Sanjay Mittal

Autonomic Regulation Therapy via Left or Right Cervical Vagus Nerve Stimulation in Patients With Chronic Heart Failure: Results of the ANTHEM-HF Trial

OBJECTIVE ANTHEM-HF evaluated a novel autonomic regulation therapy (ART) via either left or right vagus nerve stimulation (VNS) in patients with heart failure (HF) and reduced ejection fraction (HFrEF). METHODS AND RESULTS Sixty subjects (New York Heart Association [NYHA] functional class II-III, left ventricular ejection fraction (LVEF) ≤ 40%, left ventricular end-diastolic diameter ≥ 50 mm to < 80 mm) receiving optimal pharmacologic therapy were randomized at 10 sites. VNS systems were randomly implanted on the left (n = 31) or right (n = 29) side. All patients were successfully implanted and 59 were titrated over 10 weeks to a well tolerated stimulation intensity. One patient died 3 days after an embolic stroke that occurred during implantation. Common device-related adverse events after VNS titration were transient mild dysphonia, cough, and oropharyngeal pain, which were similar for left- and right-side VNS. After 6 months of ART, the adjusted left-right differences in LVEF, left ventricular end-systolic volume (LVESV), and left ventricular end-systolic diameter (LVESD) were 0.2% (95% CI -4.4 to 4.7), 3.7 mL (95% CI -7.0 to 14.4), and 1.3 mm (95% CI -0.9 to 3.6), respectively. In the combined population, absolute LVEF improved by 4.5% (95% CI 2.4-6.6), LVESV improved by -4.1 mL (95% CI -9.0 to 0.8), and LVESD improved by -1.7 mm (95% CI -2.8 to -0.7). Heart rate variability improved by 17 ms (95% CI 6.5-28) with minimal left-right difference. Six-minute walk distance improved an average of 56 m (95% CI 37-75); however, improvement was greater for right-side ART (77 m [95% CI 49-105]). NYHA functional class improved in 77% of patients (baseline to 6 months). CONCLUSIONS Chronic open-loop ART via left- or right-side VNS is feasible and well tolerated in HFrEF patients. Safety and efficacy measures are encouraging and warrant further study.

Outcomes of the RESTOR-MV Trial (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve)

OBJECTIVES we sought to determine whether patients with functional mitral regurgitation (FMR) would benefit from ventricular reshaping by the Coapsys device (Myocor, Inc., Maple Grove, Minnesota). BACKGROUND FMR occurs when ventricular remodeling impairs valve function. Coapsys is a ventricular shape change device placed without cardiopulmonary bypass to reduce FMR. It compresses the mitral annulus and reshapes the ventricle. We hypothesized that Coapsys for FMR would improve clinical outcomes compared with standard therapies. METHODS RESTOR-MV (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve) was a randomized, prospective, multicenter study of patients with FMR and coronary disease with core laboratory analysis. After enrollment, patients were stratified to the standard indicated surgery: either coronary artery bypass graft alone or coronary artery bypass graft with mitral valve repair. In each stratum, randomization was to either control (indicated surgery) or treatment (coronary artery bypass graft with Coapsys ventricular reshaping). RESULTS the study was terminated when the sponsor failed to secure ongoing funding; 165 patients were randomized. Control and Coapsys both produced decreases in left ventricular (LV) end-diastolic dimension and MR at 2 years (p < 0.001); Coapsys provided a greater decrease in LV end-diastolic dimension (p = 0.021). Control had lower MR grades during follow-up (p = 0.01). Coapsys showed a survival advantage compared with control at 2 years (87% vs. 77%) (hazard ratio: 0.421; 95% confidence interval: 0.200 to 0.886; stratified log-rank test; p = 0.038). Complication-free survival (including death, stroke, myocardial infarction, and valve reoperation) was significantly greater with Coapsys at 2 years (85% vs. 71%) (hazard ratio: 0.372; 95% confidence interval: 0.185 to 0.749; adjusted log-rank test; p = 0.019). CONCLUSIONS analysis of RESTOR-MV indicates that patients with FMR requiring revascularization treated with ventricular reshaping rather than standard surgery had improved survival and a significant decrease in major adverse outcomes. This trial validates the concept of the ventricular reshaping strategy in this subset of patients with heart failure. (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve [RESTOR-MV]; NCT00120276).

