Abhinav C. Krishnan

Blood flow restriction training and the exercise pressor reflex: a call for concern

Blood flow restriction (BFR) training (also known as Kaatsu training) is an increasingly common practice employed during resistance exercise by athletes attempting to enhance skeletal muscle mass and strength. During BFR training, blood flow to the exercising muscle is mechanically restricted by placing flexible pressurizing cuffs around the active limb proximal to the working muscle. This maneuver results in the accumulation of metabolites (e.g., protons and lactic acid) in the muscle interstitium that increase muscle force and promote muscle growth. Therefore, the premise of BFR training is to simulate and receive the benefits of high-intensity resistance exercise while merely performing low-intensity resistance exercise. This technique has also been purported to provide health benefits to the elderly, individuals recovering from joint injuries, and patients undergoing cardiac rehabilitation. Since the seminal work of Alam and Smirk in the 1930s, it has been well established that reductions in blood flow to exercising muscle engage the exercise pressor reflex (EPR), a reflex that significantly contributes to the autonomic cardiovascular response to exercise. However, the EPR and its likely contribution to the BFR-mediated cardiovascular response to exercise is glaringly missing from the scientific literature. Inasmuch as the EPR has been shown to generate exaggerated increases in sympathetic nerve activity in disease states such as hypertension (HTN), heart failure (HF), and peripheral artery disease (PAD), concerns are raised that BFR training can be used safely for the rehabilitation of patients with cardiovascular disease, as has been suggested. Abnormal BFR-induced and EPR-mediated cardiovascular complications generated during exercise could precipitate adverse cardiovascular or cerebrovascular events (e.g., cardiac arrhythmia, myocardial infarction, stroke and sudden cardiac death). Moreover, although altered EPR function in HTN, HF, and PAD underlies our concern for the widespread implementation of BFR, use of this training mechanism may also have negative consequences in the absence of disease. That is, even normal, healthy individuals performing resistance training exercise with BFR are potentially at increased risk for deleterious cardiovascular events. This review provides a brief yet detailed overview of the mechanisms underlying the autonomic cardiovascular response to exercise with BFR. A more complete understanding of the consequences of BFR training is needed before this technique is passively explored by the layman athlete or prescribed by a health care professional.

Muscle metaboreflex activation during dynamic exercise evokes epinephrine release resulting in β2-mediated vasodilation

Muscle metaboreflex-induced increases in mean arterial pressure (MAP) during submaximal dynamic exercise are mediated principally by increases in cardiac output. To what extent, if any, the peripheral vasculature contributes to this rise in MAP is debatable. In several studies, we observed that in response to muscle metaboreflex activation (MMA; induced by partial hindlimb ischemia) a small but significant increase in vascular conductance occurred within the nonischemic areas (calculated as cardiac output minus hindlimb blood flow and termed nonischemic vascular conductance; NIVC). We hypothesized that these increases in NIVC may stem from a metaboreflex-induced release of epinephrine, resulting in β2-mediated dilation. We measured NIVC and arterial plasma epinephrine levels in chronically instrumented dogs during rest, mild exercise (3.2 km/h), and MMA before and after β-blockade (propranolol; 2 mg/kg), α1-blockade (prazosin; 50 μg/kg), and α1 + β-blockade. Both epinephrine and NIVC increased significantly from exercise to MMA: 81.9 ± 18.6 to 141.3 ± 22.8 pg/ml and 33.8 ± 1.5 to 37.6 ± 1.6 ml·min(-1)·mmHg(-1), respectively. These metaboreflex-induced increases in NIVC were abolished after β-blockade (27.6 ± 1.8 to 27.5 ± 1.7 ml·min(-1)·mmHg(-1)) and potentiated after α1-blockade (36.6 ± 2.0 to 49.7 ± 2.9 ml·min(-1)·mmHg(-1)), while α1 + β-blockade also abolished any vasodilation (33.7 ± 2.9 to 30.4 ± 1.9 ml·min(-1)·mmHg(-1)). We conclude that MMA during mild dynamic exercise induces epinephrine release causing β2-mediated vasodilation.

