Mobin Malik

miR‐29 contributes to normal endothelial function and can restore it in cardiometabolic disorders

We investigated the role of microRNAs (miRNA) in endothelial dysfunction in the setting of cardiometabolic disorders represented by type 2 diabetes mellitus (T2DM). miR‐29 was dysregulated in resistance arterioles obtained by biopsy in T2DM patients. Intraluminal delivery of miR‐29a‐3p or miR‐29b‐3p mimics restored normal endothelium‐dependent vasodilation (EDVD) in T2DM arterioles that otherwise exhibited impaired EDVD. Intraluminal delivery of anti‐miR‐29b‐3p in arterioles from non‐DM human subjects or rats or targeted mutation of Mir29b‐1/a gene in rats led to impaired EDVD and exacerbation of hypertension in the rats. miR‐29b‐3p mimic increased, while anti‐miR‐29b‐3p or Mir29b‐1/a gene mutation decreased, nitric oxide levels in arterioles. The mutation of Mir29b‐1/a gene led to preferential differential expression of genes related to nitric oxide including Lypla1. Lypla1 was a direct target of miR‐29 and could abrogate the effect of miR‐29 in promoting nitric oxide production. Treatment with Lypla1 siRNA improved EDVD in arterioles obtained from T2DM patients or Mir29b‐1/a mutant rats or treated with anti‐miR‐29b‐3p. These findings indicate miR‐29 is required for normal endothelial function in humans and animal models and has therapeutic potential for cardiometabolic disorders.

Dynamin-related protein 1 mediates low glucose-induced endothelial dysfunction in human arterioles

Intensive glycemic regulation has resulted in an increased incidence of hypoglycemia. Hypoglycemic burden correlates with adverse cardiovascular complications and contributes acutely and chronically to endothelial dysfunction. Prior data indicate that mitochondrial dysfunction contributes to hypoglycemia-induced endothelial dysfunction, but the mechanisms behind this linkage remain unknown. We attempt to determine whether clinically relevant low-glucose (LG) exposures acutely induce endothelial dysfunction through activation of the mitochondrial fission process. Characterization of mitochondrial morphology was carried out in cultured endothelial cells by using confocal microscopy. Isolated human arterioles were used to explore the effect LG-induced mitochondrial fission has on the formation of detrimental reactive oxygen species (ROS), bioavailability of nitric oxide (NO), and endothelial-dependent vascular relaxation. Fluorescence microscopy was employed to visualize changes in mitochondrial ROS and NO levels and videomicroscopy applied to measure vasodilation response. Pharmacological disruption of the profission protein Drp1 with Mdivi-1 during LG exposure reduced mitochondrial fragmentation among vascular endothelial cells (LG: 0.469; LG+Mdivi-1: 0.276; P = 0.003), prevented formation of vascular ROS (LG: 2.036; LG+Mdivi-1: 1.774; P = 0.005), increased the presence of NO (LG: 1.352; LG+Mdivi-1: 1.502; P = 0.048), and improved vascular dilation response to acetylcholine (LG: 31.6%; LG+Mdivi-1; 78.5% at maximum dose; P < 0.001). Additionally, decreased expression of Drp1 via siRNA knockdown during LG conditions also improved vascular relaxation. Exposure to LG imparts endothelial dysfunction coupled with altered mitochondrial phenotypes among isolated human arterioles. Disruption of Drp1 and subsequent mitochondrial fragmentation events prevents impaired vascular dilation, restores mitochondrial phenotype, and implicates mitochondrial fission as a primary mediator of LG-induced endothelial dysfunction.NEW & NOTEWORTHY Acute low-glucose exposure induces mitochondrial fragmentation in endothelial cells via Drp1 and is associated with impaired endothelial function in human arterioles. Targeting of Drp1 prevents fragmentation, improves vasofunction, and may provide a therapeutic target for improving cardiovascular complications among diabetics.Listen to this articles corresponding podcast @ http://ajpheart.podbean.com/e/mitochondrial-dynamics-impact-endothelial-function/.

Associations of Reducing Sedentary Time With Vascular Function and Insulin Sensitivity in Older Sedentary Adults

