Routine Laboratory Biomarkers As Prognostic Indicators of Cardiac Sarcoidosis Outcomes.

Background: Biomarkers to monitor disease activity and predict major adverse cardiac events (MACE) in CS have not been described previously. We aimed to identify biomarkers to predict MACE in cardiac sarcoidosis (CS). Methods: Patients (N=232) diagnosed with CS were retrospectively enrolled. Biomarkers including angiotensin-converting enzyme (ACE), N-terminal brain natriuretic peptide (NT-proBNP), troponin T, and creatinine levels were evaluated against a primary end point of left ventricular assist device implantation, heart transplantation, or death, and a secondary end point of cardiac hospitalization-free survival. Results: Troponin T (hazard ratio [HR], 1.06 per 0.01 ng/mL; P=.006), NT-proBNP (HR, 1.31 per 1,000 pg/mL; P<.001), and creatinine (HR, 4.02 per mg/dL; P=.01) were associated with the primary end point, even after adjusting for ejection fraction. NT-proBNP, B-type natriuretic peptide (BNP), creatinine, albumin, and calcium were associated with the secondary end point (P<.05). ACE levels were associated with presence of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging (mean difference, 14.7; P=.03); 1,25 dihydroxyvitamin D (1,25-OHVit-D) was associated with uptake on cardiac 18F-flurodeoxyglucose position emission tomography (FDG-PET, P=.03). Conclusions: Troponin T, NT-proBNP, and creatinine predict clinically significant outcomes in CS. ACE levels correlated with LGE on CMR, and 1,25-OHVit-D levels correlated with FDG-PET activity.

Electrogram-guided endomyocardial biopsy yield in patients with suspected cardiac sarcoidosis and relation to outcomes.

OBJECTIVE: Endomyocardial biopsy (EMB) is a useful diagnostic tool though the yield may be limited in many myocardial diseases. Data on the diagnostic yield and prognostic significance of EMB guided by abnormal electrograms (EGM-Bx) in suspected cardiac sarcoidosis (CS) are scarce. METHODS: Seventy-nine patients (mean age: 56 ± 12 years; 61% men) with suspected CS based on clinical and imaging features underwent right or left ventricular EGM-Bx guided by electroanatomic mapping. Tissue samples were obtained from sites with abnormal EGMs and/or abnormal cardiac imaging. The diagnostic yield of EGM-Bx was evaluated in reference to histopathologic analysis. Left ventricular assist device (LVAD) and transplantation-free survival were compared between patients with positive and negative EGM-Bx for CS. RESULTS: A total of 254 samples were obtained from abnormal EGM sites, and 126 samples from normal EGM sites guided by pre-procedure imaging findings. Abnormal histopathology was noted in 65 (26%) and 10 (8%) samples from abnormal and normal EGM sites, respectively. Histopathology confirmed CS in 16 (20%) patients, while an alternative tissue diagnosis emerged in 10 (13%) patients. Abnormal EGMs at the biopsy site had sensitivity 89% and specificity 33% for a histopathologic diagnosis of CS. LVAD and transplantation-free survival were not significantly associated with the EGM-Bx result (log-rank p = .91). CONCLUSION: In patients with suspected CS, abnormal EGM-Bx has high sensitivity and low specificity for establishing a definite CS diagnosis. Consideration of substrate abnormalities apparent on preprocedural imaging as an adjunct for selection of biopsy sites may further improve EGM-Bx yield.

Natural History of Patients Diagnosed with Cardiac Sarcoidosis at Left Ventricular Assist Device Implantation or Cardiac Transplantation.

