As a means of assessing ventricular performance, we analyzed the time-varying ratio of instantaneous pressure, P(t), to instantaneous volume, V(t), in the canine left ventricle. Intraventricular volume was measured by plethysmography, while the right heart was totally bypassed. The cardiac nerves were sectioned, and an epinephrine infusion was used to alter the contractile state. The instantaneous pressure-volume ratio was defined as E(t) = P(t)/[V(t) - Vd], where Vd is an experimentally determined correction factor. We found that (1) all the E(t) curves thus defined were similar in their basic shape and attained their peak near the end of the ejection phase regardless of the mechanical load, the contractile state, or the heart rate, (2) under a constant heart rate and contractile state extensive changes in preload, afterload, or both did not alter the peak value of E(t), Emax, or the time to Emax from the onset of systole, Tmax, and (3) these parameters of E(t) markedly changed with epinephrine infusion ...

Load Independence of the Instantaneous Pressure-Volume Ratio of the Canine Left Ventricle and Effects of Epinephrine and Heart Rate on the Ratio

Pulse wave velocity (PWV) was measured by means of transcutaneous Doppler techniques in the aorta, right arm, and right leg of 480 normal subjects of both sexes in urban Beijing, China (age range 3 to 89 years, mean age 41 +/- 20.8 SD); supine blood pressure was recorded in the brachial artery of each subject with standard sphygmomanometric procedures. Serum cholesterol was determined in a subgroup of 79 subjects (age 17 to 85 years, mean 47 +/- 26 SD). PWV (y in cm/sec) was found to vary with age (x, years) at each of the three locations according to the following regression equations: aorta, y = 9.2x + 615, r = .673 (p less than .001); right arm, y = 4.8x + 998, r = .453 (p less than .001); right leg, y = 5.6x + 791, r = .630 (p less than .001). Systolic, diastolic, mean, and pulse pressures were found to increase with age. PWV also increased with mean supine blood pressure but was not related to serum cholesterol (average 4.49 +/- 0.11 [SEM], mmol/l). Compared with that of Western populations, serum cholesterol tended to be lower at all age groups, systolic pressure higher at ages over 35 years, and PWV higher at all ages. Because change in PWV is directly related to change in arterial compliance, these results indicate that aging and not concomitant atherosclerosis (known to be rare in Asian populations) is the dominant factor associated with reduced arterial compliance and increased left ventricular load in these subjects.

Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community.

BASIC RESEARCH on the ventricular pressure-volume loop diagram has been revived.' Several investigators2-8 proposed that the relationship of end-systolic pressure (or wall stress) to end-systolic volume (or some dimension) may be useful in evaluating the contractile state of the heart. Grossman et al. published an important clinical study\" in 1977; many others followed. At the 1980 annual meetings of the American Heart Association and American College of Cardiology, at least 11 papers0-21 were presented concerning the end-systolic relationship between pressure and volume, pressure and thickness, and wall stress and normalized volume. Several significant studies2' 39 have also appeared in the past 5 years; a dozen clinical studies have been published. With this popularity, the original meanings of end-systolic pressure-volume relation and its parameters (e.g., Emax, m, V0 and Vd) have become ambiguous. Sometimes they were purposely modified to attempt to improve their value and other times just to make the measurement easy. Whatever the reasons, it seems appropriate to review these modifications with reference to the proponents' original ideas about fundamental aspects.

The end-systolic pressure-volume relation of the ventricle: definition, modifications and clinical use.

The intrinsic physiologic properties of the developing heart.

There is good evidence that elevated [Ca2+]i, produced by an influx of Ca2+ in exchange for Na+, is the underlying pathology in reperfusion or reoxygenation damage. Further measurements of [Na+]i and [Ca2+]i during ischemia and reperfusion, coupled with information about metabolic levels, are needed to confirm or refute this hypothesis. Contributions to cell damage by other mechanisms, e.g., oxygen free radicals, certainly cannot yet be excluded.

Myocardial contractile function during ischemia and hypoxia.

Circadian clock mechanisms are far-from-equilibrium dissipative structures. Peroxisome proliferator-activated receptors (PPAR alpha, beta/delta and gamma) play a key role in metabolic regulatory processes, particularly in heart muscle. Links between circadian rhythms (CRs) and PPARs have been established. Mammalian CRs involve at least two critical transcription factors, CLOCK and BMAL1 (Gekakis et al., 1998; Hogenesch et al., 1998). PPAR gamma plays a major role in both glucose and lipid metabolisms and presents circadian properties which coordinate the interplay between metabolism and CRs. PPAR gamma is a major component of the vascular clock. Vascular PPAR gamma is a peripheral regulator of cardiovascular rhythms controlling circadian variations in blood pressure and heart rate through BMAL1. We focused our review on diseases with abnormalities of CRs and with primary or secondary cardiac dysfunction. Moreover, these diseases presented changes in the Wnt/beta-catenin pathway and PPARs, according to two opposed profiles. Profile 1 was defined as follows: inactivation of the Wnt/beta-catenin pathway with increased expression of PPAR gamma. Profile 2 was defined as follows: activation of the Wnt/beta-catenin pathway with decreased expression of PPAR gamma. A typical profile 1 disease is arrhythmogenic right ventricular cardiomyopathy, a genetic cardiac disease which presents mutations of the desmosomal proteins and is mainly characterized by fatty acid accumulation in adult cardiomyocytes mainly in the right ventricle. The link between PPAR gamma dysfunction and desmosomal genetic mutations occurs via inactivation of the Wnt/beta-catenin pathway presenting oscillatory properties. A typical profile 2 disease is type 2 diabetes, with activation of the Wnt/beta-catenin pathway and decreased expression of PPAR gamma. CRs abnormalities are present in numerous pathologies such as cardiovascular diseases, sympathetic/parasympathetic dysfunction, hypertension, diabetes, neu

