which may be important in contributing to a greater risk of adverse events under cfLVAD support.

Association between Brachial-Ankle Pulse Wave Velocity as a Marker of Arterial Stiffness and Body Mass Index in a Chinese Population.

Objectives: Arterial stiffness is widely accepted as an important predictor of cardiovascular disease (CVD) development. While obesity is generally associated with increased CVD risk, there is evidence that overweight patients with existing CVD may have better clinical outcomes than their lean counterparts. Our study sought to observe any potential association between brachial−ankle pulse wave velocity (BAPWV), a marker of arterial stiffness related to CVD risk, and Body Mass Index (BMI), a crude and widely used measure of obesity. Methods: Adult individuals (n = 857) assessed for routine CV risk were included and grouped according to their BMI (<25 kg/m2: normal; 25−30 kg/m2: overweight, ≥30 kg/m2: obese). Their anthropometric parameters, brachial cuff pressures, and BAPWV were measured. Results: Brachial pressure was significantly higher as BMI increased. BAPWV showed a positive linear association with systolic (r = 0.66, p < 0.01), mean (r = 0.60, p < 0.01), diastolic (r = 0.51, p < 0.01), and pulse (r = 0.53, p < 0.01) pressures. However, a linear relationship between BMI and BAPWV was only apparent in males aged <50 years (p = 0.01) and in females aged ≥50 years (p < 0.01). In individuals with similar brachial systolic pressure, BAPWV was higher in normal-weight subjects compared to overweight−obese ones. Conclusions: This conflicting finding is attributed to an overestimation of the degree of arterial stiffness as a measure of CVD risk in individuals with a less 'healthy' BMI. This suggests that BMI may not the appropriate obesity indicator to assess CV risk. Our finding emphasizes the importance of establishing a non-linear relationship between CVD risk, age, and BMI, taking into account apparent sex differences, to predict future CV events. While this finding may suggest a lower degree of stiffness in large arteries of overweight−obese subjects compared to their normal-weight counterparts, the potential implications for individuals with higher BMI need be explored further.

Female Gender Is Associated with Higher Susceptibility of Weight Induced Arterial Stiffening and Rise in Blood Pressure.

Arterial stiffness is an important predictor of cardiovascular events, independent of traditional risk factors. Stiffening of arteries, though an adaptive process to hemodynamic load, results in substantial increase in the pulsatile hemodynamic forces that detrimentally affects the microcirculation perfusing the vital organs such as the brain, heart and kidneys. Studies have proposed that arterial stiffness precedes and may contribute to the development of hypertension in individuals with obesity. Our study sought to determine the gender-based effects on arterial stiffening in obesity which may predispose to the development of hypertension. We found female sex is associated with higher susceptibility of weight-related arterial stiffening and rise in blood pressure in obesity. Women had significantly higher carotid-femoral pulse wave velocity (CF-PWV) with higher body mass index (BMI) status (normal: 7.9 ± 2 m/s; overweight: 9.1 ± 2 m/s; obese: 9 ± 2 m/s, p < 0.001), whereas it was similar in males across all BMI categories. The linear association between arterial stiffness and BMI following adjustment for age and brachial systolic and diastolic blood pressure (BP), remained significant in females (ß = 0.06; 95% CI 0.01 to 0.1; p < 0.05) but not in males (ß = 0.04; 95% CI -0.01 to 0.1; p > 0.05). The mean CF-PWV values increased by 0.1 m/s for every 1 kg/m2 increase in BMI in the female subjects in the age adjusted linear model, while such effect was not seen in the male subjects. In line with arterial stiffening, the overweight and obese females demonstrated significantly higher systolic brachial BP. (BP difference: ΔBP 9-11 mmHg, p < 0.01) and central systolic pressure (ΔBP 8-10 mmHg, p < 0.05) compared to their lean counterparts, unlike the male subjects. Our results suggest that female gender is associated with higher susceptibility of weight-related arterial stiffening and rise in blood pressure.

Ageing, Hypertension and Aortic Valve Stenosis: A Conscious Uncoupling.

Aortic valve stenosis (AS) is no longer considered to be a disease of fixed left ventricular (LV) afterload (due to an obstructive valve), but rather, functions as a series circuit with important contributions from both the valve and ageing vasculature. Patients with AS are frequently elderly, with hypertension and a markedly remodelled aorta. The arterial component is sizable, and yet, the contribution of ventricular afterload has been difficult to determine. Arterial stiffening increases the speed of propagation of the blood pressure wave along the central arteries (estimated as the pulse wave velocity), which results in an earlier return of reflected waves. The effect is to augment blood pressure in the proximal aorta during systole, increasing the central pulse pressure and, in turn, placing even greater afterload on the heart. Elevated global LV afterload is known to have adverse consequences on LV remodelling, function and survival in patients with AS. Consequently, there is renewed focus on methods to estimate the relative contributions of local versus global changes in arterial mechanics and valvular haemodynamics in patients with AS. We present a review on existing and upcoming methods to quantify valvulo-arterial impedance and thereby global LV load in patients with AS.

Phenotyping of Stable Left Ventricular Assist Device Patients Using Noninvasive Pump Flow Responses to Acute Loading Transients.

