Sunil K. Ohri

Long-term maternal high-fat feeding from weaning through pregnancy and lactation predisposes offspring to hypertension, raised plasma lipids and fatty liver in mice

In rodents, adverse prenatal nutrition, such as a maternal diet rich in fat during pregnancy, enhances susceptibility of the offspring to hypertension, type 2 diabetes and other features of the human metabolic syndrome in adulthood. However, previous experimental studies were confined to short-term modifications of the maternal diet during pregnancy and/or lactation periods, a situation uncommon in humans. Moreover in humans, the offspring may also consume a high-fat diet, which may take them beyond the range to which their development has adapted them to respond healthily. We examined in C57 mice the effects on offspring of feeding their mothers a high-fat (HF) or standard chow (C) diet from weaning through pregnancy and lactation, and whether there are additive phenotypic effects of feeding the offspring an HF diet from weaning to adulthood (dam-offspring dietary group HF-HF). This group was compared with offspring from HF-fed dams fed a C diet from weaning to adulthood (HF-C) and offspring from C-fed mothers fed the C or HF diet (C-C and HF-C, respectively). HF-HF, HF-C and C-HF adult female offspring were heavier, fatter, and had raised serum cholesterol and blood pressure compared with C-C female offspring. We observed a similar trend in male offspring except for the HF-C group which was not heavier or fatter than male C-C offspring. Histology showed lipid vacuoles within hepatocytes in the HF-HF, HF-C and C-HF but not the CC offspring. Serum C-reactive protein was elevated in female (C-HF and HF-HF) but not in male offspring. Elevated blood pressure in the HF-C and C-HF groups was attenuated in the HF-HF group in males but not in females. These findings indicate that long-term consumption of an HF diet by the mother predisposes her offspring to developing a metabolic syndrome-like phenotype in adult life, although cardiovascular effects of an HF diet are related to sex specificity in the HF-HF group.

Cardiopulmonary bypass impairs small intestinal transport and increases cut permeability

Gastrointestinal damage occurs in 0.6% to 2% of patients after cardiopulmonary bypass (CPB), and carries a mortality of 12% to 67%. The incidence of subclinical gastrointestinal damage may be much greater. We examined the effects of nonpulsatile, hypothermic CPB on intestinal absorption and permeability in 41 patients. Bowel mucosal saccharide transport and permeation were evaluated using 100 mL of an oral solution containing 3-O-methyl-D-glucose (0.2 g), D-xylose (0.5 g), L-rhamnose (1.0 g), and lactulose (5.0 g) to assess active carrier-mediated, passive carrier-mediated, transcellular, and paracellular transport, respectively, with a 5-hour urine analysis. Patients were studied before, immediately after, and 5 days after CPB. Immediately after CPB there was a decrease in urinary excretion of 3-O-methyl-D-glucose (from 34% +/- 2.2% to 5.2% +/- 0.7%; p < 0.0001), D-xylose (from 25.4% +/- 1.4% to 4.1% +/- 0.8%; p < 0.0001), and L-rhamnose (from 8.3% +/- 0.6% to 2.6% +/- 0.4%; p < 0.0001). The permeation of 3-O-methyl-D-glucose and D-xylose returned to normal levels 5 days after CPB, but that of L-rhamnose remained significantly below pre-CPB values at 6.6% +/- 0.5% (p = 0.004). However, the permeation of lactulose increased after CPB (from 0.35% +/- 0.04% to 0.59% +/- 0.1%; p = 0.018), and the lactulose/L-rhamnose gut permeability ratio increased markedly (from 0.045 +/- 0.04 to 0.36 +/- 0.08; normal = 0.06 to 0.08; p = 0.004). Patients who had a CPB time of 100 minutes or more had a greater increase in gut permeability (p = 0.049).(ABSTRACT TRUNCATED AT 250 WORDS)

Transgenerational effects of prenatal nutrient restriction on cardiovascular and hypothalamic-pituitary-adrenal function

