Throughout this application, various publications and patents are referred to by an identifying citation. The disclosures of the publications and patents referenced in this application are hereby incorporated by reference into the present disclosure to more fully describe the state of the art to which this invention pertains.
Almost any cardiac disorder that impairs the ability of the ventricle to eject blood suffers a progression toward an inexorable deterioration of cardiac structure and function, producing the complex clinical syndrome of heart failure, which is a common medical condition that afflicts approximately 1.5 to 2.0% of the population (4.8 million people in the United States) and which has a risk of death of 5 to 10% annually in patients with mild symptoms and increases to as high as 30 to 40% annually in patients with advanced disease, as, for example, described in 1998 Heart and Stroke Statistical Update by the American Heart Association, Dallas, Tex., 1997; Am. Heart J., Vol. 133, pages 703 to 712 (1997) by Massie et al.; J. Heart Lung Transplant, Vol. 13, pages S107 to S112 (1994) by O'Connell et al.; and Am. Coll. Cardiol., Vol. 22 (Suppl. A.), pages 6A to 13A (1993) by Ho et al. Annual direct expenditures for heart failure in the United States have been estimated at $20 to 40 billion, twice that for all forms of cancer, as described in the above-mentioned references by Massie et al. and O'Connell et al.
The core of the altered cardiac function in heart failure is a depression of cardiac contractility, as, for example, described in Lancet, Vol. 352 (Suppl. I), pages 8 to 14 (1998) by Bristow. Therefore, an adequate assessment of cardiac contractility has important diagnostic and therapeutic implications. Patients with acute heart failure, particularly as a complication of acute myocardial infarction or as an acute exacerbation of a previously compensated chronic heart failure, have a high mortality rate of about 30% within the first 12 months. In this clinical condition, a proper evaluation of cardiac contractility is extremely important for diagnostic purposes to assess the severity of the process and as a guide for the inotropic therapy. Typically, ejecting phase indices are used to evaluate ventricular function with the serious limitations that these parameters have, especially in this clinical setting where frequent and prominent hemodynamic load changes occur, as, for example, described in Arch. Mal. Coeur. Vaiss., Vol. 91, pages 1349 to 1358 (1998) by Bosio et al.; Rev. Prat., Vol. 47, pages 2146 to 2152 (1997) by Garot et al.; and Fortschr. Med., Vol. 115, pages 30 to 34 (1997) by Schwinger et al.
In regards to chronic heart failure, perhaps as many as 20 million individuals in the United States have an asymptomatic impairment of cardiac function and are likely to develop symptoms in the next 1 to 5 years. At this stage of heart failure, a reliable index of cardiac contractility is required for an early identification and appropriate treatment to achieve the greatest impact on individual and public health, as, for example, described in Am. J. Cardiol., Vol. 83, pages 1A to 38A (1999) by Parker et al.
In more advanced stages of heart failure, ventricular function parameters are measured to identify the severity of the cardiac abnormality. In this setting, ejection fraction is widely used. However, it has no good correlation with the physical capacity of the patient, as, for example, described in Circulation, Vol. 87 (Suppl. VI), pages VI-88 to VI-93 (1993) by Smith et al.; and Am. J. Cardiol., Vol. 47, pages 33 to 39 (1981) by Franciosa et al. There is debate about the value of repeated measurement of ejection fraction to evaluate the course, prognosis or therapeutic response, as, for example, described in the above-mentioned reference by Parker et al. It is expected that a more refined assessment of cardiac contractility, together with a better knowledge of the peripheral circulation and the neuro-endocrine axes, will improve the evaluation and treatment of these patients.
In severe valve diseases with striking modifications in cardiac loads, adequate information in relation to cardiac contractility, but different to the typically used ejection phase indices, is most important to choose the proper time for surgical treatment, as, for example, described in Heart Disease, Braunwald (ed.), W. B. Saunders Company, Philadelphia, 1977, pages 1007 to 1076, by Braunwald.
Contractility or inotropic state of the heart refers to a fundamental property of cardiac tissue and represents the intensity of the active state of the muscle. The level of the inotropic state is given by the interaction of calcium ions and the contractile protein reflecting the level of activation and the formation and cycling of the cross bridges between actin and myosin filaments, as, for example, described in Heart Disease, Brunwald (ed.), W.B. Saunders Company, Philadelphia, 1977, pages 421 to 444 by Little et al. This interaction is able to be widely modified by multiple and simultaneous factors such as force-frequency relation, circulating catecholamines, sympathetic nerve impulses, anoxia, hypercapnia, acidosis, pharmacologic intervention, etc., as, for example, described in J. Cardiovasc. Pharmacol., Vol. 26 (Suppl. 1), pages S1 to S9 (1995) by Opie. However, no absolute measure of myocardial contractility exists.
Many indices have been proposed as measures of left ventricular contractile function, analyzing the behavior of changes in pressure and/or volume during the isovolumetric or ejection phase of the left ventricular systole. Some of these indices are shown in Table 1.
