In vivo fluid dynamics of the Ventura interatrial shunt device in patients with heart failure.

AIMS: Interatrial shunts are under evaluation as a treatment for heart failure (HF); however, their in vivo flow performance has not been quantitatively studied. We aimed to investigate the fluid dynamics properties of the 0.51 cm orifice diameter Ventura shunt and assess its lumen integrity with serial transesophageal echocardiography (TEE). METHODS AND RESULTS: Computational fluid dynamics (CFD) and bench flow tests were used to establish the flow-pressure relationship of the shunt. Open-label patients from the RELIEVE-HF trial underwent TEE at shunt implant and at 6 and 12 month follow-up. Shunt effective diameter (Deff) was derived from the vena contracta, and flow was determined by the continuity equation. CFD and bench studies independently validated that the shunt's discharge coefficient was 0.88 to 0.89. The device was successfully implanted in all 97 enrolled patients; mean age was 70 ± 11 years, 97% were NYHA class III, and 51% had LVEF ≤40%. Patency was confirmed in all instances, except for one stenotic shunt at 6 months. Deff remained unchanged from baseline at 12 months (0.47 ± 0.01 cm, P = 0.376), as did the trans-shunt mean pressure gradient (5.1 ± 3.9 mmHg, P = 0.316) and flow (1137 ± 463 mL/min, P = 0.384). TEE measured flow versus pressure closely correlated (R2 ≥ 0.98) with a fluid dynamics model. At 12 months, the pulmonary/systemic flow Qp/Qs ratio was 1.22 ± 0.12. CONCLUSIONS: When implanted in patients with advanced HF, this small interatrial shunt demonstrated predictable and durable patency and performance.

Relaxin-2 and Soluble Flt1 Levels in Peripartum Cardiomyopathy: Results of the Multicenter IPAC Study.

OBJECTIVES: This study explored the association of vascular hormones with myocardial recovery and clinical outcomes in peripartum cardiomyopathy (PPCM). BACKGROUND: PPCM is an uncommon disorder with unknown etiology. Angiogenic imbalance may contribute to its pathophysiology. METHODS: In 98 women with newly diagnosed PPCM enrolled in the Investigation in Pregnancy Associated Cardiomyopathy study, serum was obtained at baseline for analysis of relaxin-2, prolactin, soluble fms-like tyrosine kinase 1 (sFlt1), and vascular endothelial growth factor (VEGF). Left ventricular ejection fraction (LVEF) was assessed by echocardiography at baseline and 2, 6, and 12 months. RESULTS: Mean age was 30 ± 6 years, with a baseline of LVEF 0.35 ± 0.09. Relaxin-2, prolactin, and sFlt1 were elevated in women presenting early post-partum, but decreased rapidly and were correlated inversely with time from delivery to presentation. In tertile analysis, higher relaxin-2 was associated with smaller left ventricular systolic diameter (p = 0.006) and higher LVEF at 2 months (p = 0.01). This was particularly evident in women presenting soon after delivery (p = 0.02). No relationship was evident for myocardial recovery and prolactin, sFlt1 or VEGF levels. sFlt1 levels were higher in women with higher New York Heart Association functional class (p = 0.01) and adverse clinical events (p = 0.004). CONCLUSIONS: In women with newly diagnosed PPCM, higher relaxin-2 levels soon after delivery were associated with myocardial recovery at 2 months. In contrast, higher sFlt1 levels correlated with more severe symptoms and major adverse clinical events. Vascular mediators may contribute to the development of PPCM and influence subsequent myocardial recovery. (Investigation in Pregnancy Associate Cardiomyopathy [IPAC]; NCT01085955).

Worldwide surgical experience with the Paracor HeartNet cardiac restraint device.