To our knowledge, natural history has not been reported for cardiac sarcoidosis (CS) diagnosed by pathologic evaluation of the apical core at left ventricular assist device (LVAD) implantation or cardiac transplantation. We retrospectively identified 232 consecutive patients meeting CS criteria. Of these patients, 54 were diagnosed by pathologic confirmation of CS, 10 after evaluation of the apical core (LVAD implant) or explanted heart (transplant). We compared clinical characteristics at initial evaluation and outcomes for these 10 patients with those of 10 patients with known CS before LVAD implant/transplant. In the study group, five patients (50%) had confirmed extracardiac sarcoidosis before LVAD implant/transplant; five had not been diagnosed with sarcoidosis. Mean (standard deviation) left ventricular ejection fraction at initial evaluation was 23% (16%), and left ventricular end-diastolic dimension was 61 (10) mm. Four patients died during follow-up; however, no survival difference was found for the 10 patients diagnosed incidentally and the group with a previous diagnosis or institutional LVAD/transplant cohorts. Patients diagnosed with CS on pathological examination of the apical core/explanted heart may have severe dilated cardiomyopathy as the initial presentation. Outcomes for patients with CS after advanced heart failure therapies may be comparable with those of non-CS patients.

Heart-After-Liver Transplantation Attenuates Rejection of Cardiac Allografts in Sensitized Patients.

BACKGROUND: In patients undergoing heart transplantation, significant allosensitization limits access to organs, resulting in longer wait times and high waitlist mortality. Current desensitization strategies are limited in enabling successful transplantation. OBJECTIVES: The purpose of this study was to describe the cumulative experience of combined heart-liver transplantation using a novel heart-after-liver transplant (HALT) protocol resulting in profound immunologic protection. METHODS: Reported are the results of a clinical protocol that was instituted to transplant highly sensitized patients requiring combined heart and liver transplantation at a single institution. Patients were dual-organ listed with perceived elevated risk of rejection or markedly prolonged waitlist time due to high levels of allo-antibodies. Detailed immunological data and long-term patient and graft outcomes were obtained. RESULTS: A total of 7 patients (age 43 ± 7 years, 86% women) with high allosensitization (median calculated panel reactive antibody = 77%) underwent HALT. All had significant, unacceptable donor specific antibodies (DSA) (>4,000 mean fluorescence antibody). Prospective pre-operative flow cytometric T-cell crossmatch was positive in all, and B-cell crossmatch was positive in 5 of 7. After HALT, retrospective crossmatch (B- and T-cell) became negative in all. DSA fell dramatically; at last follow-up, all pre-formed or de novo DSA levels were insignificant at <2,000 mean fluorescence antibody. No patients experienced >1R rejection over a median follow-up of 48 months (interquartile range: 25 to 68 months). There was 1 death due to metastatic cancer and no significant graft dysfunction. CONCLUSIONS: A heart-after-liver transplantation protocol enables successful transplantation via near-elimination of DSA and is effective in preventing adverse immunological outcomes in highly sensitized patients listed for combined heart-liver transplantation.

B-type natriuretic peptide and cardiac remodelling after myocardial infarction: a randomised trial.

OBJECTIVE: B-type natriuretic peptide (BNP) has favourable effects on left ventricular remodelling, including antifibrotic and antiapoptotic properties. We tested the hypothesis that infusion of BNP after an acute myocardial infarction would reduce left ventricular systolic and diastolic volumes and improve left ventricular ejection fraction compared with placebo. METHODS: A total of 58 patients who underwent successful revascularisation for an acute ST elevation anterior myocardial infarction were randomised to receive 72-hour infusion of BNP at 0.006 µg/kg/min or placebo. Left ventricular end diastolic and systolic volumes and left ventricular ejection fraction were measured at baseline and at 30 days by multigated acquisition scan. Left ventricular infarction size was measured by cardiac MRI. RESULTS: BNP infusion led to significantly higher BNP levels and plasma cyclic guanosine monophosphate at 72 hours. No significant difference in change of left ventricular volumes or ejection fraction from baseline to 30 days was observed between groups. Although left ventricular infarction size measured by cardiac MRI was not significantly different between BNP infusion versus placebo (p=0.39), there was a trend towards reduced infarction size in patients with a baseline ejection fraction of <40% (p=0.14). CONCLUSIONS: Infusion of BNP in patients with an anterior myocardial infarction did not affect parameters of left ventricular remodelling. Patients treated with BNP who had a baseline left ventricular ejection fraction of <40% had a trend towards reduced left ventricular infarction size compared with placebo. These results do not support the use of intravenous BNP in patients after recent myocardial infarction. TRIAL REGISTRATION NUMBER: NCT00573144.

