Cardiovascular diseases, cold exposure and exercise

Figures & data

Table 1. Cold and cardiovascular responses in CVD obtained from controlled (n = 27) studies.

	Subjects	Cold exposure	Measured CV parameters	Results	Conclusion
WHOLE-BODY COLD EXPOSURE
Greaney et al. (2017) [76]	7 males and 6 females with HTN (mean 58 yrs.) and 6 normotensive males and 4 females (mean 53 yrs.)	Whole-body cold exposure, water-perfused suit with aim to decrease Tsk to 30 °C	HR, BP, MSNA, BRS	MAP response to skin cooling exaggerated in HTN. MSNA activity (burst frequency and incidence) and BRS higher in HTN than NTN. No effects on HR.	Hypertension alters sympathetic function during whole-body cold exposure, as judged by the higher BP and MSNA response and increased BRS.
Greaney et al. (2017) [61]	6 males and 8 females with HTN (mean 56 yrs.) and 7 males and 7 females, normotensive (mean 55 yrs.)	Whole-body cold exposure, water-perfused suit with aim to decrease Tsk to 30 °C	HR, BP, MAP, SSNA, CVC	Cooling increased SSNA and reduced skin blood flow in HTN more than NTN. Non-adrenergic sympathetic co-transmitters mediated the vasoconstrictor response to cold in HTN.	Hypertension increases the peripheral cutaneous vasoconstrictor response to cold via greater increases in skin sympathetic outflow coupled with an increased reliance on non-adrenergic neurotransmitters.
Missmann et al. (2016) [68]	23 subjects (8 female, 15 male, 35–69 yrs), divided to treated HTN (n = 5), untreated HTN (n = 5) and normotensives (n = 13)	Cryotherapy/repeated exposures (21 times over 3–4 wks. period) to −110 °C for 3 min each time	SBP, DBP, MAP measured before and after exposure	BP increased modestly following cryotherapy in all groups, no changes in BP over time	Cryotherapy was safe with respect to unwanted BP alterations for adult subjects below 70 yrs. regardless of a pre-existing untreated mild or pharmacologically treated arterial hypertension.
Radtke et al (2016) [67]	37 males, 12 with CHF (62 yrs.), 13 with CAD (61 yrs.) and 12 controls (61 yrs.).	Exposure to Finnish sauna followed by a head-out cold water immersion (CWI)	CO, HR, BP, HRV	CO and HR increased in Sauna and CWI in all patients, but not for CAD after sauna. SBP decreased in sauna and increased in CWI in all groups. No change in HF/LF-ratio in CHF patients.	Finnish sauna and cold-water immersion causes haemodynamic alterations in heart failure patients similarly to control subjects and did not provoke an excessive increase in adrenergic activity or complex arrhythmias.
Hintsala et al. (2016) [42]	24 men with untreated HTN and 17 controls (55–65 yrs.)	Whole body/facial cold exposure (−10 °C) for 15 min, 30 min follow-up	ECG and continuous BP for computing spectral powers of SBP and HRV	Cold exposure resulted in comparable increases in BRS in the HTN and control groups. Instead, a larger increase in LF blood pressure variability occurred in controls.	Untreated HTN does not disturb cold-related cardiovascular protective mechanisms. Blunted response of the peripheral sympathetic modulation may indicate higher tonic sympathetic activity and decreased sympathetic responsiveness to cold in hypertension.
Zalewski et al. (2014) [69]	13 men with HTN (mean 30 yrs.) and 26 normotensive controls (mean 33 yrs.)	Whole-body/cryotherapy (−115 °C to −125 °C, 3 min), measurements before and after, supine position + tilt test	HR, BP, BRS, CO, SV, EDI, TPR, TFC, + cardiac and contractibility parameters (IC, LVET, PEP, ER)	Decreased HR, SBP (HTN group), ER, increased SV, EDI, TFC, LVET, PEP and BRS, mostly similar responses among both groups	Centralization of circulation, increased myocardial preload and venous return in both groups. Less pronounced changes in cardiac contractibility in HTN.
Hintsala et al. (2014) [43]	51 untreated hypertensive and 32 normotensive controls (55–65 yrs.)	Whole body/facial cold exposure (−10 °C) for 15 min, 30 min follow-up	Conduction times and amplitudes, vectorcardiography, arrhythmias, HRV, ectopic beats	Higher T-peak to T-end interval, T-wave amplitude and shortened QTc interval in both groups. LH and HF HRV increased and LF/HF ratio decreased. The amount of ventricular ectopic beats increased slightly during cold exposure.	Altered ventricular repolarization was detected which may be due to altered cardiac autonomic regulation and was unaffected by untreated hypertension.