TABLE 1Indices of Cardiac ContractilityI.Isovolumetric Phase Indices1. Rate of rise of ventricular pressure (dP/dt): a. maximum b. dP/dt/P c. dP/dt DP40 d. VPM (dP/dt/28P)2. VmaxII.Ejection Phase Indices1. Stroke volume or work/diastolic volume2. Ejection fraction (EF)3. Velocity of circumferential shortening (Vcf)4. Mean normalized systolic ejection rate (MNSER)5. FE or Vcf/end-systolic stress
Most of these indices of cardiac contractility, such as maximum rate of rise of dP/dt, EF, and Vcf, are highly sensitive to acute inotropic changes, as, for example, described in From Cardiac Catheterization Data to Hemodynamic Parameters, F. A. Davis Company, Philadelphia, 1988, by Yang et al.; J. Clin. Invest., Vol. 41, page 80 (1962) by Gleason et al.; Am. J. Cardiol., Vol. 31, page 415 (1973) by Krayenbuehl et al.; Circ. Res., Vol. 56, page 808 (1985) by Little; and Circulation, Vol. 76, page 1422, by Kass et al. However, these indices are markedly modified by preload or afterload alterations, as described, for example, in the above-mentioned references by Gleason et al., Little, and Kass et al. To overcome these limitations, some modifications of these indices have been proposed, such as for dP/dt/P, dP/dt/DP, VPM, stroke volume, MNSER, and FE or Vcf/end-systolic stress, which make them less sensitive, though still sensitive, to changes in loads, as, for example, described in Circulation, Vol. 44, page 47 (1971) by Mason et al.; Cardiovasc. Res., Vol. 8, page 299 (1974) by Davidson et al.; Circulation, Vol. 53, page 293 (1976) by Quinones et al.; Am. J. Physiol., Vol. 240, page H80 (1981) by Carabello et al.; Ann. Intern. Med., Vol. 99, page 750 (1983) by Borow et al.; J. Am. Coll. Cardiol., Vol. 4, page 715 (1984) by Colan et al.; Circulation, Vol. 73, page 47 (1986) by Wisenbaugh et al.; Circulation, Vol. 78, page 68 (1988) by Mirsky et al.; Ann. Intern. Med., Vol. 108, page 524 (1988) by Lang et al.; and J. Am. Coll. Cardiol., Vol. 20, page 787 (1992) by Borow et al. Even Vmax, which was originally proposed as being independent of load index of cardiac contractility, has theoretical and practical limitations, and it is no longer used for clinical purposes, as, for example, described in Ann. Rev. Physiol., Vol. 34, page 47 (1972) by Ross et al.
Another way to assess cardiac contractility is by analyzing the end-systolic pressure/volume relation (ESPVR or ESP/ESV). The generation of variably afterloaded beats allows determination of several relationships. The slope of this line, usually known as Ecs or Emax, denotes the maximum stiffness or elastance of the left ventricle, as, for example, described in Circ. Res., Vol. 35, pages 117 to 126 (1974) by Suga et al.; and Circulation, Vol. 69, pages 1058 to 1064 (1984) by Carabello et al. The slope and/or position of the ESPVR respond to changes in myocardial contractile state, as for example, described in Circulation, Vol. 69, pages 1058 to 1064 (1984) by Carabello et al.; and Cardiovasc. Res., Vol. 9, pages 447 to 455 (1975) by Mahler et al. This index is independent of preload, and afterload is the controlled variable, as, for example, described in the above-mentioned reference by Suga et al. However, it is not possible to know the resting value of the relationship since alterations in the afterload are required to obtain the slope of the ESPVR. This slope behaves as a straight line for only part of the range of the physiologic values of afterload, as, for example, described in Am. J. Physiol., Vol. 252, pages H1218 to H1227 (1987) by Burkhoff et al.; and Circulation, Vol. 79, pages 167 to 178 (1989) by Kass et al. Additionally, no normal value of this slope has been established, and this technique is less sensitive than the isovolumetric and ejection phase indices to assess changes in the inotropic state of the heart, as, for example, described in Circulation, Vol. 76, pages 1115 to 1126 (1987) by Crottogini et al.; and Circulation, Vol. 76, pages 1422 to 1436 (1987) by Kass et al.
U.S. Pat. No. 5,400,793 to Wesseling describes a method of determining the stroke volume and cardiac output of the human heart from a pulse-type blood-stream pressure signal. U.S. Pat. No. 5,265,615 to Frank et al. describes a method and apparatus for continuous measurement of cardiac output by analyzing the blood pressure signal. U.S. Pat. Nos. 5,535,753 and 5,647,369, both to Petrucelli et al., describe apparatus and methods for non-invasively measuring cardiovascular system parameters involving sensing a time varying arterial pressure pulse waveform.
U.S. Pat. No. 5,584,298 to Kabal describes a noninvasive method for calculating stroke volume and cardiac output of a human heart using computerized algorithms. U.S. Pat. No. 5,758,652 to Nikolic describes a system and method for measuring the heart condition of a patient by utilizing blood pressure signals. U.S. Pat. No. 5,836,884 to Chio describes a method for determining the cardiovascular condition of a patient by determining peripheral resistance and diastolic flow velocity of the patient.
U.S. Pat. Nos. 5,390,679 and 5,797,395, both to Martin, relate to a cardiac output determining device and method which senses an arterial pressure waveform and compares the sensed waveform to a plurality of stored waveforms representative of known states. U.S. Pat. No. 5,913,826 to Blank describes an apparatus and method for assessing the cardiovascular status of a mammal by utilizing arterial pressure waveforms and systolic and diastolic pressures.
In summary, there are no simple and reliable indices of cardiac contractility, since they are not load independent. The most precise indices (dP/dt, Vmax, or Ees) require invasive and/or sophisticated techniques and usually no normal values have been defined. These indices have been more useful in assessing directional changes in cardiac contractility during acute interventions.