Clinical Outcomes of Patients Treated With Pulmonary Vasodilators Early and in High Dose After Left Ventricular Assist Device Implantation.

Right ventricular failure (RVF) is common after left ventricular assist device (LVAD) implantation and a major determinant of adverse outcomes. Optimal perioperative right ventricular (RV) management is not well defined. We evaluated the use of pulmonary vasodilator therapy during LVAD implantation. We performed a retrospective analysis of continuous-flow LVAD implants and pulmonary vasodilator use at our institution between September 2004 and June 2013. Preoperative RVF risk was assessed using recognized variables. Sixty-five patients (80% men, 50 ± 14 years) were included: 52% HeartWare ventricular assist device (HVAD), 11% HeartMate II (HMII), 17% VentrAssist, 20% Jarvik. Predicted RVF risk was comparable with contemporary LVAD populations: 8% ventilated, 14% mechanical support, 86% inotropes, 25% BUN >39 mg/dL, 23% bilirubin ≥2 mg/dL, 31% RV : LV (left ventricular) diameter ≥0.75, 27% RA : PCWP (right atrium : pulmonary capillary wedge pressure) >0.63, 36% RV stroke work index <6 gm-m/m(2)/beat. The majority (91%) received pulmonary vasodilators early and in high dose: 72% nitric oxide, 77% sildenafil (max 200 ± 79 mg/day), 66% iloprost (max 126 ± 37 µg/day). Median hospital stay was 26 (21) days. No patient required RV mechanical support. Of six (9%) patients meeting RVF criteria based on prolonged need for inotropes, four were transplanted, one is alive with an LVAD at 3 years, and one died on day 35 of intracranial hemorrhage. Two-year survival was 77% (92% for HMII/HVAD): transplanted 54%, alive with LVAD 21%, recovery/explanted 2%. A low incidence of RVF and excellent outcomes were observed for patients treated early during LVAD implantation with combination, high-dose pulmonary vasodilators. The results warrant further investigation in a randomized controlled study.

Relation between serum N-terminal pro-brain natriuretic peptide and prognosis in patients with hypertrophic cardiomyopathy.

AIMS: To determine the relation between serum concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and prognosis in patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: In total, 847 patients (53 ± 15 years; 67% male) with HCM (28% with left ventricular outflow tract obstruction ≥ 30 mmHg at rest) were followed for 3.5 years (IQR 2.5-4.5 years). The median NT-proBNP concentration was 78 pmol/L (range < 5-1817 pmol/L and IQR 31-183 pmol/L). Sixty-eight patients (8%) reached the primary endpoint of all-cause mortality or cardiac transplantation. NT-proBNP concentration predicted long-term survival from the primary endpoint [area under the receiver operating characteristic curve of 0.78 (95% confidence interval 0.73-0.84)]. A serum concentration of ≥ 135 pmol/L was associated with an annual event rate of 6.1% (95% CI 4.4-7.7). Three independent predictors of primary outcome were identified in a multivariable Cox model: New York Heart Association class III/IV (HR 2.10, 95% CI 1.21-3.65, P = 0.008), ejection fraction (HR 0.98, 95% CI 0.96-1.00, P = 0.035), log NT-proBNP (HR 2.04, 95% CI 1.56-2.66, P < 0.001). Log NT-proBNP was a significant predictor of heart failure (HF) and transplant-related deaths (n = 23; HR 3.03, 95% CI 1.99-4.60, P < 0.001) but not sudden death or appropriate implantable cardioverter defibrillator shock (n = 11; HR 1.54, 95% CI 0.91-2.60, P = 0.111). In patients with ejection fraction ≥ 50% (n = 673), log NT-proBNP remained an independent predictor of the primary outcome (HR 2.11, 95% CI 1.54-2.90, P < 0.001). CONCLUSION: In patients with HCM, elevated NT-proBNP concentration is a strong predictor of overall prognosis, particularly HF-related death and transplantation.