Left ventricle assist device pulsatility index at the time of implantation is associated with follow-up pulmonary hemodynamics.

HeartMate II left ventricular assist device controllers provide data including pulsatility index, reflecting the relationship between pump function and hemodynamics. We propose that a higher pulsatility index at hospital discharge following implant may be associated with less vascular congestion and improved clinical outcomes. A retrospective analysis of 40 patients (age 59.2 ± 10.3 years) supported with the HeartMate II devices was conducted. Data revealed moderate Pearson correlations between pulsatility index at discharge and right atrial pressure, pulmonary artery systolic pressure, pulmonary artery diastolic pressure, mean pulmonary arterial pressure, and pulmonary capillary wedge pressure, respectively, post-surgery (median of 377 days), demonstrating a stronger relationship when analyzed for the EPC controller (n = 28) only (r = -.57, p < .01; r = -.38, p < .05; r = -.59, p < .01; r = -.47, p = .01 and r = -.53, p < .01, respectively). The pulsatility index derived from the EPC controller was associated with the significant risk of re-hospitalization within 1 and 2 years after the implantation of left ventricular assist device; hazard ratio = 0.557 with 95% confidence interval (0.315-0.983), p = .04 and hazard ratio = .579 (0.341-0.984), p = .04. A higher pulsatility index at discharge was associated with greater volume unloading, lower pulmonary pressures, and lower risk of all-cause re-hospitalizations within 1 and 2 years post-surgery. As such, pump-derived data may provide additional value in predicting left ventricular assist device hemodynamics.

Non-invasive assessment of arterial pulsatility in patients with continuous-flow left ventricular assist devices.

INTRODUCTION: Long-term use of continuous-flow left ventricular assist devices may have negative consequences for autonomic, cardiovascular and gastrointestinal function. It has thus been suggested that non-invasive monitoring of arterial pulsatility in patients with a left ventricular assist device is highly important for ensuring patient safety and longevity. We have developed a novel, semi-automated frequency-domain-based index of arterial pulsatility that is obtained during suprasystolic occlusions of the upper arm: the 'cuff pulsatility index'. PURPOSE: The purpose of this study was to evaluate the relationship between the cuff pulsatility index and invasively determined arterial pulsatility in patients with a left ventricular assist device. METHODS: Twenty-three patients with a left ventricular assist device with end-stage heart failure (six females: age = 65 ± 9 years; body mass index = 30.5 ± 3.7 kg m-2) were recruited for this study. Suprasystolic occlusions were performed on the upper arm of the patient's dominant side, from which the cuff pressure waveform was obtained. Arterial blood pressure was obtained from the radial artery on the contralateral arm. Measurements were obtained in triplicate. The relationship between the cuff pressure and arterial blood pressure waveforms was assessed in the frequency-domain using coherence analysis. A mixed-effects approach was used to assess the relationship between cuff pulsatility index and invasively determined arterial pulsatility (i.e. pulse pressure). RESULTS: The cuff pressure and arterial blood pressure waveforms demonstrated a high coherence up to the fifth harmonic of the cardiac frequency (heart rate). The cuff pulsatility index accurately tracked changes in arterial pulse pressure within a given patient across repeated measurements. CONCLUSIONS: The cuff pulsatility index shows promise as a non-invasive index for monitoring residual arterial pulsatility in patients with a left ventricular assist device across time.

Pulmonary function assessment post-left ventricular assist device implantation.

