Franklin Rosenfeldt

Pharmacology of Coronary Artery Bypass Grafts

Spasm of arterial and venous graft conduits can occur both during harvesting and after the graft is connected. Attempts to overcome spasm during harvesting by probing or hydraulic distension can cause structural damage to the graft, which may impair short- and long-term patency. After a coronary artery bypass graft is connected, spasm can cause major problems with myocardial perfusion. To select the best pharmacologic agent to prevent or reverse vasoconstriction in a graft requires an understanding of the reactivity of that particular type of graft to vasoconstrictor and vasodilator agents. The pharmacologic reactivity of venous and arterial graft conduits has been documented through extensive studies of isolated vessels in the organ bath and of in situ grafts in the body. In this review we summarize the current state of knowledge of the reactivity of arterial and venous grafts to vasoconstrictor and vasodilator agents and describe the practical application of this knowledge in the operating room and in the postoperative period.

Reactivity of the canine isolated internal mammary artery, saphenous vein, and coronary artery to constrictor and dilator substances : relevance to coronary bypass graft surgery

The internal mammary artery (IMA) and saphenous vein (SV) are used routinely in coronary artery (CA) bypass graft surgery. The IMA may develop spasm during surgery, and the SV often develops spasm during removal from the leg. We sought to determine the relative reactivity of the canine CA, IMA, and SV to potential vasoconstrictor substances and especially to determine which vasodilator agents were effective in these different blood vessels. All vessels were arranged as ring segments suspended at optimal stretch in organ baths. Glyceryl trinitrate (GTN) caused relaxation of the three vessels but was less sensitive, less potent (as determined by EC50 values), and had a reduced range of relaxation in the IMA. Papaverine was less sensitive in the IMA as compared with the CA and SV. Nifedipine, verapamil, and diltiazem were potent relaxing agents in all three vessels when precontracted by K+, but were less potent in vessels contracted by the thromboxane mimetic U46619 or phenylephrine, especially in the SV. These studies highlight the marked differences in the response of IMA and CA to constrictor and dilator agents and reinforce the notion that calcium antagonists of different chemical classes have widely differing activities in vascular tissue.

Early Lung Transplantation Success Utilizing Controlled Donation After Cardiac Death Donors

Donation‐after cardiac death (DCD) donor organs have potential to significantly alleviate the shortage of transplantable lungs. However, only limited data so far describes DCD lung transplantation (LTx) techniques and results. This study aims to describe the Alfred Hospitals early and intermediate outcomes following DCD donor LTx. Following careful experimentation and consultation DCD guidelines were created to utilize Maastricht category III lung donors from either the ICU or operating room(OR), with a warm ischemic time(WIT) of <60 min. Between May 2006 and December 2007, 22 referred DCD donors led to 11 attempted retrievals after withdrawal, resulting in 8 actual bilateral LTx (2 donors did not arrest in prescribed period and 1 donor had nonacceptable lungs). ICU WIT = 38.4 min (range 20–54, OR WIT = 12.7 min (11–15), p < 0.05. Post‐LTx, 1 pulmonary hypertensive patient required ECMO for PGD3. The mean group pO2/FiO2 ratio at 24 hours was 307.7 (240–507) with an ICU stay of 9.5 days (2–21) and ward stay of 21.5 days (11–76). All 8 survive at a mean of 311 days (10–573) with good performance status and lung function. In conclusion, the use of Maastricht category III lungs for human LTx is associated with acceptable early clinical outcomes.

The Effect of Coenzyme Q10 on Morbidity and Mortality in Chronic Heart Failure: Results From Q-SYMBIO: A Randomized Double-Blind Trial

OBJECTIVES This randomized controlled multicenter trial evaluated coenzyme Q10 (CoQ10) as adjunctive treatment in chronic heart failure (HF). BACKGROUND CoQ10 is an essential cofactor for energy production and is also a powerful antioxidant. A low level of myocardial CoQ10 is related to the severity of HF. Previous randomized controlled trials of CoQ10 in HF were underpowered to address major clinical endpoints. METHODS Patients with moderate to severe HF were randomly assigned in a 2-year prospective trial to either CoQ10 100 mg 3 times daily or placebo, in addition to standard therapy. The primary short-term endpoints at 16 weeks were changes in New York Heart Association (NYHA) functional classification, 6-min walk test, and levels of N-terminal pro-B type natriuretic peptide. The primary long-term endpoint at 2 years was composite major adverse cardiovascular events as determined by a time to first event analysis. RESULTS A total of 420 patients were enrolled. There were no significant changes in short-term endpoints. The primary long-term endpoint was reached by 15% of the patients in the CoQ10 group versus 26% in the placebo group (hazard ratio: 0.50; 95% confidence interval: 0.32 to 0.80; p = 0.003) by intention-to-treat analysis. The following secondary endpoints were significantly lower in the CoQ10 group compared with the placebo group: cardiovascular mortality (9% vs. 16%, p = 0.026), all-cause mortality (10% vs. 18%, p = 0.018), and incidence of hospital stays for HF (p = 0.033). In addition, a significant improvement of NYHA class was found in the CoQ10 group after 2 years (p = 0.028). CONCLUSIONS Long-term CoQ10 treatment of patients with chronic HF is safe, improves symptoms, and reduces major adverse cardiovascular events. (Coenzyme Q10 as adjunctive treatment of chronic heart failure: a randomised, double-blind, multicentre trial with focus on SYMptoms, BIomarker status [Brain-Natriuretic Peptide (BNP)], and long-term Outcome [hospitalisations/mortality]; ISRCTN94506234).