Cardiac output response and peripheral oxygen extraction during exercise among symptomatic hypertrophic cardiomyopathy patients with and without left ventricular outflow tract obstruction.

OBJECTIVE: Reduction of left ventricular outflow tract obstruction (LVOTO) often improves symptoms in hypertrophic cardiomyopathy (HCM), but the correlation between exercise performance and measured LVOT gradients is weak. We investigated the relationship between LVOTO and cardiorespiratory responses during exercise. METHODS: The study cohort included 70 patients with HCM (32 with LVOTO, 55 male, age 47±13) attending a dedicated cardiomyopathy clinic and 28 normal volunteers. All underwent cardiopulmonary exercise testing with simultaneous non-invasive haemodynamic assessment using finger plethysmography. Main outcome measures were peak oxygen consumption, cardiac index and arteriovenous oxygen difference. RESULTS: When compared with controls, patients had reduced peak exercise oxygen consumption (22.4±6.1 vs 34.7±7.7 mL/kg/min, p<0.0001) and cardiac index (5.5±1.9 vs 9.4±2.9 L/min/m(2), p<0.0001). At all workloads, stroke volume index (SVI) was lower and arteriovenous oxygen difference greater in patients. During all stages of exercise, LVOTO in patients was associated with failure to augment SVI and higher oxygen consumption; cardiac reserve (4.4±2.7 vs 6.3±3.6 L/min, p=0.025) and peak mean arterial pressure (104±16 vs 112±16 mm Hg, p=0.033) were lower. Multivariable predictors of cardiac output response were age (ß: -0.11; CI -0.162 to -0.057; p<0.0001), peak LVOT gradient (ß: -0.018; CI -0.034 to -0.002; p=0.031) and gender (ß: -2.286; CI -0.162 to -0.577; p=0.01). Within the obstructive cohort, different patterns of SV response were elicited in patients with similar clinical features. CONCLUSIONS: Cardiac reserve is reduced in HCM because of failure of SV augmentation. LVOTO exacerbates this abnormal response, but haemodynamic responses vary significantly. Non-invasive exercise haemodynamic assessment may improve understanding of symptoms and help tailor therapy.

Heart rate recovery in patients with hypertrophic cardiomyopathy.

Recovery in heart rate (HR) after exercise is a measure of autonomic function and a prognostic indicator in cardiovascular disease. The aim of this study was to characterize heart rate recovery (HRR) and to determine its relation to cardiac function and morphology in patients with hypertrophic cardiomyopathy (HC). We studied 18 healthy volunteers and 41 individuals with HC. All patients underwent clinical assessment and transthoracic echocardiography. Continuous beat-by-beat assessment of HR was obtained during and after cardiopulmonary exercise testing using finger plethysmography. HRR and power spectral densities were calculated on 3 minutes of continuous RR recordings. Absolute HRR was lower in patients than that in controls at 1, 2, and 3 minutes (25.7 ± 8.4 vs 35.3 ± 11.0 beats/min, p <0.001; 36.8 ± 9.4 vs 53.6 ± 13.2 beats/min, p <0.001; 41.2 ± 12.2 vs 62.1 ± 14.5 beats/min, p <0.001, respectively). HRR remained lower in patients at 2 and 3 minutes after normalization to peak HR. After normalization to the difference in HR between peak exercise and rest, HRR was significantly impaired in individuals with obstructive HC at 3 minutes compared with controls. HR at 3 minutes correlated with peak left ventricular outflow tract gradient (B 0.154 beats/min/mm Hg, confidence interval 0.010 to 0.299, p = 0.037) and remained a significant predictor of HRR after multivariable analysis. Spectral analysis showed a trend toward an increased low-frequency to high-frequency ratio in patients (p = 0.08) suggesting sympathetic predominance. In conclusion, HRR is impaired in HC and correlates with the severity of left ventricular outflow tract gradient. Prospective studies of the prognostic implications of impaired HRR in HC are warranted.