AIM: The lungs-and particularly the alveolar-capillary membrane-may be sensitive to continuous flow (CF) and pulmonary pressure alterations in heart failure (HF). We aimed to investigate long-term effects of CF pumps on respiratory function. METHODS AND RESULTS: We conducted a retrospective study of patients with end-stage HF at our institution. We analysed pulmonary function tests [e.g. forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1 )] and diffusing capacity of the lung for carbon monoxide (DLCO ) from before and after left ventricular assist device (LVAD) implantation and compared them with invasive haemodynamic studies. Of the 274 patients screened, final study analysis involved 44 patients with end-stage HF who had CF LVAD implantation between 1 February 2007 and 31 December 2015 at our institution. These patients [mean (standard deviation, SD) age, 50 (9) years; male sex, n = 33, 75%] received either the HeartMate II (Thoratec Corp.) pump (77%) or the HeartWare (HeartWare International Inc.) pump. The mean (SD) left ventricular ejection fraction was 21% (13%). At a median of 237 days post-LVAD implantation, we observed significant DLCO decrease (-23%) since pre-implantation (P < 0.001). ΔDLCO had an inverse relationship with changes in pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP) from pre-LVAD to post-LVAD implantation: ΔDLCO to ΔPCWP (r = 0.50, P < 0.01) and ΔDLCO to ΔRAP (r = 0.39, P < 0.05). We observed other reductions in FEV1 , FVC, and FEV1 /FVC between pre-LVAD and post-LVAD implantation. In mean (SD) values, FEV1 changed from 2.3 (0.7) to 2.1 (0.7) (P = 0.005); FVC decreased from 3.2 (0.8) to 2.9 (0.9) (P = 0.01); and FEV1 /FVC went from 0.72 (0.1) to 0.72 (0.1) (P = 0.50). Landmark survival analysis revealed that ΔDLCO from 6 months after LVAD implantation was predictive of death for HF patients [hazard ratio (95% confidence interval), 0.60 (0.28-0.98); P = 0.03]. CONCLUSIONS: Pulmonary function did not improve after LVAD implantation. The degree of DLCO deterioration is related to haemodynamic status post-LVAD implantation. The ΔDLCO within 6 months post-operative was associated with survival.

Noninvasive Blood Pressure Monitor Designed for Patients With Heart Failure Supported with Continuous-Flow Left Ventricular Assist Devices.

The gold standard for noninvasive blood pressure (BP) measurement, the Doppler technique, does not provide systolic blood pressure (SBP) and diastolic blood pressure (DBP) and may limit therapy outcomes. To improve patient care, we tested specifically designed experimental BP (ExpBP) monitor and the Doppler technique by comparing noninvasive measures to the intraarterial (I-A) BP in 31 patients with end-stage heart failure (4 females) 2.6 ± 3.4 days post-LVAD implantation (20 HeartMate II and 11 HeartWare). Bland-Altman plots revealed that the ExpBP monitor overestimated mean arterial pressure (MAP) by 1.2 (4.8) mm Hg (mean difference [standard deviation]), whereas the Doppler by 6.7 (5.8) mm Hg. The ExpBP SBP was overestimated by 0.8 (6.1) mm Hg and DBP by 1.9 (5.3) mm Hg compared with the respective I-A pressures. Both techniques achieved similar measurement reliability. In the measurement "success rate" expressed as a frequency (percent) of readable BP values per measurement attempts, Doppler accomplished 100% vs. 97%, 97%, and 94% of successful detections of MAP, SBP, and DBP provided by the ExpBP monitor. The ExpBP monitor demonstrated higher accuracy in the MAP assessment than the Doppler in addition to providing SBP and DBP in majority of subjects. Improved BP control may help to mitigate related neurologic adverse event rates.

Long-Term Sirolimus for Primary Immunosuppression in Heart Transplant Recipients.