OBJECTIVE: An elastic ventricular restraint device has been developed for patients with heart failure who remain symptomatic despite treatment with standard therapies. The safety and efficacy of this device are under clinical investigation. Six-month data for the first 51 patients treated worldwide are reported. We hypothesize that the Paracor HeartNet device (Paracor Medical, Sunnyvale, Calif), placed through a minithoracotomy in patients with severe dilated cardiomyopathy, improves clinical and functional status. METHODS: Fifty-one patients with an ejection fraction of 35% or less, with a New York Heart Association class II or III, and receiving optimal medical therapy for at least 3 months, were selected at 15 sites (3 in Europe, 12 in the United States) to undergo implantation of the HeartNet device through a minithoracotomy. Patients were evaluated at baseline and at 6-month follow-up by echocardiography, the 6-minute walk test, cardiopulmonary exercise testing (partial oxygen pressure in mixed venous blood), New York Heart Association class, and (in the United States) the Minnesota Living with Heart Failure questionnaire. RESULTS: The average age was 52 years (30-73 years), with a preponderance of men and nonischemic cause of heart failure. Implantation was accomplished in 50 of 51 patients (98%). Adverse events included 2 in-hospital deaths secondary to pulmonary complications (4%), additional pulmonary complications in 7 patients (14%), arrhythmia in 14 patients (27%), epicardial laceration in 2 patients (4%), and empyema in 1 patient (2%). Six-month data demonstrated significant improvement in the 6-minute walk test (+65.7, P = .002) and Minnesota Living with Heart Failure scores (-15.7, P = .002) and improvement in echocardiographic findings. CONCLUSION: The Paracor HeartNet device can be reliably implanted in patients with heart failure and marked reduction of left ventricular function. These data suggest a functional and clinical benefit, with a trend toward reverse remodeling, and support the conduct of a randomized controlled pivotal trial.

Initial United States experience with the Paracor HeartNet myocardial constraint device for heart failure.

OBJECTIVE: This study was undertaken to review the initial results and surgical safety data for the US Food and Drug Administration safety and feasibility trial of the Paracor HeartNet (Paracor Medical, Inc, Sunnyvale, Calif.) myocardial constraint device. METHODS: Patients with New York Heart Association functional class II or III heart failure underwent device implantation (n = 21) through a left minithoracotomy. RESULTS: The average age was 53 years (31-72 years). There were 18 men and 3 women, and 17 patients had nonischemic etiology of heart failure. Mean heart failure duration was 8.3 years (1.4-18.8 years). Average ejection fraction was 22% (11%-33%), with an average left ventricular end-diastolic dimension of 74 mm (55-94 mm). Previous medical therapy included angiotensin-converting enzyme inhibitors, beta-blockers, diuretics, digoxin, and aldosterone receptor blockers. At implantation, 17 patients had implantable electronic devices: 1 biventricular pacemaker, 11 biventricular pacemakers with cardioverter-defibrillators, and 5 implantable cardioverter-defibrillators. Patient comorbidities included hypertension in 10 cases, diabetes mellitus in 8, myocardial infarction in 1, and ventricular tachycardia in 8. Mean operative time was 68 minutes (42-102 minutes), and implantation time averaged 15 minutes (5-51 minutes). The average time to ambulation was 1.6 days (1-4 days). The intensive care unit stay averaged 3.3 days (1-16 days), and hospital stay averaged 6.3 days (4-16 days). Atrial fibrillation occurred in 2 patients, and there were 2 in-hospital deaths. CONCLUSIONS: The Paracor device can be implanted in patients with heart failure and reduced left ventricular function with a high degree of success. Significant surgical complications were infrequent. The initial US experience supports the conduct of a randomized, controlled, pivotal trial.

Predictors of sudden cardiac death and appropriate shock in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial.

BACKGROUND: The factors that determine the risk for sudden death or implantable cardioverter defibrillator therapy in patients receiving cardiac resynchronization therapy (CRT) therapies are largely unknown. METHODS AND RESULTS: We hypothesized that clinical measures of heart failure severity and the presence of comorbid conditions would predict the risk of malignant arrhythmias in the 1520 patients enrolled in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial. Outcomes in the CRT group after implantable cardioverter defibrillator therapy were also evaluated. The CRT-defibrillator device reduced the risk of sudden death by 56% compared with drug therapy (17 of 595 [2.9%] versus 18 of 308 [5.8%], P<0.02). CRT therapy was not associated with sudden death risk reduction (48 of 617 [7.8%]). Other factors associated with reduced sudden death risk were left ventricular ejection fraction >20% (HR, 0.55 [95% CI, 0.35 to 0.87]; P=0.01), QRS duration >160 ms (HR, 0.63 [95% CI, 0.40 to 0.997]; P=0.05), and female gender (HR, 0.56 [95% CI, 0.34 to 0.94]; P=0.003). The risk for sudden death was increased by advanced New York Heart Association class IV heart failure (HR, 2.62 [95% CI, 1.61 to 4.26]; P<0.011) and renal dysfunction (HR, 1.69 [95% CI, 1.06 to 2.69]; P=0.03). An appropriate shock was experienced in 88 (15%) of the 595 CTR-D patients. In the CRT-defibrillator patients, female gender (HR, 0.54 [95 % CI, 0.31 to 0.94]; P=0.03) and use of neurohormonal antagonists were associated with reduced risk. Class IV heart failure status increased risk. Appropriate implantable cardioverter defibrillator therapy was positively associated with risk of death or all-cause hospitalization (HR, 1.57; P<0.002), pump failure death or hospitalization (HR, 2.35; P<0.001), and sudden death (HR, 2.99; P=0.03), but not total mortality (HR, 1.3; P=0.28). CONCLUSIONS: In CRT candidates, sudden cardiac death risk is associated with higher New York Heart Association class and renal dysfunction. In CRT-defibrillator recipients, reduction in the risk of an appropriate shock is associated with medical therapy with neurohormonal antagonists, female gender, and New York Heart Association functional class III versus IV clinical status. Shock therapy was associated with worse outcome.