The influence of aortoseptal angulation on provocable left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.

OBJECTIVES: Aortoseptal angulation (AoSA) can predict provocable left ventricular outflow tract obstruction (LVOTO) in patients with symptomatic hypertrophic cardiomyopathy (HCM). Lack of a standardised measurement technique in HCM without the need for complex three-dimensional (3D) imaging limits its usefulness in routine clinical practice. This study aimed to validate a simple measurement of AoSA using 2D echocardiography and cardiac MR (CMR) imaging as a predictor of LVOTO. METHODS: We retrospectively assessed 160 patients with non-obstructive HCM, referred for exercise stress echocardiography. AoSA was measured using resting 2D echocardiography in all patients, and CMR in 29. Twenty-five controls with normal echocardiograms were used for comparison. RESULTS: Patients with HCM had a reduced AoSA compared with controls (113°±12 vs 126°±6), p<0.0001. Sixty (38%) patients had provocable LVOTO, with smaller angles than non-obstructive patients (108°±12 vs 116°±12, p<0.0001). AoSA, degree of mitral valvular regurgitation and incomplete systolic anterior motion (SAM) were associated with peak left ventricular outflow tract gradient (r=0.508, p<0.0001). An angle ≤100° had 27% sensitivity, 91% specificity and 59% positive predictive value for predicting provocable LVOTO. When combined with SAM, specificity was 99% and positive predictive value 88%. Intraclass correlation coefficient of AoSA measured by two observers was 0.901 (p<0.0001). Bland-Altman analysis of echocardiographic AoSA showed good agreement with the CMR-derived angle. CONCLUSIONS: Measurement of AoSA using echocardiography in HCM is easy, reproducible and comparable to CMR. Patients with provocable LVOTO have reduced angles compared with non-obstructive patients. AoSA is highly specific for provocable LVOTO and should prompt further evaluation in symptomatic patients without resting obstruction.

Non-invasive assessment of cardiac output at rest and during exercise by finger plethysmography.

AIMS: We sought to determine the accuracy of finger plethysmography using pulse waveform analysis with brachial calibration for measurement of cardiac output during submaximal exercise by comparing it against an acetylene (C2H2) uptake technique. METHODS: The study included 24 healthy volunteers (12 males, age 35 ± 8 years). Testing was performed on an upright cycle ergometer using an incremental protocol. Cardiac output measurements were performed at rest and during sub-maximal exercise using a single breath C2H2 uptake technique and continuously using finger plethysmography with brachial calibration. RESULTS: Valid results at rest and during sub-maximal exercise were achieved in 20 of 24 participants. Cardiac output at rest was 5.3 ± 1.1 and 5.2 ± 1.2 l min(-1) for finger plethysmography and C2H2, respectively, P = 0.712. Mean difference between techniques was -0.1 ± 0.5 l min(-1). Cardiac output during submaximal exercise was 10.2 ± 2.3 and 10.3 ± 2.1 l min(-1) for finger plethysmography and C2H2, respectively, P = 0.898. Mean difference between techniques was 0.1 ± 1.5 l min(-1). The overall correlation between finger plethysmography and C2H2 data obtained during rest and exercise was r(2) = 0.872, P<0.0001. Mean rise in cardiac output during exercise was 4.9 ± 1.5 (finger plethysmography) and 5.1 ± 1.5 l min(-1) (C2H2), P = 0.64. CONCLUSION: Finger plethysmography determined cardiac output values both at rest and during sub-maximal exercise are comparable with those obtained using a single breath C2H2 uptake technique.

Multivariate classification of systemic vascular resistance using photoplethysmography.