The perinatal environment is a powerful determinant of risk for developing disease in later life. Here, we have shown that maternal undernutrition causes dramatic changes in heart structure and hypothalamo‐pituitary‐adrenal (HPA) function across two generations. Pregnant guinea pigs were fed 70% of normal intake from gestational days 1–35 (early restriction; ER), or 36–70 (late restriction; LR). Female offspring (F1) were mated and fed ad libitum to create second generation (F2) offspring. Heart morphology, blood pressure, baroreceptor and HPA function were assessed in male F1 and F2 offspring. ERF1 males exhibited elevated blood pressure, increased left ventricular (LV) wall thickness and LV mass. These LV effects were maintained in the ERF2 offspring. Maternal undernutrition increased basal cortisol and altered HPA responsiveness to challenge in both generations; effects were greatest in LR groups. In conclusion, moderate maternal undernutrition profoundly modifies heart structure and HPA function in adult male offspring for two generations.

A prospective randomized study to evaluate the renoprotective action of beating heart coronary surgery in low risk patients.

OBJECTIVES Cardiopulmonary bypass (CPB) is widely regarded as an important contributor to renal failure, a well recognized complication following coronary artery surgery (coronary artery bypass grafting (CABG)). Anecdotally off-pump coronary surgery (OPCAB) is considered renoprotective. We examine the extent of renal glomerular and tubular injury in low-risk patients undergoing either OPCAB or on-pump coronary artery bypass (ONCAB). METHODS Forty low-risk patients with normal preoperative cardiac and renal functions awaiting elective CABG were prospectively randomized into those undergoing OPCAB (n=20) and ONCAB (n=20). Glomerular and tubular injury were measured respectively by urinary excretion of microalbumin and retinol binding protein (RBP) indexed to creatinine (Cr). Daily measurements were taken from admission to postoperative day 5. Fluid balance, serum Cr and blood urea were also monitored. RESULTS No mortality or renal complication were observed. Both groups had similar demographic makeup, Parsonnet score, functional status and extent of coronary revascularization (2.1+/-1.0 vs. 2.5+/-0.7 grafts; P=0.08). Serum Cr and blood urea remained normal in both groups throughout the study. A significant and similar rise in urinary RBP:Cr occurred in both groups peaking on day 1 (3183+/-2534 vs. 4035+/-4079; P=0.43) before reapproximating baseline levels. These trends were also observed with urinary microalbumin:Cr (5.05+/-2.66 vs. 6.77+/-5.76; P=0.22). Group B patients had a significantly more negative fluid balance on postoperative day 2 (-183+/-1118 vs. 637+/-847 ml; P=0.03). CONCLUSIONS Although renal complication or serum markers of kidney dysfunction were absent, sensitive indicators revealed significant and similar injury to renal tubules and glomeruli following either OPCAB or ONCAB. These results suggest that avoidance of CPB does not offer additional renoprotection to patients at low risk of perioperative renal insult during CABG.

Novel application of vacuum assisted closure technique to the treatment of sternotomy wound infection

Infection of the sternotomy wound is a potentially devastating and sometimes lethal complication following cardiac surgery. Established treatment may involve a combination of debridement, packing, delayed closure, plastic reconstruction, re-wiring and irrigation dependent on the severity of infection. Vacuum assisted closure, originally adopted for the treatment of non-healing wounds, has recently gained popularity among various surgical specialities in managing complex wound infection. Here we describe this novel technique of managing postoperative sternal wound infection.

Statin Treatment in Hypercholesterolemic Pregnant Mice Reduces Cardiovascular Risk Factors in Their Offspring