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Circadian rhythms, Wnt/beta-catenin pathway and PPAR alpha/gamma profiles in diseases with primary or secondary cardiac dysfunction

The time course of the relationship between force, shortening velocity, and length during shortening was examined in mammalian heart muscle in calcium (Ca)-containing solutions and solutions with strontium (Sr) substituted for Ca by imposing load clamps of various amplitudes at various times during external shortening. The onset of this force-velocity-length relationship was measured by abruptly unloading the muscle at different times to nearly zero external load--by zero load clamping the muscle--under conditions of optimal damping; the subsequent unloaded active muscle shortening velocity was then analyzed with respect to time and length. In Ca- containing solution, the unloaded velocity in the length range around 90% of L max rose within 16% of the time required to reach peak isometric force to a maximum level appropriate to a given contractile state. Subsequently, the force-velocity-length relationship was independent of time at any load over a well-determined portion of external shortening. In Sr-containing solution, unloaded active velocity rose much slower to reach a steady state after 30-35% of the time to peak force, and the time independence of the force-velocity-length relationship was delayed until after this time. In Na-free Sr-containing solution, maximum unloaded shortening velocity and the time-independent portion of the force-velocity-length relationship were achieved again within 20% of the time to peak force. The effects of substitution of Sr for Ca thus resemble those of caffeine on mammalian heart muscle. These findings suggest a close relationship between the time course of the force-velocity-length relationship and the degree of activation.

Onset of Mechanical Activation of Mammalian Heart Muscle in Calcium- and Strontium-Containing Solutions

A new technique permits removal of the resting force from the muscle during the course of shortening and study of the maximum velocity of shortening with almost zero load at physiological initial muscle lengths. This unloading has been performed as a sudden unloading to zero total load (zero load clamping), or according to the resting length-tension relations, or according to an arbitrary unloading intermediate between both former modes of unloading. Using these various modes of unloading to zero load during shortening, it has been demonstrated that the maximum velocity of shortening Vmax remains constant between maximum length (lmax) and a length 12.5% shorter than lmax. This unique force (zero load)-velocity (Vmax)-length (up to 12.5% below lmax) relation is independent of die initial muscle length over this range of lengths, independent of the time after the stimulus over the largest portion of the shortening phase, and independent of the sequence of length change and mode of unloading through which it...

Velocity of shortening of unloaded heart muscle and the length-tension relation.

In both colon cancer and type 2 diabetes, metabolic changes induced by upregulation of the Wnt/beta-catenin signaling and downregulation of peroxisome proliferator-activated receptor gamma (PPAR gamma) may help account for the frequent association of these two diseases. In both diseases, PPAR gamma is downregulated while the canonical Wnt/beta-catenin pathway is upregulated. In colon cancer, upregulation of the canonical Wnt system induces activation of pyruvate dehydrogenase kinase and deactivation of the pyruvate dehydrogenase complex. As a result, a large part of cytosolic pyruvate is converted into lactate through activation of lactate dehydrogenase. Lactate is extruded out of the cell by means of activation of monocarboxylate lactate transporter-1. This phenomenon is called Warburg effect. PPAR gamma agonists induce beta-catenin inhibition, while inhibition of the canonical Wnt/beta-catenin pathway activates PPAR gamma.

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Interactions between PPAR Gamma and the Canonical Wnt/Beta-Catenin Pathway in Type 2 Diabetes and Colon Cancer

The influence of calcium concentration in the bathing solution on the force-velocity relations of the isolated, electrically excited cat papillary muscle was examined. Shortening velocity was directly measured at minimum loads by unloading or load clamping the muscle from the preload (at the length, Lmax, where maximum active tensio was developed) to 0 (zero-load clamp), 2, 5, 10, and 15% of the total tension, P0. All measurements were made in the physiological length range between Lmax and 12.5% below Lmax. Increasing the calcium concentration augmented the measured maximum unloaded shortening velocity and shifted the normalized force-velocity relation when force was expressed as a fraction of P0. These observations suggest that the activating calcium has an action more complex than the binding to troponin alone.

Victor Claes

Papers

Circadian rhythms, Wnt/beta-catenin pathway and PPAR alpha/gamma profiles in diseases with primary or secondary cardiac dysfunction

Onset of Mechanical Activation of Mammalian Heart Muscle in Calcium- and Strontium-Containing Solutions

Velocity of shortening of unloaded heart muscle and the length-tension relation.

Interactions between PPAR Gamma and the Canonical Wnt/Beta-Catenin Pathway in Type 2 Diabetes and Colon Cancer

Effect of Calcium on Force-Velocity-Length Relations of Heart Muscle of the Cat