Hintsala et al. (2014) [38]	41 untreated hypertensive men and 20 normotensive controls (55–65 yrs.)	Whole body/facial cold exposure (−10 °C) for 15 min, 30 min follow-up	Central aortic blood pressure, AIx, and SEVR measured by radial artery applanation tonometry.	Cold exposure increased the central aortic blood pressure similarly both in both hypertensive men. AIx increased by 12%, whereas SEVR decreased by 10% in both hypertensive and control subjects.	Short-term cold exposure increases central aortic blood pressure. Cardiac workload, and myocardial oxygen demand increases slightly in relation to blood supply in untreated hypertensive men.
Seifert et al. (2013) [62]	53 treated hypertensive subjects (23 males, 30 females, mean 57 yrs.)	Cold chamber, −5 °C for 1 h, winter clothing, with or without protective mask (heat and moisture exchanger)	HR, BP	Increased SBP and MAP in cold, lesser increase with the use of HME mask.	Use of HME mask attenuated the increase in BP in cold and especially in persons above 60 yrs.
Komulainen et al. (2004 a) [63]	7 subjects with borderline HTN (30 ± 9 yrs.)	Whole-body cold exposure to −15 °C for 15 min x three times, testing of metoprolol (beta-blocking agent)	SBP, DBP, MAP, HR	increased SBP, DBP, MAP, decreased HR in both therapy and placebo group.	Metoprolol lowered BP, but did not affect the cold-induced response.
Komulainen et al. (2004 b) [64]	6 subjects (4 females, 2 males, mean 28 yrs.)	Whole-body cold exposure to −15 °C for 15 min x three times, testing of hydrochlorothiazide, HCTZ (diuretic) compared with placebo	SBP, DBP, MAP, HR, PP	SBP, DBP, MAP increased, HR decreased in both the therapy and placebo group. HCTZ did not change CV responses before, during or after cold exposure.	HCTZ did not affect CV responses during whole-body cold exposure in mild HTN.
Komulainen et al. (2000) [65]	10 subjects (2 females, 8 males, 27 ± 8 yrs.) with HTN and 12 normotensive controls (5 females, 7 males, 24 ± 3 yrs.)	Whole-body cold exposure to −15 °C for 15 min x three times, testing of carvedilol (combined alpha- and beta blocking agent) compared with placebo	SBP, DBP, HR, MAP, PP	SBP, DBP and MAP increased and HR decreased in cold. Cardevilol reduces BP in both groups compared with placebo.	Carvedilol reduced BP in both HTN and normotensive subjects, but did not affect the cold-induced rise in BP.
LOCAL COLD EXPOSURE
Prodel et al. (2017) [36]	6 males with HTN (mean 51 yrs.)	Icepack for face cooling for 3 min, supine position	HR, BP, MAP, MSNA, aortic pressure waveform parameters (AIx, Tr, AG, Ew)	Higher peripheral and central MAP and sympathetic activity. AIx, AG and EW increased and TR decreased with sympathetic stimulation.	Trigeminal nerve stimulation with facial cooling increases cardiac workload (higher BP, augmentation pressure, AIx) in subjects with HTN simultaneously with increased sympathetic activation.
Smith et al. (2013) [66]	9 subjects of pre- to stage 1 HTN (5 men, 4 women, 50 ± 1 yrs.) and 11 controls (51 ± 1 yrs.)	Local cooling of forearm skin (clamped to 24 °C). Inhibition of ROCK (Rho/Rho-Kinase and adrenoceptors while cooling.	Cutaneous vascular conductance, Rho/Rho-Kinase (ROCK), skin blood flow	Pre to 1-stage HTN subjects demonstrated higher ROCK activity in early and later phases of skin cooling.	The magnitude of vasoconstriction does not differ between HTN and controls, but ROCK activity increases. Functional vasoconstriction is more dependent upon Rho/ROCK mechanisms in HTN.
Neill et al. (1974) [84]	total 25 persons (23 males, 2 females, mean 49 yrs); 19 persons with CAD, 6 with chest pain	Application of cold to forehead. Responses compared with pacing tachycardia.	HR, SBP, DBP, CBF, MVO2	Cutaneous cold increased systemic arterial and left ventricular end-diastolic BP. CBF increased in proportion to increased MVO2. Angina and myocardial ischemia in some patients. Cold intolerance did not alter systemic or coronary circulatory responses.	Myocardial hypoxia is related to restricted coronary reserve, rather than to an effect of cold.