BACKGROUND We previously reported increased moderate-intensity (3-6 metabolic equivalents (METs)) physical activity (PA) reverses aging-associated vascular endothelial dysfunction, a surrogate marker of cardiovascular risk. Whether reductions in sedentary time alone contribute to this improvement is unknown. METHODS Data from 96 adults (aged ≥50 years) enrolled in a randomized control trial evaluating a 12-week intervention to increase PA in sedentary individuals were analyzed. Amount and intensity of activity were measured pre- and post-intervention by step count and accelerometry. Subjects were divided into 3 categories based on change in sedentary activity (<1. 5 METs): (i) ≥5% reduction in sedentary time, (ii) 0-4.99% reduction, and (iii) increase sedentary time. Vascular endothelial function was measured by brachial artery flow-mediated dilation (FMD%) pre- and post-intervention. RESULTS Sedentary time decreased overall (P = 0.001), with a 101-minute decrease in category 1 (N = 27, P < 0.001), a 42-minute decrease in category 2 (N = 29, P = 0.003), and a 44-minute increase in category 3 (N = 40, P = 0.02). While FMD% increased in the entire study population (P = 0.008) over 12 weeks, no differences were observed between the categories (P = 0.73). In category 1, FMD% improvement was associated achievement of ≥20 minutes/day of moderate intensity PA in bouts ≥ 10 minutes in length. CONCLUSIONS Reductions of up to 100 minutes of sedentary time per day over 12 weeks was not significantly associated with improved vascular endothelial function in older adults. FMD% was significantly higher among those with lower sedentary behavior and concomitant moderate-intensity PA of ≥20 minutes/day in bouts.

Mineralocorticoid exposure and receptor activity modulate microvascular endothelial function in African Americans with and without hypertension

Prior work suggests blood pressure in African Americans is more sensitive to the effects of aldosterone than in Caucasians. This mechanism may relate to a negative response of the vascular endothelium to aldosterone, including reduced glucose-6-phosphate dehydrogenase (G6PD) activity. Thirty-three African Americans (11 hypertensives, 22 controls) without evidence of diabetes or metabolic syndrome completed the protocol. The protocol included measurement of in vivo microvascular endothelial function by digital pulse arterial tonometry and ex vivo measurement of endothelial function by videomicroscopy of arterioles obtained from these same subjects with and without exposure to aldosterone or spironolactone. Systemic and arteriolar G6PD activities were also measured. In vivo and ex vivo microvascular endothelial function were impaired in African Americans with hypertension. One-hour exposure with aldosterone impaired endothelium-dependent vasodilation in arterioles from normotensive subjects, while 1 hour of spironolactone exposure reversed endothelial dysfunction in arterioles from hypertensive subjects. G6PD activity was impaired in hypertensive arterioles. Aldosterone-related endothelial dysfunction may be responsible for at least a portion of the greater blood pressure sensitivity to aldosterone in African Americans. This may be in part related to vascular suppression of G6PD activity.

Impact of DPP-4 inhibition on acute and chronic endothelial function in humans with type 2 diabetes on background metformin therapy

Cell culture and animal work indicate that dipeptidyl peptidase-4 (DPP-4) inhibition may exert cardiovascular benefits through favorable effects on the vascular endothelium. Prior human studies evaluating DPP-4 inhibition have shown conflicting results that may in part be related to heterogeneity of background anti-diabetes therapies. No study has evaluated the acute response of the vasculature to DPP-4 inhibition in humans. We recruited 38 patients with type 2 diabetes on stable background metformin therapy for a randomized, double-blind, placebo-controlled crossover trial of DPP-4 inhibition with sitagliptin (100 mg/day). Each treatment period was 8 weeks long separated by 4 weeks of washout. Endothelial function and plasma markers of endothelial activation (intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)) were measured prior to and 2 hours following acute dosing of sitagliptin or placebo, as well as following 8 weeks of intervention with each pill. Thirty subjects completed the study and were included in analyses. Neither acute nor chronic sitagliptin therapy resulted in significant changes in vascular endothelial function. While post-acute sitagliptin ICAM-1 levels were lower than that post-chronic sitagliptin, the ICAM-1 concentration was not significantly different than pre-acute sitagliptin levels or levels measured in relationship to placebo. There were no significant changes in plasma VCAM-1 levels at any time point. Acute and chronic sitagliptin therapies have neutral effects on the vascular endothelium in the setting of metformin background therapy. In conclusion, our findings suggest DPP-4 inhibition has a neutral effect on cardiovascular risk in patients without a history of heart failure or renal insufficiency. Trial Registration: NCT01859793

The impact of moderate intensity physical activity on cardiac structure and performance in older sedentary adults

Background Sedentary aging leads to adverse changes in vascular function and cardiac performance. We published improvements in vascular function with moderate intensity physical activity (PA) in continuous bouts. Whether moderate intensity PA also impacts cardiac structure and cardiovascular performance of the aging left ventricle (LV) is unknown. Methods We recruited and analyzed results from 102 sedentary older adults ages ≥ 50 from a randomized controlled trial with 3 study groups: control (group 1), a pedometer-only intervention (group 2), or a pedometer with an interactive website employing strategies to increase habitual physical activity (PA, group 3) for 12 weeks. Transthoracic echocardiograms were performed prior to and following the 12 week intervention period to assess cardiac morphology, left ventricular (LV) systolic performance, LV diastolic function, and arterial and LV ventricular elastance. Step count and PA intensity/distribution were measured by a pedometer and an accelerometer. Results We found no significant changes in cardiac morphology. Further, we found no improvement in the aforementioned cardiac functional parameters. Comparing those who achieved the following benchmarks to those who did not showed no significant changes in cardiac structure or performance: 1) 10,000 steps/day, 2) ≥ 30 min/day of moderate intensity physical activity, or 3) moderate intensity PA in bouts ≥ 10 min for ≥ 20 min/day Conclusions In sedentary older adults, increasing moderate intensity PA to currently recommended levels does not result in favorable changes in LV morphology or performance over 12 weeks. More prolonged exposure, higher PA intensity, or earlier initiation of PA may be necessary to see benefits.