Increasing evidence suggests that hypercholesterolemia during pregnancy initiates pathogenic events in the fetus leading to increased risk of cardiovascular disease in the adult offspring. In this study we examined in mice whether pharmacological intervention using statins in late pregnancy could alleviate the detrimental effects of a high-fat, high-cholesterol (45% fat) maternal diet on the health of the dams and their offspring. Pregnant C57 mice on high-fat, high-cholesterol diet were given the 3hydroxy3methylglutaryl-coenzyme A reductase inhibitor pravastatin in the drinking water (5 mg/kg of body weight per day) in the second half of pregnancy and during lactation to lower cholesterol and improve postweaning maternal blood pressure. Weaned offspring were then fed the high-fat, high-cholesterol diet until adulthood (generating dam/offspring dietary groups high-fat, high-cholesterol/high-fat, high-cholesterol and high-fat, high-cholesterol plus pravastatin during the second half of pregnancy and lactation/high-fat, high-cholesterol). These groups were compared with offspring from mothers fed standard chow (control), which were then fed control diet to adulthood (control/control). Compared with high-fat, high-cholesterol, high-fat, high-cholesterol plus pravastatin during second half of pregnancy and lactation dams showed significantly reduced total cholesterol concentrations and reduced systolic blood pressure. The high-fat, high-cholesterol plus pravastatin during second half of pregnancy and lactation/high-fat, high-cholesterol offspring were significantly lighter, less hypertensive, and more active compared with the high-fat, high-cholesterol/high-fat, high-cholesterol group. Total serum and low-density lipoprotein cholesterol concentrations were significantly lower, and high-density lipoprotein cholesterol concentrations were raised in high-fat, high-cholesterol plus pravastatin during the second half of pregnancy and lactation/high-fat, high-cholesterol offspring, compared with the high-fat, high-cholesterol/high-fat, high-cholesterol group. The control/control offspring showed the lowest blood pressure and cholesterol levels. These findings indicate that the cholesterol-lowering effect of statins in pregnant dams consuming a high-fat, high-cholesterol diet leads to reduced cardiovascular risk factors in offspring that are sustained into adulthood.

A prospective randomized study to evaluate splanchnic hypoxia during beating-heart and conventional coronary revascularization

OBJECTIVE Cardiopulmonary bypass (CPB) is associated with gut mucosal hypoxia, which may contribute to gastrointestinal complications. We examined gastric mucosal oxygenation together with whole-body oxygen flux in low-risk patients undergoing coronary artery bypass grafting (CABG) with and without CPB. METHODS Fifty-four patients undergoing primary CABG by the same surgeon were randomized into either on-pump (ONCAB, n=27) or off-pump (OPCAB, n=27) groups. The ONCAB group underwent mild hypothermic (35 degrees C) pulsatile CPB with arterial line filtration. Each patient underwent perioperative monitoring with continuous tonometry and cardiac output devices. Gastric intramucosal pH (pHi), gastric-arterial carbon dioxide partial pressure difference (CO(2) gap), whole-body oxygen delivery (DO(2)) and consumption (VO(2)) and whole-body oxygen extraction fraction were measured at sequential time-points intraoperatively and up to 6 h postoperatively. Anaesthetic management was standardized. RESULTS Both groups had similar demographic makeup and extent of revascularization (ONCAB 2.6+/-0.9 grafts versus OPCAB 2.5+/-0.8 grafts; P=0.55). The ONCAB group had a mean (+/-SD) CPB time of 62+/-25 min and aortic cross-clamp time of 32+/-11 min. In both groups there was a similar and progressive drop in pHi intraoperatively. Postoperatively, there was a gradual separation between the groups with ONCAB patients showing no further decline in pHi, while further deterioration was observed in the OPCAB group up to 6 h postoperatively. There was a significant difference between the groups over time (P=0.03). There was a corresponding progressive rise in CO(2) gap perioperatively in both groups, with ONCAB patients demonstrating superior preservation of gastric mucosal oxygenation in the early postoperative period. Global oxygen utilization measurements showed superior DO(2) and VO(2) in the OPCAB group throughout the study. CONCLUSIONS Despite superior global oxygen flux associated with beating-heart revascularization, gastric mucosal hypoxia occurred to similar extents in both groups with worsening trends for the OPCAB patients postoperatively. The splanchnic pathophysiology during beating-heart revascularization should be further explored.

Enhanced excretion of urinary leukotriene E4 in coronary artery disease and after coronary artery bypass surgery.