COLD PRESSOR TEST
Matthews et al. (2017) [57]	16 (mean 20 yrs.) women with family history of HTN and 16 (mean 20 yrs.) without family history of HTN	Cold pressor test (cold water for 2 min)	SBP, DBP, MAP, HR CO, TPR	Increased MAP, SBP, DBP, HR and CO, but no effect of family history.	Family history of HTN did not affect CV responses to CPT.
Jarvis et al (2015) [40]	19 mildly hypertensive subjects (females and males 50:50, 66–68 yrs.)	Cold pressor test (water 2–4 °C for 2 min), use of Alisikern (renin inhibitor) or Hydrocholorthiazide (diuretic) for 6 mo., pre-post assessment	HR (ECG), BP, MSNA, hemodynamics	Increased HR, SBP, DBP and MSNA in CPT. Cardiovascular and MSNA responses were similar between pre- and post- treatment.	Antihypertensive medication lowered BP, but did not lower responsiveness to CPT.
Greaney et al. (2015) [71]	14 females with positive history of HTN (22 ± 1 yrs.) and 14 females without history of HTN (22 ± 1 yrs.)	Cold pressor test for 2 min, followed by isometric handgrip	HR, SBP,DBP, MSNA	CPT increased DBP more in those with positive history of HTN; handgrip resulted in more pronounced increase in SBP and DBP, and post-exercise ischemia. MSNA increased more with positive history of HTN.	Reactivity (BP and MSNA response), to stressors increases among young women with a positive history of hypertension.
Park et al. (2005) [88]	14 subjects with vasospastic angina (f:m 5:9, 37–67 yrs.) and 15 controls (f:m 4:11, 23–70 yrs.)	Cold pressor test for 2 min	HR, SBP,DBP, RPP, coronary flow reserve, coronary vascular resistance	Decrease of coronary flow reserve and increased in resistance.	Endothelial dependent vasodilation is impaired at the coronary microvascular and epicardial artery level in those with vasospastic angina.
Kudaiberdieva et al. (2003) [70]	25 men with CAD (50.8 ± 8.1 yrs.) and previous MI. Patients with (n = 10) or without ischemia (n = 15)	Cold pressor test (ice water for 2 min)	HR, SBP, DBP, ST-depression, MBF	Higher SBP, DBP but not HR after CPT. Reduced ESVI and EF%. Patients with ischemia in cold had lower E, prolonged IVRT, shortened DtE, and higher IVRT+ICT/ET index.	Cold pressor test-related vasoconstriction and ischemia was associated with deranged left ventricular myocardial performance manifested as delayed myocardial relaxation, impaired stiffness and contractibility.
Sevre & Rostrup (1999) [58]	20 patients with chest pain, 10 with confirmed CAD (3 females, 7 males, 57 ± 3 yrs.) and 10 without (2 females, 8 males, 52 ± 4 yrs.)	Cold pressor test (0 °C for 1 min), supine	BP, HR	Larger response in SBP and HR in CAD patients with chest pain compared with those with only chest pain.	Higher cardiovascular reactivity in persons with CAD than those with chest pain, but no diagnosis of CAD.
Lafleche et al. (1998) [59]	10 subjects with borderline HTN (8 males, 2 females, mean 33 yrs.) and ten controls (7 males, 2 females, mean 35 yrs.)	Cold pressor test (4 °C for 5 min)	Carotid-brachial pulse-pressure amplification and changes in brachial and carotid distensibility	Increased BP but unaltered HR, HTN does not alter responses. Disappearance of PP amplification due to higher increase in carotid PP. Decrease in carotid aortic distensibility in HTN.	CPT reduces pulse pressure amplification. In subjects with HTN the increase in PP contributed to decreased carotid aortic distensibility.
Benetos & Safar (1991) [60]	73 patients with HTN (24 females, 49 males, 45 ± 1 yrs.) and 49 normotensive (17 females, 32 males, 42 ± 2 yrs.)	Cold pressor test (4–5 °C water for 90 sec.)	SBP,DBP, MBP, HR	Aggravated BP response in HTN to CPT. Slightly higher (ns.) HR response in HTN. Active renin was positively related to mean BP increase during CPT in HTN.	Increased BP response in HTN reflects an age-independent sympathetic overactivity.
Zeiher et al. (1989) [51]	32 patients (17 females, 15 males, 45.2 yrs.) without CAD and 55 patients (10 females, 45 males, 54.3 yrs.) with CAD	Cold pressor test (ice water for 90 sec.)	HR, SBP RPP, CBF	The dilation of normal and the constriction of atherosclerotic coronary arteries with CPT.	Endothelial dysfunction in coronary atherosclerosis resulted in a loss of normal dilator function and permitted vasoconstrictor responses to sympathetic stimulation.