Firefighting: can our arteries take the heat?

Currently, there are approximately 1.1 million volunteer and career firefighters in the United States.1 Firefighting remains one of the most hazardous and challenging lines of work with multiple occupational hazards including smoke inhalation, exposure to high-intensity heat, dehydration, potential falls and vehicular collisions. Since 1977, sudden cardiac death has accounted for the largest share of on-duty cardiac deaths among firefighters – surpassing burns, trauma, asphyxiation and smoke inhalation. Despite the steady decline in the average number of deaths among firefighters over the past decade, sudden cardiac death still accounts for 42% of the on-duty deaths in the last five years.2 Adverse cardiovascular (CV) events in firefighters, including sudden cardiac death, most commonly coincide with active strenuous duties rather than non-emergency situations. Thus, while traditional CV risk factors are prevalent in firefighters and are associated with greater CV risk in this population,3–6 the unique physical and environmental hazards faced by firefighters likely acutely magnify their CV risk in the peri-emergency setting. Research to determine the most important factors with an adverse impact remains speculative. Firefighters are subjected to high levels of dynamic and static physical exertion during performance of duties while wearing heavy, insulating protective equipment (PPE) often weighing in excess of 25 kg. Emergency situations are highly stressful and often chaotic, leading to profound sympathetic activation that manifests in part with elevated blood pressure and maximal or near maximal heart rates in firefighters during emergencies. Working under these conditions can rapidly lead to dehydration, reduced plasma volume and potentially stroke volume. Firefighting is also associated with increased number and aggregability of circulating platelets, attributable at least in part to hemoconcentration and increased sympathetic activity.7 Together with exposure to smoke containing toxic chemicals and carbon monoxide, the cardiovascular system is placed under significant strain during firefighting. Firefighters also experience significant heat stress. Firefighting produces large amounts of metabolic heat while insulating PPE limits its dissipation. In addition, fire-related heat also adds further thermal strain. The core temperature can increase as much as 0.05 degrees Celsius/min or 1°C over 20 minutes of acute firefighting activity.8,9 The increase in core temperature experienced by firefighters is significantly greater than that seen during routine aerobic exercise. Prior work by Fahs and colleagues demonstrates that three hours of firefighting activity results in impairment of microvascular endothelial function, faster wave reflection and increased vascular stiffness when assessed within 30 minutes of cessation of these activities.10 These effects were not mitigated by oral supplementation with ascorbic acid (2 grams) prior to activity.10 These data suggest firefighting activities adversely impact vascular physiology, leading to elevated blood pressure, reduced coronary perfusion and increased plaque vulnerability in a manner that is not mitigated by oral antioxidants. The specific contribution of heat stress to the acute adverse vascular effects of firefighting and whether these effects can be mitigated pharmacologically are unclear. These open questions are the subject of two articles published in the current issue of Vascular Medicine.11,12 Lefferts and colleagues explore the impact of moderate exercise induced heat stress (EIHS) compared to normothermic exercise on aortic stiffness, pressure from wave reflections and non-invasive estimates of myocardial work and coronary perfusion.11 Twelve young, healthy, and physically active men were randomized in a crossover design to two distinct alternative exercise/rest protocols: no heat stress (NHS) and heat stress (HS). Peripheral artery tonometry was performed prior to and within 15–30 minutes following each activity session. Compared to NHS, HS protocol resulted in significant increases in both rate pressure product (RPP) and systolic pressure time integral (SPTI) with concomitant decreases in both diastolic pressure time integral (DPTI) and reflected wave velocity. These data suggest heat stress results in an increase in myocardial workload with concomitant reductions in coronary perfusion. However, in contrast to prior work, no appreciable effect on aortic stiffness was noted as measured by carotid-femoral pulse wave velocity. The lack of impact of heat stress on large elastic artery stiffness reported by Lefferts and colleagues suggests that the effect on elastic arteries may require the presence of Firefighting: Can our arteries take the heat?

IMPACT OF INCREASING PHYSICAL ACTIVITY OVER 12 WEEKS IN PREVIOUSLY SEDENTARY OLDER ADULTS: A 1-YEAR FOLLOW UP

Sedentary lifestyle is associated with increased cardiovascular risk. We have previously demonstrated that use of pedometer based interventions result in increased moderate physical activity (MPA) among sedentary adults over a 12 week period. Whether these interventions result in long term benefits