Pharmacological Relaxation of the Saphenous Vein During Harvesting for Coronary Artery Bypass Grafting

Spasm of the saphenous vein frequently occurs during harvesting from the leg and high-pressure distension is required to restore an adequate diameter for grafting. Forceful distention has been shown to damage the intima and media and may predispose to subsequent occlusion of the vein graft. Various pharmacologic vasodilators are capable of relaxing veins; in this study, we carried out a systematic investigation to determine the appropriate agents and concentrations for use during vein graft operations. In organ baths, human saphenous vein segments were contracted with potassium or a thromboxane mimetic, and vasodilator agents were then applied. Glyceryl trinitrate, 7.2 micrograms/mL, or papaverine hydrochloride, 11.9 micrograms/mL, caused 80% to 100% relaxation of contraction induced by potassium or thromboxane. Verapamil, 15.5 micrograms/mL, relaxed the potassium contraction by 100% and the thromboxane contraction by 75%. Comparison of the time course of action showed that glyceryl trinitrate had a rapid onset and a short duration of maximal action, whereas verapamil (like papaverine) had delayed onset and a long duration. A mixture of glyceryl trinitrate and verapamil combined rapid onset with long duration of action. We now use a mixture of glyceryl trinitrate and verapamil (pH 7.4) topically and intraluminally during harvesting of the saphenous vein to provide a relaxed conduit for coronary artery bypass grafting.

Improved Preservation of Saphenous Vein Grafts by the Use of Glyceryl Trinitrate–Verapamil Solution During Harvesting

BACKGROUND High-pressure distension during harvesting damages the saphenous vein (SV) and may contribute to subsequent coronary artery bypass graft (CABG) occlusion. Application of vasodilator agents to the SV during harvesting may reduce the need for high-pressure distension and improve graft quality. We tested the effects of a vasodilator solution containing glyceryl trinitrate and verapamil (GV) or the conventional agent papaverine (Pap) on the pressure necessary to overcome SV spasm and on the structure and biochemistry of the SV graft. METHODS AND RESULTS Thirty-six patients undergoing CABG were randomly allocated to receive an application of either topical and intraluminal GV solution, topical Pap, or topical and intraluminal Ringers solution (untreated) to the SV during harvesting. The peak and mean pressures required to distend the vein were recorded. Samples of SV were taken for microscopy and biochemical analysis just before we performed the anastomosis. The percentage of endothelial coverage was calculated by area measurements of stained en face preparations of the vein intima. The results for peak pressures (mmHg) were: untreated, 479.2 +/- 27.5; Pap, 384.8 +/- 29.0; and GV, 309.5 +/- 28.3 (P < .001, GV plus Pap versus untreated); and the results for mean pressures (mm Hg) were untreated, 136.2 +/- 9.6; Pap, 102.2 +/- 10.8; and GV, 98.0 +/- 8.3 (P < .01, GV plus Pap versus untreated). The results for endothelial cover (%) were: untreated, 43.7 +/- 7.0; Pap, 44.1 +/- 9.2; and GV, 68.7 +/- 7.0 (P < .05, GV versus Pap); and the results for ATP (nmol/g wet wt) were: untreated, 67.3 +/- 12.7; Pap, 112.0 +/- 19.4; and GV, 132.5 +/- 22.7 (P < .05, GV plus Pap versus untreated). CONCLUSIONS First, pharmacological treatment of SV during harvesting, especially with GV solution, allows the use of a lower distension pressure and reduces the breakdown of high-energy phosphates in the vein wall. Second, topical and intraluminal use of GV solution during vein harvesting improves endothelial coverage compared with the topical use of Pap or no pharmacological treatment.

Antiatherosclerotic and renoprotective effects of ebselen in the diabetic apolipoprotein E/GPx1-double knockout mouse.