Nabel et al. (1988) [54]	9 patients with normal coronary arteries (5 males, 3 females, mean 37 yrs.), 9 with mild atherosclerosis (six males, three women, mean 48 yrs.), 13 with advanced stenosis 10 males, 3 females, mean 59 yrs.)	Cold pressor test (ice water for 90 sec.)	HR, BP, CBF velocity, β-blockade studies, quantitative coronary angiography	The majority of coronary arteries dilated in those with normal arteries, but constrict more often with advancing stenosis. CBF increased by 65% in those with normal arteries, 15% in mild atherosclerosis, but decreased by 39% with advanced stenosis.	Normal coronary arteries dilate in response to the cold pressor test, in part related to beta-adrenoreceptor stimulation and possibly flow-mediated endothelial dilation or alpha 2-adrenergic activity. The vasoconstrictor response in atherosclerosis may relate to altered catecholamine sensitivity and/or a defect in endothelial vasodilator function.
Rodger et al. (1984) [85]	12 patients with CAD (3 females, 9 males, 46 ± 7 yrs.), 9 subjects with chest pain (5 females, 4 males, 45 ± 6 yrs.) and 10 controls (10 men, 27 ± 5 yrs.)	Cold pressor test (both hands immersed in ice water for 2 min)	HR, BP, thallium scintigraphy	Increased HR, BP and RPP, but no differences between groups. Transient perfusion defects in response to CPT were observed in some persons from all study groups.	Cold can provoke transient abnormalities in myocardial perfusion not only in persons with coronary heart diseases but also in healthy subjects.
Mudge et al. (1976) [55]	12 patient with CAD (9 males, 3 females, 47 ± 1 yrs.) and 12 controls (6 males and 6 females, 46 ± 2 yrs.),	Cold pressor test (cold water for 1 min)	Cardiac catheterization (assessment of BP and CBF)	BP increases to similar extent in CAD and controls. Increased coronary resistance and decreased BF in CAD. Application of phentolamine (adrenergic blocking agent) eliminated the increase in coronary vascular resistance.	Higher coronary vascular resistance and reduced BF during the cold pressor test in patients with CAD.

Abbreviations: AIx = augmentation index), A_G = augmented pressure of reflected wave, BP = blood pressure, BRS = baroreflex sensitivity, CAD = coronary artery disease, CHF = chronic heart failure, CO = cardiac output, CPT = cold pressor test, CVC = cutaneous vascular conductance, CWI = cold water immersion, DBP = diastolic blood pressure, EDI = end diastolic index, EW = wasted left ventricle pressure, ER = ejection rate, HF = high frequency spectral power, HTN = hypertension, HR = heart rate, HRV = heart rate variability, LF = low frequency spectral power, LVET = left ventricular ejection time, MAP = mean arterial pressure, MBF = myocardial blood flow, MSNA = muscle sympathetic nerve activity, NTN = normotensive, PEP = pre-ejection period, ROCK = Rho/Rho-Kinase, RPP = rate pressure product, SBP = systolic blood pressure, SEVR = subendocardial viability ratio, SSNA = skin sympathetic nerve activity, SV = stroke volume, Tr = systolic duration of reflected wave, TFC = thoracic fluid content, TPR = total peripheral resistance.

Figure 1. Effects of cold and exercise and their combination on cardiovascular responses in healthy subjects [13,39]. In addition, potential mechanisms explaining cardiovascular events [2,4,83] in both healthy and those with hypertension [73], coronary artery disease [80] and heart failure [91] are presented. Abbreviations: CBF = coronary blood flow, CO = cardiac output, DBP = diastolic blood pressure, HR = heart rate, MI = myocardial infarction, RAAS = renin-angiotensin system, RPP = rate pressure product, SBP = systolic blood pressure, SCD = sudden cardiac death, SV = stroke volume, SVR = systemic vascular resistance.

Table 2. Exercise, cold and cardiovascular responses among persons with CVD obtained from controlled (n = 23) studies.

Study	Patient group	Type of exercise	Type of cold exposure	Parameters	Results	Conclusion
WHOLE-BODY COLD EXPOSURE
Meyer et al. (2010) [94]	13 men (mean 67 yrs.) ischemia during exercise, and ≥70% diameter stenosis of major artery, prior MI or reversible perfusion defect during exercise testing.	Maximal treadmill exercise tests	Cold air exposure (−20 °C) compared with +20 °C (t-shirt, pants)	ECG, HR, total exercise time, MET, RPP, HRR	Ischemic threshold was reached earlier (ca. 50 sec.) at −20 °C. No differences in other CV parameters or exercise performance.	Extreme cold lowered ischemic threshold even in the absence of, or without a history of angina. Cold did not affect exercise time, CV parameters (RPP), or result in arrhythmias.