BACKGROUND: Small studies have reported superiority of sirolimus (SRL) over calcineurin inhibitor (CNI) in mitigating cardiac allograft vasculopathy (CAV) after heart transplantation (HT). However, data on the long-term effect on CAV progression and clinical outcomes are lacking. OBJECTIVES: The aim of this study was to test the long-term safety and efficacy of conversion from CNI to SRL as maintenance therapy on CAV progression and outcomes after HT. METHODS: A cohort of 402 patients who underwent HT and were either treated with CNI alone (n = 134) or converted from CNI to SRL (n = 268) as primary immunosuppression was analyzed. CAV progression was assessed using serial coronary intravascular ultrasound during treatment with CNI (n = 99) and after conversion to SRL (n = 235) in patients who underwent at least 2 intravascular ultrasound studies. RESULTS: The progression in plaque volume (2.8 ± 2.3 mm3/mm vs. 0.46 ± 1.8 mm3/mm; p < 0.0001) and plaque index (plaque volume-to-vessel volume ratio) (12.2 ± 9.6% vs. 1.1 ± 7.9%; p < 0.0001) were significantly attenuated when treated with SRL compared with CNI. Over a mean follow-up period of 8.9 years from time of HT, all-cause mortality occurred in 25.6% of the patients and was lower during treatment with SRL compared with CNI (adjusted hazard ratio: 0.47; 95% confidence interval: 0.31 to 0.70; p = 0.0002), and CAV-related events were also less frequent during treatment with SRL (adjusted hazard ratio: 0.35; 95% confidence interval: 0.21 to 0.59; p < 0.0001). Further analyses suggested more attenuation of CAV and more favorable clinical outcomes with earlier conversion to SRL (≤2 years) compared with late conversion (>2 years) after HT. CONCLUSIONS: Early conversion to SRL is associated with attenuated CAV progression and with lower long-term mortality and fewer CAV-related events compared with continued CNI use.

A Human Study to Evaluate Safety, Tolerability, and Cyclic GMP Activating Properties of Cenderitide in Subjects With Stable Chronic Heart Failure.

Cenderitide is a novel designer natriuretic peptide (NP) composed of C-type natriuretic peptide (CNP) fused to the C-terminus of Dendroaspis natriuretic peptide (DNP). Cenderitide was engineered to coactivate the two NP receptors, particulate guanylyl cyclase (pGC)-A and -B. The rationale for its design was to achieve the renal-enhancing and antifibrotic properties of dual receptor activation, but without clinically significant hypotension. Here we report the first clinical trial on the safety, tolerability, and cyclic guanosine monophosphate (cGMP) activating properties of Cenderitide in subjects with stable heart failure (HF). Four-hour infusion of Cenderitide was safe, well-tolerated, and significantly increased plasma cGMP levels and urinary cGMP excretion without adverse effects with no change in blood pressure. Thus, Cenderitide has a favorable safety profile and expected pharmacological effects in stable human HF. Our results support further investigations of Cenderitide in HF as a potential future cGMP-enhancing therapeutic strategy.

Noninvasive assessment of cardiac output by brachial occlusion-cuff technique: comparison with the open-circuit acetylene washin method.

Cardiac output (CO) assessment as a basic hemodynamic parameter has been of interest in exercise physiology, cardiology, and anesthesiology. Noninvasive techniques available are technically challenging, and thus difficult to use outside of a clinical or laboratory setting. We propose a novel method of noninvasive CO assessment using a single, upper-arm cuff. The method uses the arterial pressure pulse wave signal acquired from the brachial artery during 20-s intervals of suprasystolic occlusion. This method was evaluated in a cohort of 12 healthy individuals (age, 27.7 ± 5.4 yr, 50% men) and compared with an established method for noninvasive CO assessment, the open-circuit acetylene method (OpCirc) at rest, and during low- to moderate-intensity exercise. CO increased from rest to exercise (rest, 7.4 ± 0.8 vs. 7.2 ± 0.8; low, 9.8 ± 1.8 vs. 9.9 ± 2.0; moderate, 14.1 ± 2.8 vs. 14.8 ± 3.2 l/min) as assessed by the cuff-occlusion and OpCirc techniques, respectively. The average error of experimental technique compared with OpCirc was -0.25 ± 1.02 l/min, Pearson's correlation coefficient of 0.96 (rest + exercise), and 0.21 ± 0.42 l/min with Pearson's correlation coefficient of 0.87 (rest only). Bland-Altman analysis demonstrated good agreement between methods (within 95% boundaries); the reproducibility coefficient (RPC) = 0.84 l/min with R2 = 0.75 at rest and RPC = 2 l/min with R2 = 0.92 at rest and during exercise, respectively. In comparison with an established method to quantify CO, the cuff-occlusion method provides similar measures at rest and with light to moderate exercise. Thus, we believe this method has the potential to be used as a new, noninvasive method for assessing CO during exercise.

Current Status of Left Ventricular Assist Device Therapy.

