Chris Baldi

Background: Low cardiorespiratory fitness predicts worse postoperative outcomes, exacerbated by age and frailty. Preoperative High-Intensity Interval Training (HIIT) improves cardiorespiratory fitness and postoperative outcomes but is challenging to implement in frailty due to perceived risks.

Purpose: The aim of this case report was to demonstrate feasibility of HIIT in a patient with frailty and multimorbidity.

Case presentation: An 83-year-old frail male with atrial fibrillation and limited mobility presenting with locally advanced rectal cancer was assessed as unfit for major surgery unless his cardiorespiratory fitness improved. Initial cardiopulmonary exercise testing demonstrated low cardiorespiratory fitness (peak oxygen consumption (𝓥O₂) of 11.45 mL·min-1·kg-1). He subsequently underwent 15 supervised HIIT sessions targeting a Rating of Perceived Exertion ≥ 15.

Outcomes: The patient demonstrated initial substantial improvements in his physical condition, increasing maximal work rate from 27.5 W to 55 W. However, there was no additional progress following session eight. At his post-exercise CPET he rapidly fatigued, resulting in a 𝓥O₂ peak of 7.4 mL·min-1kg-1. Clinical investigations revealed a worsening anemia with a hemoglobin of 92 g/L caused by an undiagnosed synchronous cecal tumor which was corrected preoperatively. Postoperatively, the patient recovered without complications and was successfully discharged home.

Conclusion: Personalized HIIT improved exercise duration and work rate and was associated with positive postoperative outcomes in this patient with frailty and multimorbidity. A unique feature of this case was the unexpected loss of training progress and 𝓥O₂ peak deterioration post-HIIT, which prompted further clinical investigations. These identified a worsening anemia and resulted in important changes in both the preoperative and intraoperative treatment.

Patients undergoing cardiopulmonary bypass procedures require inotropic support to improve hemodynamic function and cardiac output. Current inotropes such as dobutamine, can promote arrhythmias, prompting a demand for improved inotropes with little effect on intracellular Ca2+ flux. Low-dose carbon monoxide (CO) induces inotropic effects in perfused hearts. Using the CO-releasing pro-drug, oCOm-21, we investigated if this inotropic effect results from an increase in myofilament Ca2+ sensitivity. Male Sprague Dawley rat left ventricular cardiomyocytes were permeabilized, and myofilament force was measured as a function of -log [Ca2+] (pCa) in the range of 9.0-4.5 under five conditions: vehicle, oCOm-21, the oCOm-21 control BP-21, and levosimendan, (9 cells/group). Ca2+ sensitivity was assessed by the Ca2+ concentration at which 50% of maximal force is produced (pCa(50)). oCOm-21, but not BP-21 significantly increased pCa(50) compared to vehicle, respectively (pCa(50) 5.52 vs. 5.47 vs. 5.44; p < 0.05). No change in myofilament phosphorylation was seen after oCOm-21 treatment. Pretreatment of cardiomyocytes with the heme scavenger hemopexin, abolished the Ca2+ sensitizing effect of oCOm-21. These results support the hypothesis that oCOm-21-derived CO increases myofilament Ca2+ sensitivity through a heme-dependent mechanism but not by phosphorylation. Further analyses will confirm if this Ca2+ sensitizing effect occurs in an intact heart.

Systolic and diastolic dysfunction in diabetes have frequently been associated with abnormal calcium (Ca2+) regulation. However, there is emerging evidence that Ca2+ mishandling alone is insufficient to fully explain diabetic heart dysfunction, with focus shifting to the properties of the myofilament proteins. Our aim was to examine the effects of diabetes on myofilament Ca2+ sensitivity and Ca2+ handling in left ventricular tissues isolated from the same type 2 diabetic rat hearts. We measured the force-pCa relationship in skinned left ventricular cardiomyocytes isolated from 20-week-old type 2 diabetic and non-diabetic rats. Myofilament Ca2+ sensitivity was greater in the diabetic relative to non-diabetic cardiomyocytes, and this corresponded with lower phosphorylation of cardiac troponin I (cTnI) at ser23/24 in the diabetic left ventricular tissues. Protein expression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), phosphorylation of phospholamban (PLB) at Ser16, and SERCA/PLB ratio were lower in the diabetic left ventricular tissues. However, the maximum SERCA Ca2+ uptake rate was not different between the diabetic and non-diabetic myocardium. Our data suggest that impaired contractility in the diabetic heart is not caused by SERCA Ca2+ mishandling. This study highlights the important role of the cardiac myofilament and provides new insight on the pathophysiology of diabetic heart dysfunction.