Muscle metaboreflex activation during dynamic exercise vasoconstricts ischemic active skeletal muscle

Metabolite accumulation due to ischemia of active skeletal muscle stimulates group III/IV chemosensitive afferents eliciting reflex increases in arterial blood pressure and sympathetic activity, termed the muscle metaboreflex. We and others have previously demonstrated sympathetically mediated vasoconstriction of coronary, renal, and forelimb vasculatures with muscle metaboreflex activation (MMA). Whether MMA elicits vasoconstriction of the ischemic muscle from which it originates is unknown. We hypothesized that the vasodilation in active skeletal muscle with imposed ischemia becomes progressively restrained by the increasing sympathetic vasoconstriction during MMA. We activated the metaboreflex during mild dynamic exercise in chronically instrumented canines via graded reductions in hindlimb blood flow (HLBF) before and after α1-adrenergic blockade [prazosin (50 μg/kg)], β-adrenergic blockade [propranolol (2 mg/kg)], and α1 + β-blockade. Hindlimb resistance was calculated as femoral arterial pressure/HLBF. During mild exercise, HLBF must be reduced below a threshold level before the reflex is activated. With initial reductions in HLBF, vasodilation occurred with the imposed ischemia. Once the muscle metaboreflex was elicited, hindlimb resistance increased. This increase in hindlimb resistance was abolished by α1-adrenergic blockade and exacerbated after β-adrenergic blockade. We conclude that metaboreflex activation during submaximal dynamic exercise causes sympathetically mediated α-adrenergic vasoconstriction in ischemic skeletal muscle. This limits the ability of the reflex to improve blood flow to the muscle.

Muscle Metaboreflex-Induced Vasoconstriction in the Ischemic Active Muscle is Exaggerated in Heart Failure

When oxygen delivery to active muscle is insufficient to meet the metabolic demand during exercise, metabolites accumulate and stimulate skeletal muscle afferents, inducing a reflex increase in blood pressure, termed the muscle metaboreflex. In healthy individuals, muscle metaboreflex activation (MMA) during submaximal exercise increases arterial pressure primarily via an increase in cardiac output (CO), as little peripheral vasoconstriction occurs. This increase in CO partially restores blood flow to ischemic muscle. However, we recently demonstrated that MMA induces sympathetic vasoconstriction in ischemic active muscle, limiting the ability of the metaboreflex to restore blood flow. In heart failure (HF), increases in CO are limited, and metaboreflex-induced pressor responses occur predominantly via peripheral vasoconstriction. In the present study, we tested the hypothesis that vasoconstriction of ischemic active muscle is exaggerated in HF. Changes in hindlimb vascular resistance [femoral arterial pressure ÷ hindlimb blood flow (HLBF)] were observed during MMA (via graded reductions in HLBF) during mild exercise with and without α1-adrenergic blockade (prazosin, 50 µg/kg) before and after induction of HF. In normal animals, initial HLBF reductions caused metabolic vasodilation, while reductions below the metaboreflex threshold elicited reflex vasoconstriction, in ischemic active skeletal muscle, which was abolished after α1-adrenergic blockade. Metaboreflex-induced vasoconstriction of ischemic active muscle was exaggerated after induction of HF. This heightened vasoconstriction impairs the ability of the metaboreflex to restore blood flow to ischemic muscle in HF and may contribute to the exercise intolerance observed in these patients. We conclude that sympathetically mediated vasoconstriction of ischemic active muscle during MMA is exaggerated in HF. NEW & NOTEWORTHY We found that muscle metaboreflex-induced vasoconstriction of the ischemic active skeletal muscle from which the reflex originates is exaggerated in heart failure. This results in heightened metaboreflex activation, which further amplifies the reflex-induced vasoconstriction of the ischemic active skeletal muscle and contributes to exercise intolerance in patients.

Interaction between the muscle metaboreflex and the arterial baroreflex in control of arterial pressure and skeletal muscle blood flow