Congestive heart failure (HF) remains a serious burden in the Western World. Despite advances in pharmacotherapy and resynchronization, many patients have progression to end-stage HF. These patients may be candidates for heart transplant or left ventricular assist device (LVAD) therapy. Heart transplants are limited by organ shortages and in some cases by patient comorbidities; therefore, LVAD therapy is emerging as a strategy of bridge to transplant or as a destination therapy in patients ineligible for transplant. Patients initially ineligible for a transplant may, in certain cases, become eligible for transplant after physiologic improvement with LVAD therapy, and a small number of patients with an LVAD may have sufficient recovery of myocardial function to allow device explantation. This clinically oriented review will describe (1) the most frequently used pump types and aspects of the continuous-flow physiology and (2) the clinical indications for and the shift toward the use of LVADs in less sick patients with HF. Additionally, we review complications of LVAD therapy and project future directions in this field. We referred to the Interagency Registry for Mechanically Assisted Circulatory Support, landmark trials, and results from recently published studies as major sources in obtaining recent outcomes, and we searched for related published literature via PubMed. This review focuses primarily on clinical practice for primary care physicians and non-HF cardiologists in the United States.

Effect of Neurohormonal Blockade Drug Therapy on Outcomes and Left Ventricular Function and Structure After Left Ventricular Assist Device Implantation.

Neurohormonal blockade drug therapy (NHBDT) is the cornerstone therapy in heart failure (HF) management for promoting reverse cardiac remodeling and improving outcomes. It's utility in left ventricular assist device (LVAD) supported patients remains undefined. Sixty-four patients who received continuous flow LVAD at our institution were retrospectively reviewed and divided into 2 groups: no-NHBDT group (n = 33) received LVAD support only and NHBDT group (n = 31) received concurrent NHBDT based on the clinical judgment of the attending physicians. Cardiac remodeling (echocardiographic parameters and biomarkers) and clinical outcome (functional status, HF-related hospital readmissions, and mortality) data were collected. A statistically significant increase in ejection fraction, decrease in LV end-diastolic diameter index and LV mass index, and a sustained reduction in N-terminal pro B-type natriuretic peptide (NTproBNP) were observed in the NHBDT group at 6 months after LVAD implant (p <0.05). NHBDT-treated patients experienced significantly greater improvement in New York Heart Association functional classification and 6-minute-walk distance throughout the study. The combined end point of cardiovascular death or HF hospitalization was significantly reduced in patients receiving NHBDT (p = 0.013) associated primarily with a 12.1% absolute reduction in HF-related hospitalizations (p = 0.046). In conclusion, NHBDT in LVAD-supported patients is associated with a significant reversal in adverse cardiac remodeling and a reduction in morbidity and mortality compared with LVAD support alone.

Differences in mean arterial pressure of young and elderly people measured by oscilometry during inflation and deflation of the arm cuff.

Systemic arterial blood pressure (BP) is one of the most important parameters of the cardiovascular system. An oscillometric NIBP monitor was specifically designed to measure oscillometric pulsations and mean arterial pressure (MAP) during inflation and deflation of the cuff. Nineteen healthy young (age 23.1±1.7 years; mean±SD) and 35 elderly (83.9±7.9 years; mean±SD) subjects were studied. Differential analysis of MAP during inflation and deflation show mean |ΔMAP|=2.9±2.6 mm Hg in the young group (mean±SD) and |ΔMAP|=6.3±5.2 mm Hg for seniors (mean±SD). There was a significant difference (p<0.05) in means of |ΔMAP| measured during cuff inflation and cuff deflation between both groups. In about 50% of elderly subjects |ΔMAP| was higher than 5 mm Hg. Potential clinical relevance of the method needs to be further evaluated.

Association Between Early Cardiac Rehabilitation and Long-term Survival in Cardiac Transplant Recipients.