Cardiac failure: mechanical support strategies.

OBJECTIVE: Mechanical support of the circulation is necessary when heart failure becomes refractory to medical support and is typically applied when organ dysfunction occurs as a result of hypoperfusion. However, in timing the intervention, it is important to apply mechanical support before multiple organ failure occurs. The objective of this work is to review the current strategies for mechanical circulatory support in patients with refractory cardiac failure. DESIGN: A review of the use of mechanical circulatory support is presented for patients with refractory cardiac failure. PATIENTS: Data are taken from human studies that were selected to best exemplify the results that may be obtained from various forms of mechanical circulatory support. INTERVENTIONS: Commonly applied forms of mechanical support include mechanical ventilatory support, intraaortic balloon counterpulsation, and hemodialysis or ultrafiltration. If these measures fail, mechanical support of the circulation with ventricular assist devices is possible in specialized centers with expertise in the implantation and management of these devices. The decision to pursue mechanical circulatory support in the critically ill patient is based on the cause of acute decompensation, the potential reversibility of the condition, and the possibility for other treatments to improve the underlying condition or, in highly selected cases, heart transplantation. Newer forms of ventricular assistance that require less surgery are becoming available and may allow use in a broader range of critically ill patients. MAIN RESULTS: There is a range of means to mechanically support the circulation in patients with advanced heart failure. CONCLUSIONS: A variety of means to support the circulation have found application in the treatment of patients with refractory heart failure. More work is required to best identify populations who will benefit from the therapy and to refine the therapy to reduce associated risks.

A multicenter, prospective, randomized, double-blind trial of basiliximab in heart transplantation.

BACKGROUND: The role and pharmacokinetics of interleukin-2 (IL-2) monoclonal antibodies (mAbs) in heart transplantation remain unclear. This 1-year double-blind, randomized, placebo-controlled study evaluated safety, tolerability, and pharmacokinetics of the IL-2 mAb basiliximab with cyclosporine, mycophenolate mofetil, and steroids in adult de novo heart transplant recipients. METHODS: Fifty-six patients received either basiliximab (20 mg) or placebo on Days 0 and 4 post-transplantation. Safety assessments included adverse events, serious adverse events, and infections. The time to and severity of biopsy-proven acute rejection (BPAR) were also assessed. RESULTS: Basiliximab was generally well tolerated. There were no significant differences between treatment groups with respect to adverse event profiles, serious adverse events (84.0% vs 61.3%), or infections (84% vs 74.2%). The mean number of days to first BPAR was longer with basiliximab (73.7 +/- 59.68) than placebo (40.6 +/- 53.30) at 6 months, but not statistically significant (trend). The duration that basiliximab concentrations exceeded the CD25 saturation threshold averaged 38 +/- 13 days. Patients with rejection did not clear basiliximab faster or have shorter durations of saturation than rejection-free patients. None of the patients screened had detectable anti-idiotype antibodies. CONCLUSIONS: These pilot results describe the pharmacokinetics of basiliximab and show that basiliximab appears to be tolerated with a similar safety profile to placebo in adult de novo heart transplant recipients. Larger scale clinical trials are feasible and warranted.

Heart allograft rejection: detection with breath alkanes in low levels (the HARDBALL study).