Schmid et al. (2009) [108]	22 males, 12 with CHF (59 yrs., EF 32%) and 10 with CAD (65 yrs., EF 52%).	Swimming (aqua therapy)	Cold water exposure (+22 °C) vs. +32 °C at rest and swimming (90 sec.) compared with 24-h Holter recording before immersion	RPP, arrhythmias (premature ventricular contractions, PVC), cardiac index, O2	RPP increased at rest in cold water, but not during exercise. Cardiac index and VO2 increased to a similar extent when swimming in cold compared with warm water. PVCs increased in cold water in CHF but not in CAD patients.	Patients with compensated chronic heart failure tolerate water immersion and swimming in cold water well. However, increased PVCs might elevate the risk of high-grade ventricular arrhythmias.
Blanchet et al. (2003) [109]	33 CHF patients (exercise limited dyspnoea, LVEF 26%, 3 females, 30 males, 60 ± 11 yrs.), and 12 healthy controls (4 females, 8 males, 52 ± 14 yrs.)	symptom-limited submaximal exercise, comparison of Cardevilol or Metoprolol treatment (beta-blockers)	Whole body exposure to cold air (−8 °C) and TN (+20 °C)	HR, SBP, NE, VO2, exercise performance, Lactate	CHF patients showed 21% decrease in exercise time in cold. Beta blockers increased exercise time and lowered peak exercise lactate levels at both temperatures. No difference in HR, SBP or RPP between temperatures. NE increased during exercise in cold only in CHF patients.	Patients with congestive heart failure showed decreased submaximal exercise time during moderate cold exposure. Beta-blocker therapy increased submaximal exercise time and attenuated the impact of cold exposure on functional capacity.
Juneau et al. (2002) [110]	11 CHF patients (males, 61 ± 6 yrs., LVEF 25 ± 6%)	Symptom-limited maximal exercise testing, Lisinopril (ACE-inhibitor, three days prior to exercise tests) vs. placebo	Cold air (−8 °C) vs. TN (+20 °C)	HR, BP, RPP, exercise capacity	Higher RPP during exercise in the cold. Decreased exercise capacity in the cold with placebo group. Lisinopril attenuated the effect of cold on exercise.	Cold temperature increases cardiac demand in response to exercise and reduces maximal exercise capacity in patients with symptomatic heart failure. Acute treatment (three days) with Lisinopril attenuates the impact of cold on exercise capacity.
Marchant et al. (1994) [96]	7 cold intolerant and 7 tolerant CAD subjects (57 ± 3 yrs.)	Symptom-limited exercise test (Bruce protocol)	Exposure to cold air (+6 °C + fan blowing 2 m/s on face and upper chest) vs. TN (+25 °C)	BP, HR, RPP, ECG, BRS, NE and E	Exercise in cold resulted in higher vascular resistance, SB, NE but not HR. SBP was higher in cold at onset of ischemia and angina. Unaltered RPP during exercise in the cold. Onset of ischemia and angina occurred earlier and BRS was impaired in cold-intolerant patients.	Higher BP during rest and exercise in cold increases myocardial oxygen demand. Cold-intolerant persons develop earlier onset of angina and ischemia in cold. They also have an impaired BRS and HR response that does not diminish due to increased BP.
Sheldahl et al. (1992) [18]	16 men with CAD (asymptomatic, 63 ± 2 yrs.), 13 without CAD (61 ± 2 yrs.) and 12 young (40 ± 2 yrs.)	Self-paced snow shoveling (three methods) + treadmill exercise test	Cold ambient air exposure (ca. −1.5 °C)	ECG, BP VO2, left ventricular function	VO2 was lowest with CAD. Peak VO2 and HR ranged between 60–78%. LVEF and arrhythmias were comparable to treadmill exercise.	Selected energy expenditure varied in relation to individual peak VO2 and occurred at similar relative work intensities between CAD, controls and young persons. Arrhythmias and LVEF were similar to treadmill testing.