OBJECTIVE: To determine whether participation in early cardiac rehabilitation (CR) after heart transplant (HTx) affects long-term survival. PATIENTS AND METHODS: A retrospective review was conducted in 201 patients who underwent HTx at Mayo Clinic between June 1, 2000, and July 31, 2013. Patients were excluded with multiorgan transplant, no CR data, and follow-up less than 90 days after HTx. Demographic and exercise data at baseline before HTx were collected. Post-HTx exercise capacity, biopsy, CR data, and medications were collected at 1 through 5 and 10 years. RESULTS: Overall survival at 1, 5, and 10 years was 98%, 88%, and 82%, respectively; 29 patients died. Number of CR sessions attended in the first 90 days after HTx predicted survival in multivariate regression, controlling for baseline post-HTx 6-minute walk test (6MWT) results and rejection episodes (hazard ratio, 0.90; 95% CI, 0.82-0.97; P=.007). Additional univariate predictors of survival included pre-HTx 6MWT results, weight at HTx, and body mass index and systolic blood pressure at CR enrollment. Pre-HTx 6MWT results, body mass index, and post-HTx were associated with improvement in peak oxygen consumption. CONCLUSION: This report demonstrates, for the first time, an association between CR and long-term survival in patients after HTx. Further work should clarify the most beneficial aspects of CR.

Chronic Peptide Therapy With B-Type Natriuretic Peptide in Patients With Pre-Clinical Diastolic Dysfunction (Stage B Heart Failure).

OBJECTIVES: This study determined whether there is development of tachyphylaxis to enhancement of cardiorenal response to acute volume loading (AVL) with B-type natriuretic peptide (BNP) after 12-week, twice-daily subcutaneous BNP administration in patients with preclinical diastolic dysfunction (PDD). BACKGROUND: PDD is characterized by normal systolic function and moderate or severe diastolic dysfunction but no symptoms of heart failure (HF). Impairment in cardiorenal endocrine response to stress by AVL exists in PDD and is corrected by acute administration of subcutaneous BNP. METHODS: A double-blinded, placebo-controlled proof-of-concept study was conducted to compare 12 weeks of twice daily subcutaneous BNP, 10 µg/kg (n = 24), versus placebo (n = 12) in PDD. Subjects underwent 2 study visits, at baseline and after 12 weeks. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular AVL. RESULTS: Among those with PDD, there was a statistically significant improvement in diastolic function after 12 weeks of BNP, as measured by a decrease in the Doppler E/e' ratio (where E is early mitral inflow velocity and e' is mitral annulus early diastolic motion) (p = 0.004) and improvement of diastolic dysfunction grade (p = 0.008). After 12 weeks, there was statistically significantly greater sodium excretion, urine flow, and urinary cyclic guanosine monophosphate excretion to AVL (all p < 0.001), as well as a trend toward greater glomerular filtration rate (p = 0.050) in the BNP group as compared to the placebo group. CONCLUSIONS: In subjects with PDD, chronic BNP administration resulted in sustained improvement in diastolic function without development of tachyphylaxis to the enhancement of cardiorenal response to volume expansion with BNP. (Human Brain Natriuretic Peptide [BNP] [or Nesiritide] to Help Heart, Kidney and Humoral Function; NCT00405548).

Chronic subcutaneous brain natriuretic peptide therapy in asymptomatic systolic heart failure.

AIMS: We have previously reported that asymptomatic systolic heart failure (HF) is characterized by an impaired renal response to volume expansion due to lack of activation of urinary cGMP which is corrected by subcutaneous (SQ) BNP. In the current study, we sought to define the cardiorenal response to intravascular volume expansion after 12 weeks of SQ BNP therapy. METHODS AND RESULTS: We utilized a double-blinded, placebo-controlled study to compare 12 weeks of twice-daily SQ BNP 10 µg/kg (n = 22) or placebo (n = 12) in asymptomatic systolic HF. Subjects underwent two study visits: baseline and after 12 weeks of therapy. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular volume expansion. The primary endpoint was change in urinary sodium excretion in response to volume expansion at 12 weeks, and we observed a greater increase in urinary sodium excretion [166 (77, 290) vs. 15 (-39, 72) mEq/min; P = 0.02] with SQ BNP treatment vs. placebo. Secondary endpoints included change in urine flow and glomerular filtration rate (GFR) in response to volume expansion at 12 weeks. We observed a significant increase in urine flow (P < 0.01) and trend for differential response in GFR (P = 0.08) with SQ BNP treatment vs. placebo. CONCLUSION: Among patients with asymptomatic systolic HF, twice-daily SQ BNP therapy improved the cardiorenal response to volume expansion at 12-week follow-up. Further studies are warranted to determine if these beneficial physiological observations with chronic natriuretic peptide administration translate into a delay in the progression to symptomatic HF.