Systemic vascular resistance (SVR) classification is useful for the diagnosis and prognosis of critical pathophysiological conditions, with the ability to identify patients with abnormally high or low SVR of immense clinical value. In this study, a supervised classifier, based on Bayes' rule, is employed to classify a heterogeneous group of intensive care unit patients (N = 48) as being below (SVR < 900 dyn s cm(-5)), within (900 ⩽ SVR ⩽ 1200 dyn s cm(-5)) or above (SVR > 1200 dyn s cm(-5)) the clinically accepted range for normal SVR. Features derived from the finger photoplethysmogram (PPG) waveform and other routine cardiovascular measurements (heart rate and mean arterial pressure) were used as inputs to the classifier. In the construction of the classifier model, two techniques were used to approximate the class conditional probability densities--a single Gaussian distribution model (also known as discriminant analysis) and a non-parametric model using the Parzen window kernel density estimation method. An exhaustive feature search was performed to select a feature subset that maximized the performance indicator, Cohen's kappa coefficient (κ). The Gaussian model with multiple features achieved the best overall kappa coefficient (κ = 0.57), although the results from the non-parametric model were comparable (κ = 0.51). The optimum subset in the Gaussian model consisted of PPG waveform variability features, including the low-frequency to high-frequency ratio (LF/HF) and the normalized mid-frequency power (MF(NU)), in addition to the PPG pulse wave features, such as pulse width, peak-to-notch time, reflection index, and notch time ratio. The classifier performed particularly well in discriminating low SVR, with a sensitivity of 85%, specificity of 86%, positive predictive value of 88% and a negative predictive value of 82%. The results highlight the feasibility of deploying a multivariate statistical approach of SVR classification in the clinical setting, simply using a non-invasive and easy-to-measure PPG waveform signal.

Fingertip photoplethysmographic waveform variability and systemic vascular resistance in intensive care unit patients.

Low frequency variability in the fingertip photoplethysmogram (PPG) waveform has been utilized for inferring sympathetic vascular control, but its relationship with a quantitative measure of vascular tone has not been established. In this study, we examined the association between fingertip PPG waveform variability (PPGV) and systemic vascular resistance (SVR) obtained from thermodilution cardiac output (CO) and intra-arterial pressure measurements in 48 post cardiac surgery intensive care unit patients. Among the hemodynamic measurements, both CO (P < 0.05) and SVR (P < 0.0001) had statistically significant relationships with the normalized low frequency power (LF(nu)) of PPGV. The LF(nu) of baseline PPGV had moderate but significant positive correlation with SVR (r = 0.54, P < 0.0001), and a value below 52.5 nu was able to identify SVR < 900 dyn s cm⁻5 with sensitivity of 59% and specificity of 95%. The results have provided quantitative evidence to confirm the link between fingertip PPGV and sympathetic vascular control. Suppression of LF vasomotor waves leading to dominance of respiration-related HF fluctuations in the fingertip circulation was a specific (though not sensitive) marker of systemic vasodilatation, which could be potentially utilized for the assessment of critical care patients.

Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy is a myocardial disease characterized by myocardial hypertrophy, disorganization of cardiac myocytes, and fibrosis. Twenty-five percent of patients have a dynamic left ventricular outflow tract gradient caused by the combined effects of rapid ventricular ejection, a narrowed outflow tract, and systolic anterior motion of the mitral valve. Most cases are caused by mutations in genes that encode cardiac sarcomeric proteins. Patients present at all ages with chest pain, dyspnea, palpitations, and syncope. The most important complications of the disease are sudden cardiac death, heart failure, and thromboembolism. The principal aims of management are the alleviation of symptoms and the prevention of sudden death. In patients with substantial left ventricular outflow tract obstruction, interventions that reduce the magnitude of the outflow tract gradient (disopyramide, verapamil, ß-blockade, alcohol ablation of the interventricular septum, dual-chamber pacing, and surgery) often improve symptoms. Therapeutic options in patients without left ventricular outflow tract obstruction are more limited. Clinical risk stratification is used to estimate the risk of sudden death and to target effective prophylactic treatment with an implantable cardioverter defibrillator.