The cardiovascular benefits of regular exercise are unequivocal, yet patients with type 2 diabetes respond poorly to exercise due to a reduced cardiac reserve. The contractile response of diabetic cardiomyocytes to beta-adrenergic stimulation is attenuated, which may result in altered myofilament calcium sensitivity and posttranslational modifications of cardiac troponin I (cTnI). Treadmill running increases myofilament calcium sensitivity in nondiabetic rats, and thus we hypothesized that endurance training would increase calcium sensitivity of diabetic cardiomyocytes and alter site-specific phosphorylation of cTnI. Calcium sensitivity, or pCa(50), was measured in Zucker diabetic fatty (ZDF), nondiabetic (nDM), and diabetic (DM) rat hearts after 8 wk of either a sedentary (SED) or progressive treadmill running (TR) intervention. Skinned cardiomyocytes were connected to a capacitance-gauge transducer and a torque motor to measure force as a function of pCa (-log[Ca2+]). Specific phospho-sites on cTnI and O-GlcNAcylation were quantified by immunoblot and total protein phosphorylation by fluorescent gel staining (ProQ Diamond). The novel finding in this study was that training increased pCa(50) in both DM and nDM cardiomyocytes (P = 0.009). Phosphorylation of cTnI amino acid residues Ser23/24, a crucial protein kinase A site, and Threonine (Thr)144 was lower in DM hearts, but there was no effect of training on site-specific phosphorylation. In addition, total phosphorylation and O-GlcNAcylation levels were not different between SED and TR groups. These findings suggest that regular exercise may benefit the diabetic heart by specifically targeting myofilament contractile function. NEW & NOTEWORTHY We examined the effects of training on the myofilament calcium in diabetic rat hearts. After 8 wk of treadmill running, both nondiabetic and diabetic cardiomyocytes had increased myofilament calcium sensitivity compared with their sedentary counterparts, but there was no effect of training on the phosphorylation or O-GIcNAcylation status of myofilament proteins measured in this study. These data highlight one potential mechanism capable of reversing, in part, reduced cardiac reserve in the diabetic heart.

Purpose Improving cardiopulmonary reserve, or peak oxygen consumption(V˙ O2peak), may reduce postoperative complications; however, this may be difficult to achieve between diagnosis and surgery. Our primary aim was to assess the efficacy of an approximate 14‐session, preoperative high‐intensity interval training(HIIT) program to increase V˙ O2peak by a clinically relevant 2 ml·kg−1·min−1. Our secondary aim was to document clinical outcomes. Methodology In this prospective study, participants aged 45–85 undergoing major abdominal surgery were randomized to standard care or 14 sessions of HIIT over 4 weeks. HIIT sessions involved approximately 30 min of stationary cycling. Interval training alternated 1 min of high (with the goal of reaching 90% max heart rate at least once during the session) and low/moderate‐intensity cycling. Cardiopulmonary exercise testing(CPET) measured the change in V˙ O2peak from baseline to surgery. Clinical outcomes included postoperative complications, length of stay(LOS), and Short Form 36 quality of life questionnaire(SF‐36). Results Of 63 participants, 46 completed both CPETs and 50 completed clinical follow‐up. There was a significant improvement in the HIIT group's mean ± SD V˙ O2peak (HIIT 2.87 ± 1.94 ml·kg1·min−1 vs standard care 0.15 ± 1.93, with an overall difference of 2.73 ml·kg1·min−1 95%CI [1.53, 3.93] p < 0.001). There were no statistically significant differences between groups for clinical outcomes, although the observed differences consistently favored the exercise group. This was most notable for total number of complications (0.64 v 1.16 per patient, p = 0.07), SF‐36 physical component score (p = 0.06), and LOS (mean 5.5 v 7.4 days, p = 0.07). Conclusions There was a significant improvement in V˙ O2peak with a four‐week preoperative HIIT program. Further appropriately powered work is required to explore the impact of preoperative HIIT on postoperative clinical outcomes.

What is the central question of this study? In Zucker Diabetic Fatty rats, does cardiomyocyte myofilament function change through the time course of diabetes and what are the mechanisms behind alterations in calcium sensitivity? What is the main finding and its importance? Zucker Diabetic Fatty rats had increased myofilament calcium sensitivity and reduced phosphorylation at cardiac troponin I without differential O-GlcNAcylation. The diabetic heart has impaired systolic and diastolic function independent of other comorbidities. The availability of calcium is altered, but does not fully explain the cardiac dysfunction seen in the diabetic heart. Thus, we explored if myofilament calcium regulation of contraction is altered while also categorizing the levels of phosphorylation and O-GlcNAcylation in the myofilaments. Calcium sensitivity (pCa ) was measured in Zucker Diabetic Fatty (ZDF) rat hearts at the initial stage of diabetes (12 weeks old) and after 8 weeks of uncontrolled hyperglycaemia (20 weeks old) and in non-diabetic (nDM) littermates. Skinned cardiomyocytes were connected to a capacitance-gauge transducer and a torque motor to measure force as a function of pCa (-log[Ca ]). Fluorescent gel stain (ProQ Diamond) was used to measure total protein phosphorylation. Specific phospho-sites on cardiac troponin I (cTnI) and total cTnI O-GlcNAcylation were quantified using immunoblot. pCa was greater in both 12- and 20-week-old diabetic (DM) rats compared to nDM littermates (P = 0.0001). Total cTnI and cTnI serine 23/24 phosphorylation were lower in DM rats (P = 0.003 and P = 0.01, respectively), but cTnI O-GlcNAc protein expression was not different. pCa is greater in DM rats and corresponds with an overall reduction in cTnI phosphorylation. These findings indicate that myofilament calcium sensitivity is increased and cTnI phosphorylation is reduced in ZDF DM rats and suggests an important role for cTnI phosphorylation in the DM heart.