Proximal thoracic aorta dimensions after continuous-flow left ventricular assist device implantation: Longitudinal changes and relation to aortic valve insufficiency.

BACKGROUND: In this study we examined the impact of continuous-flow left ventricular assist device (CF-LVAD) support on proximal thoracic aorta dimensions. METHODS: Aortic root and ascending aorta diameter were measured from serial echocardiograms before and after CF-LVAD implantation in patients with ≥6 months of support, and correlated with the development of >mild aortic valve insufficiency (AI). RESULTS: Of 162 patients included, mean age was 58 ± 11 years and 128 (79%) were male. Seventy-nine (63%) were destination therapy patients. Mean aortic root and ascending aorta diameters at baseline, 1 month, 6 months, 12 months and long-term follow-up (mean 2.0 ± 1.4 years) were 3.5 ± 0.4, 3.5 ± 0.3, 3.9 ± 0.3, 3.9 ± 0.2 and 4.0 ± 0.3, and 3.3 ± 0.2, 3.3 ± 0.3, 3.6 ± 0.2, 3.6 ± 0.3 and 3.6 ± 0.3 cm, respectively. Only change in aortic root diameter from 1-month to 6-month follow-up reached statistical significance (p = 0.03). Nine (6%) patients had accelerated proximal thoracic aorta expansion (>0.5 cm/year), occurring predominantly in the first 6 months after implantation. These patients were older and more likely to have hypertension and baseline proximal thoracic aorta dilation. Forty-five (28%) patients developed >mild AI at long-term follow-up, including 7 of 9 (78%) of those with accelerated proximal thoracic aorta expansion. All 7 had aortic valves that remained closed throughout the cardiac cycle, and this, along with duration of CF-LVAD support and increase in aortic root diameter, were significantly associated with developing >mild AI. CONCLUSION: CF-LVAD patients have small increases in proximal thoracic aorta dimensions that predominantly occur within the first 6 months after implantation and then stabilize. Increasing aortic root diameter was associated with AI development.

Temporal Differences in Causes of Mortality After Left Ventricular Assist Device Implantation.

BACKGROUND: The risk of device-related adverse events leading to death is abundant and ever-present after left ventricular assist device (VAD) implantation. Very few data specifically examine the causes of death related to length of time after VAD implantation. METHODS: Between October 2004 and February 2013, 493 patients (395 male, 80%) underwent primary continuous-flow VAD implantation at our institutions. The median age at implantation was 60 years (range, 18-79 years), and 301 patients (62%) underwent bridge to transplantation. RESULTS: Follow-up was available for all patients (median, 13 months) for a total of 717 patient-years of support. There were 132 deaths during follow-up (median, 8 months; early, 5.5 years) after VAD implantation. The patients were grouped according to temporal occurrence of deaths: (1) early (30-day or index hospitalization) in 34 of 132 patients (26%), (2) between hospital dismissal and 6 months in 29 of 132 patients (22%), (3) 6 months to 1 year in 14 of 132 patients (11%), and (4) after 1 year in 55 of 132 patients (42%). The causes of death (%) at each time period are presented; the most common early cause was right ventricular failure/multisystem organ failure in 18 of 34 patients (61%); from dismissal to 6 months, and 6 months to 1 year, cerebral hemorrhage in 6 of 29 patients (21%) and 4 of 14 patients (29%), respectively; after 1 year, cerebral hemorrhage in 12 of 55 patients (22%) and right ventricular failure/multisystem organ failure in 11 of 55 patients (20%). CONCLUSIONS: The causes of death vary according to time after VAD implantation. Understanding the temporal relationship of causes of mortality after VAD implantation is critical to the identification of varying specific risks in an effort to avoid morbidity, which may ultimately detract from a durable VAD outcome.