Background:Excretion of leukotriene (LT) E4, the major urinary metabolite of cysteinyl leukotrienes in humans, is increased in patients with unstable angina and myocardial infarction, suggesting that cysteinyl leukotrienes are released into the circulation during episodes of myocardial ischaemia. Furthermore, leukotrienes are known to induce potent vasoconstrictive effects in human atherosclerotic coronary arteries and the saphenous vein. Accordingly, we measured urinary excretion of LTE4 in patients with stable coronary artery disease both before and after coronary artery bypass surgery, and in age-matched healthy controls, to study the relation between the systemic synthesis of cysteinyl leukotrienes and stable coronary artery disease, as well as the possible changes after bypass surgery. Methods:LTE4 was isolated from urine samples by solid-phase extraction, purified by reverse-phase high-performance liquid chromatography, and subsequently quantified by radioimmunoassay. Results:In patients with coronary artery disease, preoperative urinary LTE4 levels were normally distributed on a log10 scale, with a geometric mean of 115 pmol/mmol creatinine (95% confidence interval 67–196) compared with 63.0 pmol/mmol creatinine (95% confidence interval 47.9–82.7) in healthy subjects (P<0.05). Urinary LTE4 levels increased further in patients after coronary artery bypass surgery with levels peaking on the second day after surgery (266.2 pmol/mmol creatinine, 95% confidence interval 167.2–423.9) at significantly higher than preoperative levels (P<0.02), and then decreasing by day 3. Conclusions:Levels of cysteinyl leukotrienes are raised in coronary artery disease patients both before and after coronary artery bypass surgery. As these mediators are capable of inducing potent vasoconstrictive effects on atherosclerotic coronary arteries and the saphenous vein, our results could have important clinical and possibly therapeutic implications.

Leukodepletion Reduces Renal Injury in Coronary Revascularization: A Prospective Randomized Study

BACKGROUND Cardiopulmonary bypass (CPB) is an important contributor to renal failure, which is a well-recognized complication after coronary artery bypass grafting (CABG). Leukodepletion reduces CPB-associated inflammation and resultant end-organ injuries. However, its effectiveness in renal protection has not been evaluated in a prospective randomized clinical setting. METHODS Forty low-risk patients awaiting elective CABG with normal preoperative cardiac and renal function were prospectively randomized into those undergoing nonpulsatile CPB without (group A: n = 20) and with leukodepletion (group B: n = 20). Renal glomerular and tubular injury were assessed by urinary excretion of microalbumin and retinol binding protein (RBP) indexed to creatinine (Cr), respectively. Daily measurements were taken from admission to postoperative day 5. Fluid balance, serum creatinine, and blood urea were also monitored. RESULTS No mortality or renal complication occurred. Both groups had similar demographic makeups, Parsonnet scores, extents of coronary revascularization and, durations of CPB and aortic cross-clamping. Daily fluid balance, serum creatinine, and blood urea remained comparable in both groups throughout the study period. From equal preoperative values, a significantly higher release of urinary RBP:Cr (7,807 +/- 2,227 vs 3,942 +/- 2,528; p < 0.001) and urinary microalbumin:Cr (59.4 +/- 38.0 vs 4.7 +/- 6.7; p < 0.0001) occurred in group A, peaking on day 1 before returning to approximate baseline levels. CONCLUSIONS Although clinically overt renal complications were absent, sensitive indicators revealed significantly more injury to both renal tubules and glomeruli after nonpulsatile CPB without leukodepletion. These data suggest that leukocytes play an important role in post-CPB renal dysfunction, and leukodepletion may offer some renal protection in low-risk patients during CABG.

The Inflammatory Response to Miniaturised Extracorporeal Circulation: A Review of the Literature

Conventional cardiopulmonary bypass can trigger a systemic inflammatory response syndrome similar to sepsis. Aetiological factors include surgical trauma, reperfusion injury, and, most importantly, contact of the blood with the synthetic surfaces of the heart-lung machine. Recently, a new cardiopulmonary bypass system, mini-extracorporeal circulation (MECC), has been developed and has shown promising early results in terms of reducing this inflammatory response. It has no venous reservoir, a reduced priming volume, and less blood-synthetic interface. This review focuses on the inflammatory and clinical outcomes of using MECC and compares these to conventional cardio-pulmonary bypass (CCPB). MECC has been shown to reduce postoperative cytokines levels and other markers of inflammation. In addition, MECC reduces organ damage, postoperative complications and the need for blood transfusion. MECC is a safe and viable perfusion option and in certain circumstances it is superior to CCPB.