Cardiovascular disease, often secondary to chemotherapy, is the leading cause of death in BC survivors. Increased aerobic capacity improves post-rehabilitation survival; however, many cancer rehabilitation programs are limited to lower intensity training. High-intensity interval training (HIIT) is associated with the largest improvements in aerobic capacity; therefore, this study aimed to determine whether HIIT would cause a greater increase in VO peak than continuous moderate-intensity (MICT) exercise in previously trained BC survivors. Twenty BC survivors who had completed a low/moderate-intensity exercise rehabilitation program performed a VO peak test and received a dual-energy X-ray absorptiometry (DXA) scan at baseline and after randomization into a 12-week HIIT or MICT program. ANOVA with repeated measures determined the effects of the different training programs on aerobic capacity and body composition. Both groups began the training program near or above age- and sex-matched VO peak norms. Pre- to post-intervention improvements in VO peak (P = 0.006) and waist circumference (P = 0.007) were found in both groups; however, there were no between-group differences. Minute ventilation and peak workload increased in the HIIT group (P < 0.05) but not the MICT group. Body composition was not different after either training program. These data suggest that transitioning from low/moderate-intensity exercise to moderate/high-intensity exercise causes further clinically relevant increases in VO peak in previously trained BC survivors. HIIT did not cause a significantly greater improvement in VO peak than MICT; however, future studies with greater intensity and frequency of training are encouraged.

In secondary analyses of a randomised controlled trial of exercise during pregnancy, we examined associations between mid-pregnancy maternal body mass index (BMI) and excessive gestational weight gain (GWG) with offspring health. Follow-up data were available on 57 mother–child pairs at 1-year and 52 pairs at 7-year follow-ups. Clinical assessments included body composition and fasting blood tests. At age 1 year, increased maternal BMI in mid-gestation was associated with greater weight standard deviation scores (SDS) in the offspring (p = 0.035), with no observed associations for excessive GWG. At age 7 years, greater maternal BMI was associated with increased weight SDS (p < 0.001), BMI SDS (p = 0.005), and total body fat percentage (p = 0.037) in their children. Irrespective of maternal BMI, children born to mothers with excessive GWG had greater abdominal adiposity (p = 0.043) and less favourable lipid profile (lower HDL-C and higher triglycerides). At 7 years, maternal BMI and excessive GWG had compounded adverse associations with offspring adiposity. Compared to offspring of mothers with overweight/obesity plus excessive GWG, children of normal-weight mothers with adequate and excessive GWG were 0.97 and 0.64 SDS lighter (p = 0.002 and p = 0.014, respectively), and 0.98 and 0.63 SDS leaner (p = 0.001 and p = 0.014, respectively). Both greater maternal BMI in mid-pregnancy and excessive GWG were independently associated with increased adiposity in offspring at 7 years.

O‐GlcNAcylation is a ubiquitous post‐translational modification that is extremely labile and plays a significant role in physiology, including the heart. Sustained activation of cardiac O‐GlcNAcylation is frequently associated with alterations in cellular metabolism, leading to detrimental effects on cardiovascular function. This is particularly true during conditions such as diabetes, hypertension, cardiac remodelling, heart failure and arrhythmogenesis. Paradoxically, transient elevation of cardiac protein O‐GlcNAcylation can also exert beneficial effects in the heart. There is compelling evidence to suggest that a complex interaction between O‐GlcNAcylation and phosphorylation also exists in the heart. Beyond direct functional consequences on cardiomyocytes, O‐GlcNAcylation also acts indirectly by altering the function of transcription factors that affect downstream signalling. This review focuses on the potential cardioprotective role of protein O‐GlcNAcylation during ischaemia‐reperfusion injury, the deleterious consequences of chronically elevated O‐GlcNAc levels, the interplay between O‐GlcNAcylation and phosphorylation in the cardiomyocytes and the effects of O‐GlcNAcylation on other major non‐myocyte cell types in the heart.