BACKGROUND: Although it has been established that continuous flow left ventricular assist devices are sensitive to loading conditions, the effect of acute load and postural changes on pump flow have not been explored systematically. METHODS AND RESULTS: Fifteen stable outpatients were studied. Patients sequentially transitioned from the seated position to supine, passive leg raise, and standing with transition effects documented. A modified Valsalva maneuver, consisting of a forced expiration with an open glottis, was performed in each position. A sustained, 2-handed handgrip was performed in the supine position. The pump flow waveform was recorded continuously and left ventricular end-diastolic diameter measured during each stage using transthoracic echocardiography. Transitioning from seated to supine posture produced a significant increase in the flow and the ventricular end-diastolic diameter, consistent with an increased preload. The transition from supine to standing produced a transient increase in the mean flow and decreased the flow pulsatility index. At steady state, these changes were reversed with a decrease in the mean and trough flow and increased pulsatility index, consistent with venous redistribution and possible baroreflex compensation. Four distinct patterns of standing-induced flow waveform effects were identified, reflecting varying preload, afterload, and individual compensatory effects. A sustained handgrip produced a significant decrease in flow and increase in flow pulsatility across all patients, reflecting an increased afterload pressure. A modified Valsalva maneuver produced a decrease in the flow pulsatility while seated, supine, and standing, but not during leg raise. Five patterns of pulsatility effect during Valsalva were observed: (1) minimal change, (2) pulsatility recovery, (3) rapid flatline, (4) slow flatline with delayed flow recovery, and (5) primary suction. CONCLUSIONS: Acute disturbances in loading conditions produce heterogeneous pump flow responses reflecting their complex interactions with pump and ventricular function as well as reflex compensatory mechanisms. Differences in responses and individual variabilities have significant implications for automated pump control algorithms.

Tracking of brachial and central aortic systolic pressure over the normal human lifespan: insight from the arterial pulse waveforms.

Despite multiple studies, it has not been possible to account for the normal changes of blood pressure that occur from infancy to old age. We sought a comprehensive explanation, by linking brachial pressure with the well documented changes in the arterial pulse waveform, whose peak and nadir determine systolic, diastolic and pulse pressure in brachial arteries. Changes in humans arterial pulse wave contour from birth to old age can be readily explained on (i) growth, with increasing length of the body from birth to adolescence, and adult height maintained thereafter, and (ii) degeneration and dilation of the aorta from elastic fibre fracture throughout life, causing progressive increase in aortic pressure wave amplitude from early return of wave reflection, and summation of incident with reflected waves in systole. These changes throughout life complement arterial pulse waveform analysis and explain brachial cuff pressure values, with optimal pulse wave pattern for cardiac interaction apparent in adolescence.

A novel method to assess valvulo-arterial load in patients with aortic valve stenosis.

INTRODUCTION: Ventricular function in elderly patients with aortic stenosis is impeded both by restricted aortic flow and arterial stiffening. A number of patients continue to have exertional intolerance after relief of aortic valvular obstruction due to unrecognized ventriculo-arterial coupling mismatch. HYPOTHESIS: Quantification of valvulo-arterial load (VAL), using a simultaneous applanation tonometry/cardiac magnetic resonance (CMR) technique, can accurately assess the relative contributions of aortic stiffness and valve gradient in older patients with aortic stenosis. METHODS: Elderly patients with aortic stenosis underwent a simultaneous applanation tonometry/CMR protocol. CMR provided left ventricular volume and aortic flow simultaneously with radial applanation tonometry pressure acquisition. Central aortic pressure was derived by transformation of the radial applanation tonometry waveform. VAL was determined as the relationship of derived aortic pressure to CMR aortic flow in frequency domain (central illustration). RESULTS: Twenty patients (age 80 ±â€Š9 years; 12 males; blood pressure 140/75 ±â€Š20 mmHg) with aortic stenosis on transthoracic echocardiogram (16 severe; mean gradient 45 ±â€Š16 mmHg; aortic valve area 0.8 ±â€Š0.2 cm2) were enrolled. Derived aortic pressure and flow waveforms correlated well with invasive data. Increased VAL was significantly associated with advanced age (P = 0.04) and raised SBP (P < 0.01), irrespective of aortic stenosis severity. CONCLUSION: Difficulties in the measurement and accuracy of ventriculo-arterial coupling means that it is not routinely measured in patients with aortic stenosis. We describe a new noninvasive index that provides an accurate assessment of valvular and arterial load on the left ventricle. VAL may help detect those at risk of ventriculo-arterial coupling mismatch and assist in selection of those most likely to benefit from an invasive procedure.

Non-Invasive Quantification of Ventricular Contractility, Arterial Elastic Function and Ventriculo-Arterial Coupling from a Single Diagnostic Encounter Using Simultaneous Arterial Tonometry and Magnetic Resonance Imaging.

PURPOSE: Optimal assessment of cardiovascular performance requires simultaneous measurement of load independent left ventricular (LV) contractility, arterial function and LV/arterial coupling. We aimed to demonstrate feasibility of non-invasive ventricular pressure-volume and aortic pressure-flow-impedance measurements using simultaneous arterial tonometry (AT) and cardiovascular magnetic resonance imaging (CMRI). METHODS: 21 consecutive patients referred for CMRI were enrolled to undergo a simultaneous AT and CMRI protocol. A CMRI compatible AT apparatus provided aortic end-systolic pressure, taken to be equivalent to LV end-systolic pressure in the absence of aortic stenosis. CMRI provided LV volume and aortic flow at the time of pressure acquisition. Pressure-volume relationships were determined and correlated to traditional parameters of LV function including ejection fraction and circumferential strain. Aortic pressure-flow relationships were used to determine aortic characteristic impedance and systemic vascular resistance. RESULTS: Simultaneous AT and CMRI permitted measurement of LV end-systolic elastance, preload recruitable stroke work, arterial elastance, aortic characteristic impedance and systemic vascular resistance. Absolute values were within the expected range for our cohort, were highly reproducible and showed appropriately directed correlation to traditional parameters. CONCLUSION: Non-invasive assessment of LV pressure-volume and aortic pressure-flow relationships are both feasible and reproducible using simultaneous AT and CMRI. Methods permit assessment of load independent LV contractility, arterial function and LV/arterial coupling from a single non-invasive diagnostic encounter.