OBJECTIVE To investigate the effect of the GPx1-mimetic ebselen on diabetes-associated atherosclerosis and renal injury in a model of increased oxidative stress. RESEARCH DESIGN AND METHODS The study was performed using diabetic apolipoprotein E/GPx1 (ApoE−/−GPx1−/−)-double knockout (dKO) mice, a model combining hyperlipidemia and hyperglycemia with increased oxidative stress. Mice were randomized into two groups, one injected with streptozotocin, the other with vehicle, at 8 weeks of age. Groups were further randomized to receive either ebselen or no treatment for 20 weeks. RESULTS Ebselen reduced diabetes-associated atherosclerosis in most aortic regions, with the exception of the aortic sinus, and protected dKO mice from renal structural and functional injury. The protective effects of ebselen were associated with a reduction in oxidative stress (hydroperoxides in plasma, 8-isoprostane in urine, nitrotyrosine in the kidney, and 4-hydroxynonenal in the aorta) as well as a reduction in VEGF, CTGF, VCAM-1, MCP-1, and Nox2 after 10 weeks of diabetes in the dKO aorta. Ebselen also significantly reduced the expression of proteins implicated in fibrosis and inflammation in the kidney as well as reducing related key intracellular signaling pathways. CONCLUSIONS Ebselen has an antiatherosclerotic and renoprotective effect in a model of accelerated diabetic complications in the setting of enhanced oxidative stress. Our data suggest that ebselen effectively repletes the lack of GPx1, and indicate that ebselen may be an effective therapeutic for the treatment of diabetes-related atherosclerosis and nephropathy. Furthermore, this study highlights the feasibility of addressing two diabetic complications with one treatment regimen through the unifying approach of targeted antioxidant therapy.

Quantification of mitochondrial DNA in peripheral blood mononuclear cells and subcutaneous fat using real-time polymerase chain reaction

BACKGROUND With decreased rates of HIV mortality and disease progression attributable to treatment with nucleoside analogue reverse transcriptase inhibitors (NRTIs), attention has now become focused on the toxicities of these forms of treatment. It is believed NRTIs cause a decrease in mitochondrial DNA (mtDNA) synthesis due to their inhibition of DNA polymerase gamma. This hypothesis is supported by in vitro data from muscle biopsies and human lymphoblastic cell lines. The resulting mitochondrial toxicity is thought to manifest itself in a variety of clinical symptoms including fatigue, fat wasting and peripheral neuropathy. A non-invasive test of mitochondrial toxicity is needed to assess toxicity and optimise HIV treatment strategies. Peripheral blood mononuclear cells (PBMC) and subcutaneous fat could be ideal and accessible sources of mtDNA for examining toxicity. OBJECTIVES The objectives of this study were (a) to develop an assay to quantify the mtDNA copy number of PBMC and obtain reproducible results and (b) to establish the utility of subcutaneous fat as a source of mtDNA for quantification. STUDY DESIGN PBMC were isolated from blood by centrifugation over Ficoll-Paque and subcutaneous fat was obtained from two 3 mm punch skin biopsies. Following DNA extraction, the mtDNA copy number in each sample was quantified by real-time polymerase chain reaction (PCR). RESULTS The real-time PCR assay was found to generate consistent and reproducible results with replicates of samples undertaken within the same run, and in two or more different runs, having a mean coefficient of variation of 11.3 and 17.2%, respectively. PBMC and subcutaneous fat contained 409+/-148 and 2042+/-391 copies of mtDNA per cell, respectively. CONCLUSIONS From the work carried out it can be concluded that firstly, the real-time PCR assay generates consistent and reproducible results, and secondly that mtDNA can be extracted and quantified from PBMC and subcutaneous fat.

Coenzyme Q10 Protects the Aging Heart against Stress

With aging of the population, increasing numbers of elderly patients are presenting for cardiac surgery. However, the results in the elderly are inferior to those in the young. A likely contributing factor is an age‐related reduction in cellular energy production in the myocardium during surgery, which is known to induce aerobic and ischemic stress. The lipophilic antioxidant and mitochondrial respiratory chain redox coupler, coenzyme Q10 (CoQ10), has the potential to improve energy production in mitochondria by bypassing defective components in the respiratory chain as well as by reducing the effects of oxidative stress. We hypothesized that CoQ10 pretreatment prior to stress could improve the recovery of the myocardium after stress.

A comparison of amiodarone and digoxin for treatment of supraventricular arrhythmias after cardiac surgery.

Despite the widespread use of amiodarone in non-surgical patients, its role in the management of supraventricular tachyarrhythmias after cardiac surgery is not clear. We set out to compare the relative efficacy of amiodarone and digoxin in the management of atrial fibrillation and flutter in the early postoperative period. This prospective randomised trial comprised 30 patients, previously in sinus rhythm, who developed sustained atrial fibrillation or flutter following myocardial revascularisation, valve surgery or combined procedures. Amiodarone was administered as an intravenous loading dose followed by a continuous infusion. Digoxin was given as an intravenous loading dose followed by oral maintenance therapy. Electrocardiographic and haemodynamic monitoring was continued for 24 h after the commencement of treatment. There was a marked reduction in heart rate in both groups, mainly in the first 6 h, from 146 to 89 beats per minute in the amiodarone group and from 144 to 95 in the digoxin group. At the end of the 24 h, one of the 15 patients in the amiodarone group and 3 of the 15 patients in the digoxin group remained in atrial fibrillation. No patient in either group developed adverse reactions. We conclude that intravenous amiodarone therapy is safe and at least as effective as digoxin in the initial management of arrhythmias after cardiac surgery.