Peart et al. (1989) [98]	11 men and 4 women (mean 49 yrs.) with stable CAD, no current medication (other than glyceryl trinitrates), reported cold sensitivity.	Symptom limited treadmill exercise test (Bruce protocol).	Cold air exposure (0 °C, cold air directed to face and trunk) compared with TN (+18–20 °C), treatment with either Nifedipine (calcium channel blocker) or Propranolol (beta blocker) for two weeks, repeat tests	ECG, BP, HR, RPP	Time to onset of angina, to 1 mm ST depression, and to peak exercise were shorter during exercise at 0 °C. RPP was similar between cold and TN, but was reached earlier with the different thresholds. Use of Nifedipine and Propranolol increased time to onset of angina, 1 mm ST-depression and time to peak exercise in cold and TN. Only Nifedipine enabled maintaining peak exercise time in cold.	Cold intolerance (symptom provoking) occurred in stable CAD patients during exercise testing at 0 °C. The reduction in the exercise time in cold persisted with Propranolol treatment, but to a lesser extent. Reduced exercise time in cold was not observed when treated with Nifedipine.
Juneau et al. (1989) [99]	24 stable CAD patients (2 females, 22 males, mean 57 yrs.), reported cold sensitivity	Symptom limited treadmill exercise test (modified Bruce protocol).	Cold air exposure (−8 °C) compared with TN (+20 °C), placebo, Propranolol (beta blocker) or Diltiazem (calcium channel blocker) administration in either cold or TN.	HR, BP, ECG	Cardiovascular strain (elevated HR, SBP, DBP, RPP) was not different between exercise in cold vs. TN. Reported cold sensitive patients had lower ischemic threshold in the cold. Antianginal medication delayed the onset of ischemia both in cold and TN. Only Diltiazem prolonged exercise duration.	Cold does not worsen ischaemic threshold in most stable angina patients. Cold-sensitive patients showed earlier onset of ischemia. Both antianginal medications were effective for delaying ischemia to equal amounts in cold and TN.
Rosengren et al. (1988) [111]	9 men with angina pectoris (mean 58 yrs.), ischemia during exercise (≥1 mm), cold susceptible	Symptom limited graded exercise testing (bicycle ergometer)	Whole body cold air exposure (mean −8 °C, variation from −2 °C to −13 °C), fan 3 m/s vs. TN (+22 °C)	HR, SBP, RPP, DBP, work capacity	Higher SBP, RPP, more pronounced ST-depression in 7/9 patients, higher RPP at the occurrence of ST-depression during exercise in cold. No effect on HR, or work capacity in cold.	Augmented cardiac work, secondary to increased BP, is related to cold-induced ST-depression among angina patients.
Areskog & Lassvik (1988) [81]	17 male patients with angina pectoris, cold sensitive	Graded exercise test (bicycle)	Whole body cold air (−10 °C vs. +20 °C) and airway cooling (−10 °C, −35 °C vs. +20 °C) performed in a random order	HR, SBP, RPP	10 subjects showed decreased maximal work load in cold exceeding 5% and explained by higher HR, SBP and RPP. Inhalation of −35 °C air resulted in comparable decrease in work capacity as exercise in −10 °C.	Cold susceptible persons with angina show a stronger sympathetic response during exercise in cold. A lower inhaled air temperature is required to produce the same response as with general skin cooling.
Brown & Oldridge (1985) [112]	9 patients with history of cold-induced angina, 7 of 9 with previous MI, ischaemia during exercise	Symptom-limited maximal exercise test (bicycle)	Exposure to either cold air (−7.5 °C) vs. TN (+24 °C) and while breathing either cold (0.7 °C) vs. TN (+22.5 °C) air	HR, SBP, DBP, ventilation (VE), exercise capacity	Angina occurred sooner, and mean exercise time reduced in the cold, both while inspiring air of room temperature (−24%) and cold (−15%). Breathing cold air in the TN environment did not reduce exercise tolerance. SBP and RPP was higher during submaximal exercise in the cold.	Earlier onset of angina limits exercise performance in cold among angina patients. The effects are more related to the exposure of a cold environment rather than cold air inhalation.
Lassvik & Areskog (1980) [103]	12 men with effort angina (mean 51 yrs.), cold sensitivity	Symptom-limited graded exercise test (bicycle ergometer)	Whole-body exposure to −10 °C vs. TN (+20 °C). Inhalation of cold air at various temperatures (−35 °C). Other test at either TN (+20 °C) or cold (−10 °C) climatic chamber and inhaling either TN or cold (−10 °C) air	ECG, HR, BP, exercise capacity, ST-depression	Inhalation of −35 °C decreased work capacity and caused higher HR, SBP and RPP in patients with effort angina, no changes with inhaling −10 °C in TN or cold environment. Exposure to cold while inhaling TN air decreased work capacity.	Skin cooling is more important in affecting cardiac work and working capacity than inhaling cold air in cold environment. However, inhaling very cold air decreases work capacity. Increased cardiac work reduces exercise capacity both during exercise or while inhaling cold air.