Extended Follow-Up of Patients with Heart Failure Receiving Autonomic Regulation Therapy in the ANTHEM-HF Study

OBJECTIVE Evaluate the effects of a novel autonomic regulation therapy (ART) via vagus nerve stimulation (VNS) in patients with chronic heart failure (HF) and reduced left ventricular ejection fraction during a 12-month follow-up period. METHODS The Autonomic Regulation Therapy for the Improvement of Left Ventricular Function and Heart Failure Symptoms (ANTHEM-HF) study enrolled 60 subjects with New York Heart Association class II-III HF and low left ventricular ejection fraction (≤40%), who received open-loop ART using VNS randomized to left or right cervical vagus nerve placement and followed for 6 months after titration to a therapeutic output current (2.0 ± 0.6 mA). Patients received chronic stimulation at a frequency of 10 Hz and pulse duration of 250 µsec. Forty-nine subjects consented to participate in an extended follow-up study for an additional 6 months (12 months total posttitration) to determine whether the effects of therapy were maintained. RESULTS During the 6-month extended follow-up period, there were no device malfunctions or device-related serious adverse effects. There were 7 serious adverse effects unrelated to the device, including 3 deaths (2 sudden cardiac deaths, 1 worsening HF death). There were 5 nonserious adverse events that were adjudicated to be device-related. Safety and tolerability were similar, and there were no significant differences in efficacy between left- and right-sided ART. Overall, mean efficacy measure values at 12 months were not significantly different from mean values at 6 months. CONCLUSIONS Chronic open-loop ART via left- or right-sided VNS continued to be feasible and well-tolerated in patients with HF with reduced EF. Improvements in cardiac function and HF symptoms seen after 6 months of ART were maintained at 12 months.

Mammary-Coronary Artery Anastomosis Without Cardiopulmonary Bypass Through a Minithoracotomy

BACKGROUND Coronary artery bypass grafting has been based on cardiopulmonary bypass, myocardial protection, and the median sternotomy. The recent concept of minimally invasive coronary artery bypass grafting in selected patients has dramatically affected surgical management of coronary artery disease. Coronary artery bypass grafting of anterior coronary arteries with in situ internal mammary artery through a limited anterior thoracotomy is a procedure that is gaining acceptance. METHODS Fifty-one patients were operated on by minithoracotomy and direct coronary artery bypass grafting without cardiopulmonary bypass. Left internal mammary artery-to-left anterior descending coronary artery anastomosis was done in 50 patients, and in 1 patient, left internal mammary artery-to-left anterior descending artery and right internal mammary artery-to-right coronary artery anastomoses were constructed through bilateral minithoracotomies. Left anterior minithoracotomy through the fourth intercostal space and right anterior minithoracotomy through the fifth intercostal space were used for left internal mammary artery and right internal mammary artery dissection, respectively. With this approach, a 4- to 6-cm length of mammary artery was easily dissected. Mammary-to-coronary anastomosis was performed on a beating heart without cardiopulmonary bypass through window pericardiotomy. RESULTS Twenty-five patients were extubated in the operating room and 26 in the intensive care unit 4 to 6 hours after operation. None of these patients required blood transfusion or inotropic support. Postoperative predischarge angiography in 42 patients revealed adequate mammary-to-coronary flow in 40 patients. Doppler flow studies were also in accordance with angiographic findings. Forty-five patients are in our regular follow-up (mean follow-up, 6.23 +/- 1.34 months); 44 of them are in functional class I. CONCLUSION In our experience minithoracotomy is a safe, simple, and minimally invasive procedure. Favorable cost/benefit ratio has been achieved owing to no early or late mortality and minimal early morbidity. Postoperative angiography and Doppler flow study revealed excellent predictive long-term results.

REVIVE Trial: Retrograde Delivery of Autologous Bone Marrow in Patients With Heart Failure

Cell therapy is an evolving option for patients with end‐stage heart failure and ongoing symptoms despite optimal medical therapy. Our goal was to evaluate retrograde bone marrow cell delivery in patients with either ischemic heart failure (IHF) or nonischemic heart failure (NIHF). This was a prospective randomized, multicenter, open‐label study of the safety and feasibility of bone marrow aspirate concentrate (BMAC) infused retrograde into the coronary sinus. Sixty patients were stratified by IHF and NIHF and randomized to receive either BMAC infusion or control (standard heart failure care) in a 4:1 ratio. Accordingly, 24 subjects were randomized to the ischemic BMAC group and 6 to the ischemic control group. Similarly, 24 subjects were randomized to the nonischemic BMAC group and 6 to the nonischemic control group. All 60 patients were successfully enrolled in the study. The treatment groups received BMAC infusion without complications. The left ventricular ejection fraction in the patients receiving BMAC demonstrated significant improvement compared with baseline, from 25.1% at screening to 31.1% at 12 months (p = .007) in the NIHF group and from 26.3% to 31.1% in the IHF group (p = .035). The end‐systolic diameter decreased significantly in the nonischemic BMAC group from 55.6 to 50.9 mm (p = .020). Retrograde BMAC delivery is safe. All patients receiving BMAC experienced improvements in left ventricular ejection fraction, but only those with NIHF showed improvements in left ventricular end‐systolic diameter and B‐type natriuretic peptide. These results provide the basis for a larger clinical trial in HF patients.