BACKGROUND: We evaluated a new marker of heart transplant rejection, the breath methylated alkane contour (BMAC). Rejection is accompanied by oxidative stress that degrades membrane polyunsaturated fatty acids, evolving alkanes and methylalkanes, which are excreted in the breath as volatile organic compounds (VOCs). METHODS: Breath VOC samples (n = 1,061) were collected from 539 heart transplant recipients before scheduled endomyocardial biopsy. Breath VOCs were analyzed by gas chromatography and mass spectroscopy, and BMAC was derived from the abundance of C4-C20 alkanes and monomethylalkanes. The "gold standard" of rejection was the concordant set of International Society for Heart and Lung Transplantation (ISHLT) grades in biopsies read by 2 reviewers. RESULTS: Concordant biopsies were: Grade 0, 645 of 1,061 (60.8%); 1A, 197 (18.6%); 1B, 84 (7.9%); 2, 93 (8.8%); and 3A, 42 (4.0%). A combination of 9 VOCs in the BMAC identified Grade 3 rejection (sensitivity 78.6%, specificity 62.4%, cross-validated sensitivity 59.5%, cross-validated specificity 58.8%, positive predictive value 5.6%, negative predictive value 97.2%). Site pathologists identified the same cases with sensitivity of 42.4%, specificity 97.0%, positive predictive value 45.2% and negative predictive value 96.7%. CONCLUSIONS: A breath test for markers of oxidative stress was more sensitive and less specific for Grade 3 heart transplant rejection than a biopsy reading by a site pathologist, but the negative predictive values of the 2 tests were similar. A screening breath test could potentially identify transplant recipients at low risk of Grade 3 rejection and reduce the number of endomyocardial biopsies.

Use of a wearable defibrillator in terminating tachyarrhythmias in patients at high risk for sudden death: results of the WEARIT/BIROAD.

The automatic ICD improves survival in patients with a history of sudden cardiac arrest. However, some patients do not meet the guidelines for ICD implantation or are unable to receive an implantable device. This study tested the hypothesis that these patients could benefit from a wearable cardioverter defibrillator. Patients with symptomatic heart failure and an ejection fraction of <0.30 (WEARIT Study) or patients having complications associated with high risk for sudden death after a myocardial infarction or bypass surgery not receiving an ICD for up to 4 months (BIROAD Study) were enrolled into two studies. After a total of 289 patients had been enrolled in the trial (177 in WEARIT and 112 in BIROAD), prespecified safety and effectiveness guidelines had been met. Six (75%) of eight defibrillation attempts were successful. Six inappropriate shock episodes occurred during 901 months of patient use (0.67% unnecessary shocks per month of use). Twelve deaths occurred during the study 6 sudden deaths: 5 not wearing and 1 incorrectly wearing the device). Most patients tolerated the device although 68 patients quit due to comfort issues or adverse reactions. The results of the present study suggest that a wearable defibrillator is beneficial in detecting and effectively treating ventricular tachyarrhythmias in patients at high risk for sudden death who are not clear candidates for an ICD and may be useful as a bridge to transplantation or ICD in some patients.

Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias.

OBJECTIVES: This study was conducted to assess the safety and effectiveness of cardiac resynchronization therapy (CRT) when combined with an implantable cardioverter defibrillator (ICD). BACKGROUND: Long-term outcome of CRT was measured in patients with symptomatic heart failure (HF), intraventricular conduction delay, and malignant ventricular tachyarrhythmias (ventricular tachycardia/ventricular fibrillation [VT/VF]) requiring therapy from an ICD. METHODS: Patients (n = 490) were implanted with a device capable of providing both CRT and ICD therapy and randomized to CRT (n = 245) or control (no CRT, n = 245) for up to six months. The primary end point was progression of HF, defined as all-cause mortality, hospitalization for HF, and VT/VF requiring device intervention. Secondary end points included peak oxygen consumption (VO(2)), 6-min walk (6 MW), New York Heart Association (NYHA) class, quality of life (QOL), and echocardiographic analysis. RESULTS: A 15% reduction in HF progression was observed, but this was statistically insignificant (p = 0.35). The CRT, however, significantly improved peak VO(2) (0.8 ml/kg/min vs. 0.0 ml/kg/min, p = 0.030) and 6 MW (35 m vs. 15 m, p = 0.043). Changes in NYHA class (p = 0.10) and QOL (p = 0.40) were not statistically significant. The CRT demonstrated significant reductions in ventricular dimensions (left ventricular internal diameter in diastole = -3.4 mm vs. -0.3 mm, p < 0.001 and left ventricular internal diameter in systole = -4.0 mm vs. -0.7 mm, p < 0.001) and improvement in left ventricular ejection fraction (5.1% vs. 2.8%, p = 0.020). A subgroup of patients with advanced HF (NYHA class III/IV) consistently demonstrated improvement across all functional status end points. CONCLUSIONS: The CRT improved functional status in patients indicated for an ICD who also have symptomatic HF and intraventricular conduction delay.