The muscle metaboreflex and arterial baroreflex regulate arterial pressure through distinct mechanisms. During submaximal exercise muscle metaboreflex activation (MMA) elicits a pressor response virtually solely by increasing cardiac output (CO) while baroreceptor unloading increases mean arterial pressure (MAP) primarily through peripheral vasoconstriction. The interaction between the two reflexes when activated simultaneously has not been well established. We activated the muscle metaboreflex in chronically instrumented canines during dynamic exercise (via graded reductions in hindlimb blood flow; HLBF) followed by simultaneous baroreceptor unloading (via bilateral carotid occlusion; BCO). We hypothesized that simultaneous activation of both reflexes would result in an exacerbated pressor response owing to both an increase in CO and vasoconstriction. We observed that coactivation of muscle metaboreflex and arterial baroreflex resulted in additive interaction although the mechanisms for the pressor response were different. MMA increased MAP via increases in CO, heart rate (HR), and ventricular contractility whereas baroreflex unloading during MMA caused further increases in MAP via a large decrease in nonischemic vascular conductance (NIVC; conductance of all vascular beds except the hindlimb vasculature), indicating substantial peripheral vasoconstriction. Moreover, there was significant vasoconstriction within the ischemic muscle itself during coactivation of the two reflexes but the remaining vasculature vasoconstricted to a greater extent, thereby redirecting blood flow to the ischemic muscle. We conclude that baroreceptor unloading during MMA induces preferential peripheral vasoconstriction to improve blood flow to the ischemic active skeletal muscle.

Exaggerated coronary vasoconstriction limits muscle metaboreflex-induced increases in ventricular performance in hypertension

Increases in myocardial oxygen consumption during exercise mainly occur via increases in coronary blood flow (CBF) as cardiac oxygen extraction is high even at rest. However, sympathetic coronary constrictor tone can limit increases in CBF. Increased sympathetic nerve activity (SNA) during exercise likely occurs via the action of and interaction among activation of skeletal muscle afferents, central command, and resetting of the arterial baroreflex. As SNA is heightened even at rest in subjects with hypertension (HTN), we tested whether HTN causes exaggerated coronary vasoconstriction in canines during mild treadmill exercise with muscle metaboreflex activation (MMA; elicited by reducing hindlimb blood flow by ~60%) thereby limiting increases in CBF and ventricular performance. Experiments were repeated after α1-adrenergic blockade (prazosin; 75 µg/kg) and in the same animals following induction of HTN (modified Goldblatt 2K1C model). HTN increased mean arterial pressure from 97.1 ± 2.6 to 132.1 ± 5.6 mmHg at rest and MMA-induced increases in CBF, left ventricular dP/dtmax, and cardiac output were markedly reduced to only 32 ± 13, 26 ± 11, and 28 ± 12% of the changes observed in control. In HTN, α1-adrenergic blockade restored the coronary vasodilation and increased in ventricular function to the levels observed when normotensive. We conclude that exaggerated MMA-induced increases in SNA functionally vasoconstrict the coronary vasculature impairing increases in CBF, which limits oxygen delivery and ventricular performance in HTN. NEW & NOTEWORTHY We found that metaboreflex-induced increases in coronary blood flow and ventricular contractility are attenuated in hypertension. α1-Adrenergic blockade restored these parameters toward normal levels. These findings indicate that the primary mechanism mediating impaired metaboreflex-induced increases in ventricular function in hypertension is accentuated coronary vasoconstriction.

Attenuated muscle metaboreflex-induced pressor response during postexercise muscle ischemia in renovascular hypertension

During dynamic exercise, muscle metaboreflex activation (MMA; induced via partial hindlimb ischemia) markedly increases mean arterial pressure (MAP), and MAP is sustained when the ischemia is maintained following the cessation of exercise (postexercise muscle ischemia, PEMI). We previously reported that the sustained pressor response during PEMI in normal individuals is driven by a sustained increase in cardiac output (CO) with no peripheral vasoconstriction. However, we have recently shown that the rise in CO with MMA is significantly blunted in hypertension (HTN). The mechanisms sustaining the pressor response during PEMI in HTN are unknown. In six chronically instrumented canines, hemodynamic responses were observed during rest, mild exercise (3.2 km/h), MMA, and PEMI in the same animals before and after the induction of HTN [Goldblatt two kidney, one clip (2K1C)]. In controls, MAP, CO and HR increased with MMA (+52 ± 6 mmHg, +2.1 ± 0.3 l/min, and +37 ± 7 beats per minute). After induction of HTN, MAP at rest increased from 97 ± 3 to 130 ± 4 mmHg, and the metaboreflex responses were markedly attenuated (+32 ± 5 mmHg, +0.6 ± 0.2 l/min, and +11 ± 3 bpm). During PEMI in HTN, HR and CO were not sustained, and MAP fell to normal recovery levels. We conclude that the attenuated metaboreflex-induced HR, CO, and MAP responses are not sustained during PEMI in HTN.