PARTAKE Survey of Public Knowledge and Perceptions of Clinical Research in India

Background A public that is an informed partner in clinical research is important for ethical, methodological, and operational reasons. There are indications that the public is unaware or misinformed, and not sufficiently engaged in clinical research but studies on the topic are lacking. PARTAKE – Public Awareness of Research for Therapeutic Advancements through Knowledge and Empowerment is a program aimed at increasing public awareness and partnership in clinical research. The PARTAKE Survey is a component of the program. Objective To study public knowledge and perceptions of clinical research. Methods A 40-item questionnaire combining multiple-choice and open-ended questions was administered to 175 English- or Hindi-speaking individuals in 8 public locations representing various socioeconomic strata in New Delhi, India. Results Interviewees were 18–84 old (mean: 39.6, SD±16.6), 23.6% female, 68.6% employed, 7.3% illiterate, 26.3% had heard of research, 2.9% had participated and 58.9% expressed willingness to participate in clinical research. The following perceptions were reported (% true/% false/% not aware): ‘research benefits society’ (94.1%/3.5%/2.3%), ‘the government protects against unethical clinical research’ (56.7%/26.3%/16.9%), ‘research hospitals provide better care’ (67.2%/8.7%/23.9%), ‘confidentiality is adequately protected’ (54.1%/12.3%/33.5%), ‘participation in research is voluntary’ (85.3%/5.8%/8.7%); ‘participants treated like ‘guinea pigs’’ (20.7%/53.2%/26.0%), and ‘compensation for participation is adequate’ (24.7%/12.9%/62.3%). Conclusions Results suggest the Indian public is aware of some key features of clinical research (e.g., purpose, value, voluntary nature of participation), and supports clinical research in general but is unaware of other key features (e.g., compensation, confidentiality, protection of human participants) and exhibits some distrust in the conduct and reporting of clinical trials. Larger, cross-cultural surveys are required to inform educational programs addressing these issues.

Predictors of Early Outcome After Coronary Artery Surgery in Patients with Severe Left Ventricular Dysfunction

Abstract Background: The surgical survival in patients with severe myocardial dysfunction is critically dependent on the selection of patients. The present study was undertaken to identify the prognostic factors in such patients. Methods: We analyzed the data of 176 consecutive patients (161 men, 15 women), aged 29 to 88 years (mean 58.43), with a left ventricular ejection fraction (LVEF) <30% who underwent isolated coronary artery bypass grafting. The LVEF ranged from 15% to 30% (mean 27.18%). Preoperatively, 33% had angina, 19.9% had recent myocardial infarction, and 21.6% had congestive heart failure. The mean number of grafts was 2.5/patient. The intra‐aortic balloon was used prophylactically in 20.5% of patients and therapeutically in 4.0% of patients. Results: The hospital mortality was 2.3%. The complications occurred as follows: perioperative myocardial infarction in two (1.1%), intractable ventricular arrhythmias in two (1.1%), prolonged ventilation in four (2.3%) and peritoneal dialysis in 1 (0.6%). The mean ICU and hospital stay were2.46 ± 0.76and7.57 ± 2.24days, respectively. The predictors of survival on univariate analysis were New York Heart Association (NYHA) class(x2 = 14.458, p < 0.001), recent myocardial infarction(x2 = 5.852, p = 0.016), congestive heart failure (CHF)(x2 = 5.526, p = 0.019), and left ventricular end‐systolic volume index (LVESVI)(x2 = 25.833, p < 0.001). However, on multivariate analysis, left ventricular end‐systolic volume index was the only independent left ventricular function measurement predictive of survival(x2 = 10.228, p = 0.001). Conclusion: Left ventricular end‐systolic volume index is the most important predictor of survival after coronary artery bypass surgery in patients with severe myocardial dysfunction.(J Card Surg 2003;18:101‐106)

Clinical Research Environment in India: Challenges and Proposed Solutions.