Backman et al. (1979) [104]	26 patients with angina pectoris and coronary insufficiency (mean age 50 yrs., range 36–70)	Graded maximal exercise test (bicycle ergometer)	Exposure to cold air (−15 °C) vs. TN (+22 °C) while seated and in supine position	HR, BP, RPP, PE, exercise performance	Lowered maximal performance, higher perceived exertion, lower RPP in cold. Exercise in the supine position caused more pronounced ECG changes, reduced maximal performance and RPP compared to sitting.	Cold exposure leads to lowered work capacity, RPP and higher perceived exertion in cold. A supine body position in cold further lower the angina threshold and affect ECG, by increasing the central blood volume and the diastolic volume of the left heart and also myocardial oxygen consumption.
Lassvik & Areskog (1979) [105]	11 patients with effort angina and history of cold intolerance (mean age 55 yrs., range 45–61)	Graded exercise test (bicycle ergometer) symptom limited, stopped with moderately severe angina, serial exercise tests	Exposure to +20 °C, +10 °C, 0 °C, −10 °C and −30 °C (few patients), random order	HR, BP, RPP, exercise performance	At rest SBP was progressively higher with decreasing temperature. Lesser absolute increase in BP during exercise in cold. No change in HR. Maximal workload decreased at −10 °C, maximal work capacity decreased with declining temperature. Decreased maximal capacity correlated with increase in RPP.	Decreased performance in cold may be explained by higher cardiac workload. Warm-up exercise, diminished the difference in SBP between a cold and TN environment with increasing work time.
Lassvik & Areskog (1979) [106]	17 patients with angina pectoris (mean age 52 yrs. range 45–60 yrs.), cold susceptible,	Symptom-limited graded exercise test (bicycle ergometer)	Exposure to cold air (−10 °C) vs. TN (+20 °C)	HR, BP, RPP, ST-depression	Maximal work load decrease in cold. HR, SBP and RPP were higher during submaximal exercise in cold. No difference in HR, RPP and magnitude of ST-depression at maximal workloads. Work capacity decreased more in cold susceptible persons and correlated with higher HR and BP during exercise in cold.	Patients with angina pectoris showed intolerance to exercise in the cold that was related to higher HR and BP compared with exercise at TN.
Epstein et al. (1969) [107]	6 males with CAD (age 37–60 yrs.) and 5 without CAD (2 females, 3 males, age 23–59 yrs.)	Exercise at sub anginal level (CAD patients, bicycle or treadmill), others exercised at levels that did not cause fatigue	Exposure to cold air (+15 °C) vs. TN (+25 °C)	HR, MAP,CO, SV, TPR, MCVP, LFMW	Lower temperature exercise resulted in higher SAP, TPR and left ventricular minute work. Exercise in cold did not alter HR, CO, SV.	Cold increases peripheral resistance during exercise. The rise in BP, by increasing myocardial oxygen demand, more likely provokes an attack of angina.
LOCAL COLD EXPOSURE
Dodds et al. (1995) [95]	12 men with CAD (mean age 61 yrs.), four with previous MI, stable angina, (medication stopped 2 days prior to exercise tests)	Symptom-limited treadmill tests (Bruce-protocol)	Inhalation of either cold (−15 °C) or TN (+22 °C) air while exercising	HR, BP, RPP, ECG, Endothelin (ET-1) and Angiontensin-II (AT-II)	Cold air inhalation reduced time to angina and total exercise time. No effect on time for reaching 1 mm ST-depression. RPP was unaltered at the onset of angina, or occurrence of 1 mm ST-depression, but lower at peak exercise when breathing cold air. ET-decreased and AT-II levels increased with peak exercise but did not differ between exposures.	Cold air inhalation results in earlier onset of angina and reduced exercise capacity. Peripheral ET-1 and AT-II do not explain the mechanism of cold-induced angina.
Petersen et al. (1994) [97]	10 men (mean age 59 yrs.) with CAD and MI within 6–12 mo, angina, ischemic ST-deviations during exercise	Symptom limited exercise test on bicycle ergometer	Inhalation of cold (−22 °C) or TN (+22 °C) air	A, NA, ANF, endothelin, renin, angiotensin II, MBF (scintigraphic imaging)	Myocardial ischemic score increased and endothelin levels during cold air inhalation exercise were higher compared with rest. No effect on HR, SBP, E and NE peak exercise response.	Inhalation of cold air during exercise was related to increased plasma endothelin levels and myocardial ischaemia. The ischemic response was not due to higher myocardial oxygen demand.