Altered Arterial Baroreflex - Muscle Metaboreflex Interaction in Heart Failure

Two powerful reflexes controlling cardiovascular function during exercise are the muscle metaboreflex and arterial baroreflex. In heart failure (HF), the strength and mechanisms of these reflexes are altered. Muscle metaboreflex activation (MMA) in normal subjects increases mean arterial pressure (MAP) primarily via increases in cardiac output (CO), whereas in HF the mechanism shifts to peripheral vasoconstriction. Baroreceptor unloading increases MAP via peripheral vasoconstriction, and this pressor response is blunted in HF. Baroreceptor unloading during MMA in normal animals elicits an enormous pressor response via combined increases in CO and peripheral vasoconstriction. The mode of interaction between these reflexes is intimately dependent on the parameter (e.g., MAP and CO) being investigated. The interaction between the two reflexes when activated simultaneously during dynamic exercise in HF is unknown. We activated the muscle metaboreflex in chronically instrumented dogs during mild exercise (via graded reductions in hindlimb blood flow) followed by baroreceptor unloading [via bilateral carotid occlusion (BCO)] before and after induction of HF. We hypothesized that BCO during MMA in HF would cause a smaller increase in MAP and a larger vasoconstriction of ischemic hindlimb vasculature, which would attenuate the restoration of blood flow to ischemic muscle observed in normal dogs. We observed that BCO during MMA in HF increases MAP by substantial vasoconstriction of all vascular beds, including ischemic active muscle, and that all cardiovascular responses, except ventricular function, exhibit occlusive interaction. We conclude that vasoconstriction of ischemic active skeletal muscle in response to baroreceptor unloading during MMA attenuates restoration of hindlimb blood flow. NEW & NOTEWORTHY We found that baroreceptor unloading during the muscle metaboreflex in heart failure results in occlusive interaction (except for ventricular function) with significant vasoconstriction of all vascular beds. In addition, restoration of blood flow to ischemic active muscle, via preferentially larger vasoconstriction of nonischemic beds, is significantly attenuated in heart failure.

Role of endothelial nitric oxide in control of peripheral vascular conductance during muscle metaboreflex activation

The muscle metaboreflex is a powerful pressor reflex induced by the activation of chemically sensitive muscle afferents as a result of metabolite accumulation. During submaximal dynamic exercise, the rise in arterial pressure is primarily due to increases in cardiac output, since there is little systemic vasoconstriction. Indeed, in normal animals, we have often shown a small, but significant, peripheral vasodilation during metaboreflex activation, which is mediated, at least in part, by release of epinephrine and activation of vascular β2-receptors. We tested whether this vasodilation is in part due to increased release of nitric oxide caused by the rise in cardiac output eliciting endothelium-dependent flow-mediated vasodilation. The muscle metaboreflex was activated via graded reductions in hindlimb blood flow during mild exercise with and without nitric oxide synthesis blockade [NG-nitro-l-arginine methyl ester (l-NAME); 5 mg/kg]. We assessed the role of increased cardiac output in mediating peripheral vasodilation via the slope of the relationship between the rise in nonischemic vascular conductance (conductance of all vascular beds excluding hindlimbs) vs. the rise in cardiac output. l-NAME increased mean arterial pressure at rest and during exercise. The metaboreflex-induced increases in mean arterial pressure were unaltered by l-NAME, whereas the increases in cardiac output and nonischemic vascular conductance were attenuated. However, the slope of the relationship between nonischemic vascular conductance and cardiac output was not affected by l-NAME, indicating that the rise in cardiac output did not elicit vasodilation via increased release of nitric oxide. Thus, although nitric oxide is intrinsic to the vascular tonus, endothelial-dependent flow-mediated vasodilation plays little role in the small peripheral vasodilation observed during muscle metaboreflex activation.

Reply to "Letter to the editor: Applying the blood flow restriction pressure: the elephant in the room".

reply: In their letter, Jessee et al. ([6][1]) address an important methodological concern germane to blood blow restriction (BFR) training raised in our recent review ([10][2]), namely, the standardization of BFR cuff pressure. Jessee et al. acknowledge that a generalized cuff pressure could