India has compelling need and keen aspirations for indigenous clinical research. Notwithstanding this need and previously reported growth the expected expansion of Indian clinical research has not materialized. We reviewed the scientific literature, lay press reports, and ClinicalTrials.gov data for information and commentary on projections, progress, and impediments associated with clinical trials in India. We also propose targeted solutions to identified challenges. The Indian clinical trial sector grew by (+) 20.3% CAGR (compound annual growth rate) between 2005 and 2010 and contracted by (-) 14.6% CAGR between 2010 and 2013. Phase-1 trials grew by (+) 43.5% CAGR from 2005-2013, phase-2 trials grew by (+) 19.8% CAGR from 2005-2009 and contracted by (-) 12.6% CAGR from 2009-2013, and phase-3 trials grew by (+) 13.0% CAGR from 2005-2010 and contracted by (-) 28.8% CAGR from 2010-2013. This was associated with a slowing of the regulatory approval process, increased media coverage and activist engagement, and accelerated development of regulatory guidelines and recuperative initiatives. We propose the following as potential targets for restorative interventions: Regulatory overhaul (leadership and enforcement of regulations, resolution of ambiguity in regulations, staffing, training, guidelines, and ethical principles [e.g., compensation]).Education and training of research professionals, clinicians, and regulators.Public awareness and empowerment. After a peak in 2009-2010, the clinical research sector in India appears to be experiencing a contraction. There are indications of challenges in regulatory enforcement of guidelines; training of clinical research professionals; and awareness, participation, partnership, and the general image amongst the non-professional media and public. Preventative and corrective principles and interventions are outlined with the goal of realizing the clinical research potential in India.

Transesophageal Echocardiography in Hypotensive Post-Coronary Bypass Patients:

The utility of transesophageal echocardiography in the evaluation of hypotension in the postoperative period after coronary artery bypass was assessed in 126 patients in the intensive care unit. There were 86 men and 40 women, with a mean age of 58.3 years. The indication for transesophageal echocardiography was hypotension refractory to conventional treatment. Valuable diagnostic information was obtained in 103 patients (82%). Based on the echocardiographic findings, 24 patients (19%) underwent urgent surgical intervention. The mean time required to obtain a diagnosis was 9.6 ± 2.8 min. No significant complications were noted. Our experience suggests that transesophageal echocardiography is highly specific in diagnosing the cause of postoperative hypotension, thus preventing unnecessary surgical intervention and facilitating decision making in cardiac surgical emergencies.

Mammary coronary artery anastomosis without cardiopulmonary bypass through minithoracotomy: one year clinical experience

OBJECTIVE The recent concept of minimally invasive coronary artery surgery in selected patients has dramatically affected surgical management of coronary artery disease. We explored the possibility of coronary artery bypass grafting of anterior coronary arteries with in situ internal mammary artery through a limited anterior thoracotomy on beating heart. METHOD Minithoracotomy and direct coronary artery surgery without cardiopulmonary bypass (CPB) was attempted in 116 patients. The procedure was completed in 108 cases while in eight cases minithoracotomy was converted to mid sternotomy. In 107 cases, left internal mammary artery (LIMA) to left anterior descending (LAD) coronary artery anastomosis was done through left anterior minithoracotomy and in one case LIMA to LAD and right internal mammary artery (RIMA) to right coronary artery (RCA) anastomosis was done through bilateral minithoracotomy. Left anterior minithoracotomy through 4th intercostal space and right anterior minithoracotomy through 5th intercostal space was used for left and right internal mammary artery dissection respectively. With this approach 4-8 cm length of mammary artery was easily dissected. Mammary coronary artery anastomosis were performed on a beating heart without CPB through window pericardiotomy. Two patients also underwent left carotid endarterectomy along with LIMA to LAD anastomosis. In two patients complementary percutaneous transluminal coronary angioplasty (PTCA) to circumflex artery was done 5 days after minithoracotomy and LIMA to LAD anastomosis. RESULTS Forty-two patients were extubated in the operating room and 66 in the intensive care unit 2-10 h after surgery. Blood transfusion was used in one case who was reexplored for postoperative bleeding due to a displaced hemoclip from the internal mammary artery branch. None of these patients required inotropic support. Postoperative predischarge check angiogram in 53 cases revealed adequate mammary coronary flow in 51 cases, the remaining two had anastomotic problems, one was subjected to PTCA and the other for redo coronary bypass grafting through mid sternotomy. Doppler flow assessment of anastomosis was done in 102 cases, of which two showed problems which was confirmed on check angiography. One-hundred and six patients are in our regular follow-up (mean follow-up 10+/-1.5 months), 98 of them are in functional class I. CONCLUSION In our experience mammary coronary artery anastomosis without CPB through minithoracotomy is a safe, simple and minimally invasive procedure. Favorable cost/benefit ratio, has been achieved due to no early/late mortality and minimal early morbidity. Postoperative check angiogram and Doppler flow study revealed excellent mid term results.