Hattenhauer & Neill (1975) [89]	17 men with CAD (mean age 52 yrs, range 42–66 yrs.), 13 had previous MI, 11 cold susceptible	Atrial pacing (increase by 10 bpm/min) until angina occurred	Inhalation of cold (−20 °C) vs. TN (+20 °C) air	HR, LVEDP, SBP DBP, PO2, pH, MVO2, CBF, Lactate	Inhalation of cold air during rest increased HR, SBP, DBP, O2, PO2 and pH. Exercise increased SBP, DBP, and PO2 but no other parameters.	Angina pectoris induced by breathing cold air cannot be explained by a concurrent increase in myocardial work and oxygen consumption.
COLD PRESSOR TEST
Nesto et al. (1989) [100]	16 men (mean 54 yrs.) with CAD, stable angina, ischemia during exercise	Graded maximal exercise test (Bruce protocol)	Cold pressor test during exercise compared with exercise only	HR, SBP, DBP, RPP, time to angina, time to ST-depression (1 mm)	Exercise with CPT increased SBP, DBP and RPP but did not change HR, total exercise time, time to angina or time to ST-depression.	Myocardial ischemia at a higher RPP during exercise and CPT could be due to competitive myocardial vasodilation as a result of exercise
Shea et al. (1987) [90]	35 CAD patients (mean 39–74 yrs.) compared with healthy controls (n = 10)	Graded symptom-limited supine exercise	Cold pressor test (ice water for 3 min). CPT and exercise tests (conducted at TN) were separate.	HR, SBP, ST-depression, myocardial perfusion (positron emission tomography)	CPT resulted in abnormal myocardial perfusion, but only a few experienced angina or had ST-depression. In contrast, exercise resulted in reduced myocardial perfusion, reports of angina and ST-depression in most subjects. Peak SBP after CPT and exercise were similar.	Cold produces reduced myocardial perfusion that is asymptomatic and occur at lower HR compared with exercise.
de Servi et al. (1985) [101]	11 (1 female, 10 males, mean age 53.5 ± 7 yrs.) CAD patients, ischaemia during exercise, cold susceptibility, medication ceased for the course of the study	Graded symptom limited exercise test	Exercise, followed by cold pressor test (ice water for 60 sec.) and another exercise test + cold pressor test	BP, HR, RPP, ST-depression, GCVF, ARCR	RPP increased during exercise and CPT and further when the two were combined. ARCR decreased during 1st exercise, increased (ns) during CPT, and decreased again during 2nd exercise + CPT bout. RPP increase during both exercise tests and CPT. Angina occurred at lower workload than the first exercise test.	Exercise reduced coronary resistance, but which increased during CPT. A combination of exercise and CPT reduces coronary resistance, but to a lesser extent in subjects with reduced exercise tolerance.
de Servi et al. (1980) [102]	8 patients with CAD (2 females, 6 males, 52.3 yrs.)	Isometric exercise at 50% MVC for 2 ½ min	Cold pressor test (ice water for 1 min), followed by exercise at TN. Application of nifedipine (calcium channel blocker) and repeat CPT and exercise	HR, MAP, RPP, CBF (thermodilution technique)	CPT did not change CBF, but increased coronary resistance. Nifedipine did not alter CBF, but reduced coronary resistance during CPT. Increased HR and MAP was observed during CPT, but lower MAP and higher HR occurred after nifedipine treatment. Improved CBF and reduced resistance during isometric handgrip after nifedipine treatment.	Nifedipine was successful in reducing coronary vasoconstriction during CPT and increased CBF and reduced coronary vasoconstriction during isometric exercise.

Abbreviations: ARCR = anterior region coronary resistance, BP = blood pressure, BRS = baroreflex sensitivity, CAD = coronary artery disease, CBF = coronary blood flow, CHF = chronic heart failure, CO = cardiac output, CPT = cold pressor test, CV = cardiovascular, DBP = diastolic blood pressure, E = epinephrine, ECG = electrocardiogram, GCVF = great cardiac vein flow, HR = heart rate, HRR = heart rate reserve, LVEF = left ventricular ejection fraction, LFMW = left ventricular minute work, LVEDP = left ventricular end diastolic pressure, MAP = mean arterial pressure, MBF = myocardial blood flow, MCVP = mean central venous pressure, MET = metabolic equivalent units, MVO₂ = myocardial oxygen consumption, NE = norepinephrine, O₂ = concentration of oxygen in blood (arterial, coronary-venous), PO₂ = partial pressure of oxygen in blood (arterial and coronary-venous), PVC = premature ventricular contraction, SAP = systemic arterial pressure, SBP = systolic blood pressure, SV = stroke volume, TN = thermoneutral, TPR = total peripheral resistance, V_E = ventilation, VO₂ = oxygen consumption.

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